CA2561669A1 - Methods for identifying risk of osteoarthritis and treatments thereof - Google Patents

Abstract

Provided herein are methods for identifying a risk of osteoarthritis in a subject, reagents and kits for carrying out the methods, methods for identifying candidate therapeutics for treating osteoarthritis, and therapeutic and preventative methods applicable to osteoarthritis. These embodiments are based upon an analysis of polymorphic variations in nucleotide sequences within the human genome.

Description

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METHODS FOR IDENTIFYING RISK OF OSTEOARTHRITIS AND
TREATMENTS THEREOF
Field of the Invention [0001] The invention relates to genetic methods for identifying risk of osteoarthritis and treatments that specifically target such diseases.
Back rg ound [0002] Osteoarthritis (OA) is a chronic disease usually affecting weight-bearing synovial joints.
There are approximately 20 million Americans affected by OA and it is the leading cause of disability in the United States. In addition to extensive human suffering, OA also accounts for nearly all knee replacements and more than half of all hip replacements in the United States.
Despite its prevalence, OA is poorly understood and there are few treatments available besides anti-inflammatory drugs and joint replacement.

[0003] Osteoarthritis (OA) is a disease caused by degeneration of articular cartilage and subsequent joint deformation. In addition to risk factors like body weight, joint injury and age, there is a strong hereditary component to OA, reflected by high heritability estimates from twin studies. So far, few of the genes responsible for this genetic component have been identified.
Summary [0004] It has been discovered that certain polymorphic variations in human genomic DNA are associated with osteoarthritis. In particular, polymorphic variants in loci containing KIAA0296, Chr~om 4, PSMBI, TBP, PDCD2, ELP3, LRCHl, SNWl and ERG regions and other regions in Table A of human genomic DNA have been associated with risk of osteoarthritis. Some of the associated polymorphic variants fall in an intergenic region on chromosome 4 that does not include a known gene;
therefore, the region is referred to herein as the Chronz 4 region. Also, the PSMBl, TBP and PDCD2 regions are located in a larger region referred to herein as the Chrom 6 region.

[0005] Thus, featured herein are methods for identifying a subject at risk of osteoarthritis and/or a risk of osteoarthritis in a subject, which comprise detecting the presence or absence of one or more polymorphic variations associated with osteoarthritis in or around the loci described herein in a human nucleic acid sample. In an embodiment, two or more polymorphic variations are detected in two or more regions of which one is the KIAA0296, Cht~om 4, Chrona 6, ELP3, LRCHl, SNWl or ERG region or other region in Table A. In certain embodiments, 3 or more, or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more polymorphic variants are detected.

[0006] Also featured are nucleic acids that include one or more polymorphic variations associated with occurrence of osteoarthritis, as well as polypeptides encoded by these nucleic acids. In addition, provided are methods for identifying candidate therapeutic molecules for treating osteoarthritis, as well as methods for treating osteoarthritis in a subject by identifying a subject at risk of osteoarthritis and treating the subject with a suitable prophylactic, treatment or therapeutic molecule.

[0007] Also provided are compositions comprising a cell from a subject having osteoarthritis or at risk of osteoarthritis and/or a KIAA0296, Chrona 4, Chrom 6, ELP3, LRCHI, SNWI
or ERG nucleic acid or other nucleic acid referenced in Table A, with a RNAi, siRNA, antisense DNA
or RNA, or ribozyme nucleic acid designed from a KIAA0296, Chrona 4, Chr~ona 6, ELP3, LRCHI, SNWI
or ERG nucleotide sequence or other nucleotide sequence referenced in Table A. In an embodiment, the RNAi, siRNA, antisense DNA or RNA, or ribozyme nucleic acid is designed from a KIAA0296, Chrom 4, Ch~om 6, ELP3, LRCHI, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A
that includes one or more polymorphic variations associated with osteoarthritis, and in some instances, specifically interacts with such a nucleotide sequence. Further, provided are arrays of nucleic acids bound to a solid surface, in which one or more nucleic acid molecules of the array have a KIAA0296, Ch~om 4, Cla~~om 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A, or a fragment or substantially identical nucleic acid thereof, or a complementary nucleic acid of the foregoing. Featured also are compositions comprising a cell from a subject having osteoarthritis or at risk of osteoarthritis and/or a KIAA0296, Chrorn 4, Chrom 6, ELP3, LRCHl, SNWI
or ERG polypeptide or other polypeptide referenced in Table A, with an antibody that specifically binds to the polypeptide. In an embodiment, the antibody specifically binds to an epitope in the polypeptide that includes a non-synonymous amino acid modification associated with osteoarthritis (e.g., results in an amino acid substitution in the encoded polypeptide associated with osteoarthritis). In certain embodiments, the antibody selectively binds to an epitope in the KIAA0296, Chf°ona 4, Clarom 6, ELP3, LRCHl, SNWI or ERG polypeptide, or other polypeptide referenced in Table A, having an amino acid associated with osteoarthritis. Thus, featured is an antibody that binds an epitope having an amino acid encoded by rs734784, rs1042164, rs749670, rs955592, rs241448 and/or rs1040461, such as a valine or isoleucine encoded by rs734784 (e.g., a valine at position 489 in a KCNSI
polypeptide), a valine or alanine encoded by rs1042164 (e.g., a valine at position 133 in a IER2 polypeptide), a glutamate or glycine encoded by rs749670 (e.g., a glutamate at position 327 in a KIAA0296 polypeptide), a threonine or isoleucine encoded by rs955592 (e.g., a threonine at position 70 in a RBEDl polypeptide), a glutamine or termination encoded by rs241448 (e.g., a glutamine at position 687 in a TAP2 polypeptide) or a glycine or serine encoded by rs1040461 (e.g., a glycine at position 207 in a RAB23 polypeptide) at the corresponding position in the polypeptide.
Brief Description of the Drawinus [0008] Figures lA-1G show proximal SNPs in a 100-kb window in KIAA0296, Chr~om 4, Chrofn 6, ELP3, LRCHl, SNWI and ERG regions of genomic DNA, respectively, that were compared between pools of cases and controls. The x-axis corresponds to their chromosomal position and the y-axis to the test P-values (shown on the -logo scale). The continuous dark line presents the results of a goodness-of fit test for an excess of significance (compared to 0.05) in a 10 kb sliding window assessed at 1 kb increments.
Detailed Description (0009] It has been discovered that polymorphic variants in a locus containing a KIAA0296, Chrorn 4, Ch~om 6, ELP3, LRCHl, SNWI or ERG region are associated with occurrence of osteoarthritis in subjects. Thus, detecting genetic determinants associated with an increased risk of osteoarthritis occurrence can lead to early identification of a predisposition to osteoarthritis and early prescription of preventative measures. Also, associating a KIAA0296, Chrom 4, Chr om 6, ELP3, LRCHI, SNWI or ERG polymorphic variant and other variants referenced in Table A with osteoarthritis has provided new targets for screening molecules useful in treatments of osteoarthritis.
Osteoarthritis and Sample Selection [0010] Osteoarthritis (OA), or degenerative joint disease, is one of the oldest and most common types of arthritis. It is characterized by the breakdown of the joint's cartilage. Cartilage is the part of the joint that cushions the ends of bones, and its breakdown causes bones to rub against each other, causing pain and loss of movement. Type II collagen is the main component of cartilage, comprising 15-25% of the wet weight, approximately half the dry weight, and representing 90-95% of the total collagen content in the tissue. It forms fibrils that endow cartilage with tensile strength (Mayne, R. Arthritis Rhuem. 32:241-246 (1989)).

[0011] Most commonly affecting middle-aged and older people, OA can range from very mild to very severe. It affects hands and weight-bearing joints such as knees, hips, feet and the back. Knee OA
can be as disabling as any cardiovascular disease except stroke.

[0012] Osteoarthritis affects an estimated 20.7 million Americans, mostly after age 45, with women more commonly affected than men. Physicians make a diagnosis of OA based on a physical exam and history of symptoms. X-rays are used to confirm diagnosis. Most people over 60 reflect the disease on X-ray, and about one-third have actual symptoms.

[0013] There are many factors that can cause OA. Obesity may lead to osteoarthritis of the knees.
In addition, people with joint injuries due to sports, work-related activity or accidents may be at increased risk of developing OA.

[0014] Genetics has a role in the development of OA too. Some people may be born with defective cartilage or with slight defects in the way that joints fit together. As a person ages, these defects may cause early cartilage breakdown in the joint or the inability to repair damaged or deteriorated cartilage in the joint.

[0015] Inclusion or exclusion of samples for an osteoarthritis pool may be based upon the following criteria: ethnicity (e.g., samples derived from an individual characterized as Caucasian);
parental ethnicity (e.g., samples derived from an individual of British paternal and maternal descent);
relevant phenotype information for the individual (e.g., case samples derived from individuals diagnosed with specific knee, hand or hip osteoarthritis (OA); case samples recruited from an OA knee replacement clinic). Control samples may be selected based on relevant phenotype information for the individual (e.g., derived from individuals free of OA at several sites (knee, hand, hip etc)); and no family history of OA and/or rheumatoid arthritis. Additional phenotype information collected for both cases and controls may include age of the individual, gender, family history of OA, diagnosis with osteoarthritis (joint location of OA (e.g., knee, hips, hands and spine), date of primary diagnosis, age of individual as of primary diagnosis), knee history (current symptoms, any major knee injury, menisectomy, knee replacement surgery, age of surgery), HRT history, osteoporosis diagnosis.

[0016] Based in part upon selection criteria set forth above, individuals having osteoarthritis can be selected for genetic studies. Also, individuals having no history of osteoarthritis often are selected for genetic studies, as described hereafter.
Pol,~o~hic Variants Associated with Osteoarthritis [0017] A genetic analysis provided herein linked osteoarthritis with polymorphic variant nucleic acid sequences in the human genome. As used herein, the term "polymorphic site" refers to a region in a nucleic acid at which two or more alternative nucleotide sequences are observed in a significant number of nucleic acid samples from a population of individuals. A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A
polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. A
polymorphic site is often one nucleotide in length, which is referred to herein as a "single nucleotide polymorphism" or a "SNP."

[0018] Where there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Where two polymorphic variants exist, for example, the polymorphic variant represented in a minority of samples from a population is sometimes referred to as a "minor allele" and the polymorphic variant that is more prevalently represented is sometimes referred to as a "major allele." Many organisms possess a copy of each chromosome (e.g., humans), and those individuals who possess two major alleles or two minor alleles are often referred to as being "homozygous" with respect to the polymorphism, and those individuals who possess one major allele and one minor allele are normally referred to as being "heterozygous" with respect to the polymorphism. Individuals who are homozygous with respect to one allele are sometimes predisposed to a different phenotype as compared to individuals who are heterozygous or homozygous with respect to another allele.

[0019] In genetic analysis that associate polymorphic variants with osteoarthritis, samples from individuals having osteoarthritis and individuals not having osteoarthritis often are allelotyped and/or genotyped. The term "allelotype" as used herein refers to a process for determining the allele frequency for a polymorphic variant in pooled DNA samples from cases and controls. By pooling DNA from each group, an allele frequency for each SNP in each group is calculated. These allele frequencies are then compared to one another. The term "genotyped" as used herein refers to a process for determining a genotype of one or more individuals, where a "genotype" is a representation of one or more polymorphic variants in a population.

[0020] A genotype or polymorphic variant may be expressed in terms of a "haplotype," which as used herein refers to two or more polymorphic variants occurring within genomic DNA in a group of individuals within a population. For example, two SNPs may exist within a gene where each SNP
position includes a cytosine variation and an adenine variation. Certain individuals in a population may carry one allele (heterozygous) or two alleles (homozygous) having the gene with a cytosine at each SNP position. As the two cytosines corresponding to each SNP in the gene travel together on one or both alleles in these individuals, the individuals can be characterized as having a cytosine/cytosine haplotype with respect to the two SNPs in the gene.

[0021] As used herein, the term "phenotype" refers to a trait which can be compared between individuals, such as presence or absence of a condition, a visually observable difference in appearance between individuals, metabolic variations, physiological variations, variations in the function of biological molecules, and the like. An example of a phenotype is occurrence of osteoarthritis.

[0022] Researchers sometimes report a polymorphic variant in a database without determining whether the variant is represented in a significant fraction of a population.
Because a subset of these reported polymorphic variants are not represented in a statistically significant portion of the population, some of them are sequencing errors and/or not biologically relevant. Thus, it is often not known whether a reported polymorphic variant is statistically significant or biologically relevant until the presence of the variant is detected in a population of individuals and the frequency of the variant is determined. Methods for detecting a polymorphic variant in a population are described herein, specifically in Example 2. A polymorphic variant is statistically significant and often biologically relevant if it is represented in 5% or more of a population, sometimes 10% or more, 15% or more, or 20% or more of a population, and often 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more of a population.

[0023] A polymorphic variant may be detected on either or both strands of a double-stranded nucleic acid. Also, a polymorphic variant may be located within an intron or exon of a gene or within a portion of a regulatory region such as a promoter, a 5' untranslated region (UTR), a 3' UTR, and in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or a polypeptide. Polymorphic variations may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.

[0024] It was determined that polymorphic variations associated with an increased risk of osteoarthritis existed in SEQ ID NO: 1-7 or a nucleotide sequence referenced in Table A. In certain embodiments, polymorphic variants at positions rs552, rs12904, rs2282146, rs734784, rs1042164, rs749670, rs955592, rs1143016, rs755248, rs1055055, rs835409, rs927663, rs8162, rs831038, rs33079, rs1710880, rs1078153, rs799570, rs1282730, rs1518875, rs1568694, rs905042, rs1957723, rs794018, rs707723, rs893861, rs1914903, rs2062232, rs26609, rs1370987, rs1012414, rs435903, rs1248, rs703508, rs226465, rs241448, rs763155, rs1040461, rs462832, rs804194, rs1022646, rs756519, rs1042327, rs8770, rs1569112, rs1563055, rs805623, rs1019850, rs1599931, AA, rs912428, rs279941, rs1062230, rs1859911, rs1477261, rs1191119, rs657780, rs1393890, rs1478714, rs868213, rs690115, rs1465501, rs899173, rs10477, rs926393, rs465271, rs1888475, rs13847 and/or rs738658 in the human genome were associated with an increased risk of osteoarthritis, and in specific embodiments, the corresponding allele in the right-most column in Table A for each position is associated with an increased risk of osteoarthritis. In other embodiments polymorphic variants at positions rs734784, rs1042164, rs749670, rs955592, rs241448 and rs1040461 were associated with an increased risk of osteoarthritis, and in specific embodiments, a valine encoded by rs734784, a valine encoded by rs1042164, a glutamate encoded by rs749670, a threonine encoded by rs955592, a glutamine encoded by rs241448, and a glycine encoded by rs1040461 were associated with an increased risk of osteoarthritis.

[0025] Polymorphic variants in and around the KIAA0296 locus were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
1 selected from the group consisting of 247, 1535, 2386, 6440, 9133, 9143, 9471, 13150, 13717, 14466, 15769, 16870, 18545, 18749, 19123, 20736, 21038, 21046, 21050, 21056, 21706, 23170, 25028, 27871, 28070, 31717, 32019, 32318, 33080, 33101, 34236, 34285, 34818, 35168, 37981, 38113, 38117, 38481, 38615, 38944, 39288, 41385, 42136, 42185, 42353, 42434, 44580, 44675, 45739, 46439, 47457, 47735, 50319, 50708, 51185, 53002, 53064, 53637, 55274, 55825, 55986, 56684, 57653, 57659, 57692, 57775, 61313, 61431, 61699, 62906, 63619, 64664, 68452, 69665, 69681, 70091, 74637, 74760, 76523, 78559, 79549, 79882, 81339, 81681, 81696, 83517, 85431, 86332, 87358, 87725, 89052, 90020, 90231, 90284, 90447, 90601, 90724, 92559, 95176, 95195 and 96822. Polymorphic variants at the following positions in SEQ 117 NO: 1 in particular were associated with an increased risk of osteoarthritis:
13150, 21046, 23170, 25028, 44580, 62906, 64664 and 83517. In particular, the following polymorphic variants in SEQ ID
NO: 1 were associated with risk of osteoarthritis: a guanine at position 13150, a thymine at position 21046, an adenine at position 23170, an adenine at position 25028, a guanine at position 44580, a guanine at position 62906, a cytosine at position 64664 and a cytosine at position 83517. A
polymorphic variant in a KIAA0296 polypeptide encoded by rs749670 (e.g., a glutamate at position 327 in the polypeptide) also was associated with increased risk of osteoarthritis.

[0026] Polymorphic variants in and around the clzrom 4 locus were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
2 selected from the group consisting of 211, 7217, 7895, 13308, 14279, 17026, 18271, 20417, 21843, 22069, 22145, 22519, 22539, 23236, 23256, 23402, 23499, 23620, 23871, 24136, 25427, 25866, 26541, 26576, 26689, 26720, 27113, 27164, 27186, 28341, 29160, 29844, 30665, 30830, 31061, 31523, 32326, 32346, 32358, 34909, 34975, 35066, 35096, 35375, 36304, 36712, 36770, 37342, 37412, 37884, 38077, 38300, 38301, 41189, 44408, 44493, 44571, 44670, 45219, 45258, 47261, 48473, 48771, 55292, 56479, 56747, 60620, 60688, 61058, 61129, 61577, 61961, 63351, 63926, 65798, 66043, 66044, 66246, 66318, 66547, 71238, 71283, 71492, 72274, 73762, 74209, 75284, 77347, 77589, 78096, 78606, 78862, 79135, 79146, 79456, 79609, 80086, 80119, 80766, 81110, 81269, 81668, 82433, 82559, 83298, 83821, 84121, 84147, 84543, 84554, 84691, 84727, 85678, 86699, 86700, 86792, 86832, 87045, 87140, 87365, 88342, 88498, 88589, 95502, 96968, 97448, 97568 and 98724. Polymorphic variants at the following positions in SEQ ID NO: 2 in particular were associated with an increased risk of osteoarthritis: 23236, 32358, 47261, 48771, 55292, 60688, 72274, 74209, 77589, 79135, 79456, 79609, 80119, 80766, 81110, 82433, 84121, 84147, 85678, 86699, 86832, 87140 and 88589, where specific embodiments are directed to a polymorphic variant at position 32358, 47261, 74209 and/or 79456. In particular, the following polymorphic variants in SEQ
ID NO: 2 were associated with risk of osteoarthritis: an adenine at position 23236, a cytosine at position 32358, a guanine at position 47261, a guanine at position 48771, a cytosine at position 55292, an adenine at position 60688, a guanine at position 72274, a guanine at position 74209, a cytosine at position 77589, an adenine at position 79135, a thymine at position 79456, an adenine at position 79609, an adenine at position 80119, a cytosine at position 80766, an adenine at position 81110, a cytosine at position 82433, a cytosine at position 84121, a thymine at position 84147, a cytosine at position 85678, a thymine at position 86699, an adenine at position 86832, a guanine at position 87140 and an adenine at position 88589.

[0027] Polymorphic variants in and around the ch~om 6 region were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
3 selected from the group consisting of 229, 6310, 11840, 11870, 12064, 13392, 16354, 16559, 16935, 17616, 17737, 18321, 18453, 18811, 20020, 21662, 23197, 23446, 24339, 25504, 27174, 28008, 29294, 29759, 30832, 44512, 44850, 45884, 46345, 48589, 53371, 53911, 53990, 55152, 55667, 58952, 59315, 60029, 61477, 62988, 63090, 64021, 65685, 70220, 70323, 70959, 73436, 82945, 82958, 82961, 82964, 82965, 83006, 83025, 83034, 83074 ,83132, 83155, 83172, 83174, 83206, 83216, 83234, 83252, 83260, 83263, 83296, 83319, 83322, 83324, 83357, 83375, 83381, 83389, 83443, 83499, 83545, 83566, 83591, 83619, 83698, 83780, 83784, 83826, 83832, 83852, 86297, 86315, 86420, 86460, 86714, 86718, 86736, 86753, 86766, 88162, 88218, 88246, 88255, 88309, 88310, 88471, 88619, 88904, 89044, 90531, 90534, 90613 and 46252. Polymorphic variants at the following positions in SEQ ID NO: 3 in particular were associated with an increased risle of osteoarthritis: 229, 6310, 16559, 18453, 25504, 27174, 30832, 44850, 45884, 48589, 61477, 82961 and 46252, with specific embodiments directed to variants at positions 229, 16559, 44850 and/or 46252. In particular, the following polymorphic variants in SEQ ID NO: 3 were associated with risk of osteoarthritis: a thymine at position 229, a guanine at position 6310, a thymine at position 16559, an adenine at position 18453, an adenine at position 25504, an adenine at position 27174, an adenine at position 30832, a guanine at position 44850, an adenine at position 45884, an adenine at position 48589, a cytosine at position 61477, a cytosine at position 82961 and a thymine at position 46252.

[0028] Polymorphic variants in and around the ELP3 region were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
4 selected from the group consisting of 211, 473, 1536, 5639, 17186, 17335, 25029, 25111, 28811, 28863, 30809, 40985, 45147, 45282, 46168, 46328, 49077, 51925, 52141, 52168, 60852, 62468, 65572, 79089, 79541, 79790, 90843, 90978, 91052, 91131, 91132, 94439 and 94621. Polymorphic variants at the following positions in SEQ ID NO: 4 in particular were associated with an increased risk of osteoarthritis: 40985, 46168, 51925 and 52168. In particular, the following polymorphic variants in SEQ ID
NO: 4 were associated with risk of osteoarthritis: a cytosine at position 40985, a guanine at position 46168, a thymine at position 51925 and a cytosine at position 52168.

[0029] Polymorphic variants in and around the LRCHI region were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
5 selected from the group consisting of 243, 10208, 15049, 15111, 15272, 15287, 15326, 15327, 17038, 19391, 21702, 22431, 22881, 27744, 32564, 32698, 33104, 33181, 33256, 33543, 35567, 40085, 40482, 45641, 46059, 48504, 48919, 49693, 49874, 50020, 50616, 50719, 55511, 65533, 70529, 75591, 77266, 80368, 82475, 92462, 92480, 95819 and 96275. Polymorphic variants at the following positions in SEQ ID NO: 5 in particular were associated with an increased risk of osteoarthritis: 15111, 45641, 46059, 49693, 49874, 50020, 50719, 70529, 82475, 92462, 92480 and 96275, with specific embodiments directed to variants at positions 82475 and/or 92462. In particular, the following polymorphie variants in SEQ ID NO: 5 were associated with risk of osteoarthritis: a guanine at position 15111, a thymine at position 45641, an adenine at position 46059, a cytosine at position 49693, an adenine at position 49874, an adenine at position 50020, a guanine at position 50719, an adenine at position 70529, an adenine at position 82475, a thymine at position 92462, a thymine at position 92480 and a cytosine at position 96275.

[0030] Polymorphic variants in and around the SNWI locus were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
6 selected from the group consisting of 218, 1440, 1442, 2611, 4317, 4724, 4788, 5202, 5780, 5974, 6644, 7430, 7938, 8095, 8183, 8312, 8352, 9348, 9378, 9617, 9727, 9834, 9899, 10211, 10377, 10695, 10729, 10730, 11433, 11951, 12697, 12982, 14419, 14501, 14983, 15280, 15475, 15888, 15976, 16307, 16442, 17255, 18948, 19435, 19753, 20021, 20022, 20503, 20590, 21804, 21919, 21990, 22412, 22536, 23432, 23468, 23772, 24325, 24773, 26274, 27440, 28561, 30071, 31764, 33008, 35310, 35460, 37112, 37285, 37747, 38057, 38859, 38860, 39525, 40216, 40281, 41453, 42091, 42513, 42935, 42985, 43003, 43281, 43716, 43866, 44234, 44596, 44871, 45005, 45282, 47178, 47816, 47887, 48134, 48135, 48276, 48400, 48798, 48803, 49146, 49969, 51059, 51064, 53285, 54560, 54748, 54785, 55102, 55644, 55705, 55841, 56623, 56825, 56827, 56892, 59150, 59958, 60231, 60524, 61871, 62226, 63230, 63468, 63787, 65732, 65989, 68832, 69904, 70365, 70886, 73088, 73103, 75934, 75966, 76273, 77943, 78466, 78861, 78872, 79836, 80908, 81509, 83576, 83662, 83782, 84282, 84444, 85129, 85151, 85296, 85809, 86387, 86494, 89786, 89894, 90122, 92067, 92187, 92312, 92824, 93733, 96553 and 96941. Polymorphic variants at the following positions in SEQ ID NO: 6 in particular were associated with an increased risk of osteoarthritis: 4788, 8312, 9378, 9727, 9899, 10211, 27440, 40216, 40281, 42091, 43866, 48803, 51059, 55644, 56623, 73103, 78872, 79836, 85129, 92824 and 96941. In particular, the following polymorphic variants in SEQ ID NO: 6 were associated with risk of osteoarthritis: a guanine at position 4788, a thymine at position 8312, a deletion at position 9378, a cytosine at position 9727, a guanine at position 9899, a cytosine at position 10211, a guanine at position 27440, a guanine at position 40216, a cytosine at position 40281, an adenine at position 42091, a guanine at position 43866, an adenine at position 48803, an adenine at position 51059, an adenine at position 55644, a cytosine at position 56623, a cytosine at position 73103, an adenine at position 78872, a guanine at position 79836, a cytosine at position 85129, a guanine at position 92824 and an adenine at position 96941.

[0031] Polymorphic variants in and around the ERG region were tested for association with osteoarthritis. These include polymorphic variants at positions in SEQ ID NO:
7 selected from the group consisting of 231, 882, 960, 1194, 1530, 1673, 2096, 2285, 5873, 7256, 7988, 8222, 8381, 8814, 8915, 9642, 9902, 10619, 10927, 11032, 14377, 15608, 15928, 16296, 17598, 19272, 20084, 20577, 28051, 29466, 29530, 29987, 30012, 30322, 32216, 32516, 32544, 32746, 33137, 33538, 33798, 33802, 33964, 34132, 34210, 34317, 34499, 34753, 34845, 35335, 36423, 36450, 36481, 38447, 38784, 39387, 39458, 39822, 40305, 40869, 40926, 41010, 41134, 41984, 42172, 42753, 43011, 43176, 43320, 43381, 44142, 44383, 44726, 45087, 45141, 45359, 45421, 45456, 45467, 45486, 45709, 45716, 47626, 49413, 49796, 49962, 50075, 50093, 50571, 50615, 50780, 50851, 51459, 53193, 53702, 53736, 53795, 54109, 54126, 54230, 54894, 55455, 55499, 56522, 56662, 56954, 57267, 58282, 58916, 59544, 59666, 59913, 66846, 67245, 67652, 67955, 67966, 68420, 70226, 70810, 72246, 73330, 73457, 74389, 74638, 74640, 75358, 75952, 76098, 77836, 78449, 78507, 80031, 81695, 82775, 82795, 84611, 84657, 84693, 85020, 85048, 85100, 85325, 85452, 85868, 85936, 85990, 86139, 86497, 87236, 87248, 87533, 87912, 88108, 88494, 89598, 90235, 91287, 91359, 92384, 92410, 92900, 94495, 94512, 97777 and 98333.
Polymorphic variants at the following positions in SEQ ID NO: 7 in particular were associated with an increased risk of osteoarthritis: 1673, 20577, 33137, 39822, 45716, 49962, 51459, 54894, 55455, 55499, 58282, 68420 and 80031, with specific embodiments directed to variants at positions 33137, 55499 and/or 58282. In particular, the following polymorphic variants in SEQ
ID NO: 7 were associated with risk of osteoarthritis: a guanine at position 1673, a thymine at position 20577, a guanine at position 33137, a guanine at position 39822, an adenine at position 45716, a guanine at position 49962, an adenine at position 51459, a cytosine at position 54894, an adenine at position 55455, an adenine at position 55499, a guanine at position 58282, an adenine at position 68420 and a thymine at position 80031.

[0032] Based in part upon analyses summarized in Figures lA-1G, regions with significant association have been identified in regions associated with osteoarthritis.
Any polymorphic variants associated with osteoarthritis in a region of significant association can be utilized for embodiments described herein. For example, polymorphic variants in a region spanning chromosome positions 31118000 to 31129000 (approximately 11,000 nucleotides in length) in a KIAA0296 locus, a region spanning chromosome positions 36914000 to 36931000 (approximately 17,000 nucleotides in length) in a chrona 4 region, a region spanning chromosome positions 170719500 to 170766500 (approximately 47,000 nucleotides in length) in a ch~om 6 region, a region spanning chromosome positions 27963000 to 27983000 (approximately 20,000 nucleotides in length) in an ELP3 locus, a region spanning chromosome positions 44962000 to 45013000 (approximately 51,000 nucleotides in length) in a LRCHI

locus, a region spanning chromosome positions 76196500 to 76221500 (approximately 25,000 nucleotides in length) in a SNWI locus, and a region spanning chromosome positions 38830000 to 38844000 (approximately 14,000 nucleotides in length) in an ERG locus have significant association (chromosome positions are within NCBI's Genome build 34).
Additional Polyphic Variants Associated with Osteoarthritis [0033] Also provided is a method for identifying polymorphic variants proximal to an incident, founder polymorphic variant associated with osteoarthritis. Thus, featured herein are methods for identifying a polymorphic variation associated with osteoarthritis that is proximal to an incident polymorphic variation associated with osteoarthritis, which comprises identifying a polymorphic variant proximal to the incident polymorphic variant associated with osteoarthritis, where the incident polymorphic variant is in a KIAA0296, Ch~om 4, Clz~onz 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A. The nucleotide sequence often comprises a polynucleotide sequence selected from the group consisting of (a) a polynucleotide sequence of SEQ
ID NO: 1-7 or referenced in Table A; (b) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence encoded by a polynucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A; and (c) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID
NO: 1-7 or referenced in Table A or a polynucleotide sequence 90% or more identical to the polynucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A. The presence or absence of an association of the proximal polymorphic variant with osteoarthritis then is determined using a known association method, such as a method described in the Examples hereafter. In an embodiment, the incident polymorphic variant is a polymorphic variant associated with osteoarthritis described herein.
In another embodiment, the proximal polymorphic variant identified sometimes is a publicly disclosed polymorphic variant, which for example, sometimes is published in a publicly available database. In other embodiments, the polymorphic variant identified is not publicly disclosed and is discovered using a known method, including, but not limited to, sequencing a region surrounding the incident polymorphic variant in a group of nucleic samples. Thus, multiple polymorphic variants proximal to an incident polymorphic variant are associated with osteoarthritis using this method.

[0034] The proximal polymorphic variant often is identified in a region surrounding the incident polymorphic variant. In certain embodiments, this surrounding region is about 50 kb flanking the first polymorphic variant (e.g. about 50 kb 5' of the first polymorphic variant and about 50 kb 3' of the first polymorphic variant), and the region sometimes is composed of shorter flanking sequences, such as flanking sequences of about 40 kb, about 30 kb, about 25 kb, about 20 kb, about 15 kb, about 10 kb, about 7 kb, about 5 kb, or about 2 kb 5' and 3' of the incident polymorphic variant. In other embodiments, the region is composed of longer flanking sequences, such as flanking sequences of about 55 kb, about 60 kb, about 65 kb, about 70 kb, about 75 kb, about 80 kb, about 85 kb, about 90 kb, about 95 kb, or about 100 kb 5' and 3' of the incident polymorphic variant.

[0035] In certain embodiments, polymorphic variants associated with osteoarthritis are identified iteratively. For example, a first proximal polymorphic variant is associated with osteoarthritis using the methods described above and then another polymorphic variant proximal to the first proximal polymorphic variant is identified (e.g., publicly disclosed or discovered) and the presence or absence of an association of one or more other polymorphic variants proximal to the first proximal polymorphic variant with osteoarthritis is determined.

[0036] The methods described herein are useful for identifying or discovering additional polymorphic variants that may be used to further characterize a gene, region or loci associated with a condition, a disease (e.g., osteoarthritis), or a disorder. For example, allelotyping or genotyping data from the additional polymorphic variants may be used to identify a functional mutation or a region of linkage disequilibrium. In certain embodiments, polymorphic variants identified or discovered within a region comprising the first polymorphic variant associated with osteoarthritis are genotyped using the genetic methods and sample selection techniques described herein, and it can be determined whether those polymorphic variants are in linkage disequilibrium with the first polymorphic variant. The size of the region in linkage disequilibrium with the first polymorphic variant also can be assessed using these genotyping methods. Thus, provided herein are methods for determining whether a polymorphic variant is in linkage disequilibrium with a first polymorphic variant associated with osteoarthritis, and such information can be used in prognosis/diagnosis methods described herein.
Isolated Nucleic Acids [0037] Featured herein are isolated KIAA0296, Chrom 4, Cht~om 6, ELP3, LRCHl, SNWI or ERG
nucleic acid variants depicted in SEQ 117 NO: 1-7 or referenced in Table A, and substantially identical nucleic acids thereof. A nucleic acid variant may be represented on one or both strands in a double-stranded nucleic acid or on one chromosomal complement (heterozygous) or both chromosomal complements (homozygous).

[0038] As used herein, the term "nucleic acid" includes DNA molecules (e.g., a complementary DNA (cDNA) and genomic DNA (gDNA)) and RNA molecules (e.g., mRNA, rRNA, siRNA
and tRNA) and analogs of DNA or RNA, for example, by use of nucleotide analogs.
The nucleic acid molecule can be single-stranded and it is often double-stranded. The term "isolated or purified nucleic acid" refers to nucleic acids that are separated from other nucleic acids present in the natural source of the nucleic acid. For example, with regard to genomic DNA, the term "isolated"
includes nucleic acids which are separated from the chromosome with which the genomic DNA is naturally associated. An "isolated" nucleic acid is often free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and/or 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of 5' and/or 3' nucleotide sequences which flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an "isolated" nucleic acid molecule, such as a cDNA
molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. As used herein, the term "gene" refers to a nucleotide sequence that encodes a polypeptide.

[0039] Also included herein are nucleic acid fragments. These fragments often have a nucleotide sequence identical to a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A, a nucleotide sequence substantially identical to a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A, or a nucleotide sequence that is complementary to the foregoing. The nucleic acid fragment may be identical, substantially identical or homologous to a nucleotide sequence in an exon or an intron in a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A, and may encode a domain or part of a domain of a polypeptide. Sometimes, the fragment will comprises one or more of the polymorphic variations described herein as being associated with osteoarthritis. The nucleic acid fragment is often 50, 100, or 200 or fewer base pairs in length, and is sometimes about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 2000, 3000, 4000, 5000, 10000, 15000, or 20000 base pairs in length.
A nucleic acid fragment that is complementary to a nucleotide sequence identical or substantially identical to a nucleotide sequence in SEQ 117 NO: 1-7 or referenced in Table A and hybridizes to such a nucleotide sequence under stringent conditions is often referred to as a "probe." Nucleic acid fragments often include one or more polymorphic sites, or sometimes have an end that is adjacent to a polymorphic site as described hereafter.

[0040] An example of a nucleic acid fragment is an oligonucleotide. As used herein, the term "oligonucleotide" refers to a nucleic acid comprising about 8 to about 50 covalently linked nucleotides, often comprising from about 8 to about 35 nucleotides, and more often from about 10 to about 25 nucleotides. The backbone and nucleotides within an oligonucleotide may be the same as those of naturally occurring nucleic acids, or analogs or derivatives of naturally occurring nucleic acids, provided that oligonucleotides having such analogs or derivatives retain the ability to hybridize specifically to a nucleic acid comprising a targeted polymorphism.
Oligonucleotides described herein may be used as hybridization probes or as components of prognostic or diagnostic assays, for example, as described herein.

[0041] Oligonucleotides are typically synthesized using standard methods and equipment, such as the ABITM3900 High Throughput DNA Synthesizer and the EXPEDITETM 8909 Nucleic Acid Synthesizer, both of which are available from Applied Biosystems (Foster City, CA). Analogs and derivatives are exemplified in U.S. Pat. Nos. 4,469,863; 5,536,821; 5,541,306;
5,637,683; 5,637,684;
5,700,922; 5,717,083; 5,719,262; 5,739,308; 5,773,601; 5,886,165; 5,929,226;
5,977,296; 6,140,482;
WO 00/56746; WO 01114398, and related publications. Methods for synthesizing oligonucleotides comprising such analogs or derivatives are disclosed, for example, in the patent publications cited above and in U.S. Pat. Nos. 5,614,622; 5,739,314; 5,955,599; 5,962,674; 6,117,992;
in WO 00/75372; and in related publications.

[0042] Oligonucleotides may also be linked to a second moiety. The second moiety may be an additional nucleotide sequence such as a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), and others. Alternatively, the second moiety may be a non-nucleotide moiety such as a moiety which facilitates linkage to a solid support or a label to facilitate detection of the oligonucleotide. Such labels include, without limitation, a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, and the like. The second moiety may be attached to any position of the oligonucleotide, provided the oligonucleotide can hybridize to the nucleic acid comprising the polymorphism.
Uses for Nucleic Acid Sequence [0043] Nucleic acid coding sequences may be used for diagnostic purposes for detection and control of polypeptide expression. Also, included herein are oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide. Antisense techniques and RNA
interference techniques are known in the art and are described herein.

[0044] Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example, hammerhead motif ribozyme molecules may be engineered that specifically and efficiently catalyze endonucleolytic cleavage of RNA sequences corresponding to or complementary to KIAA0296, Chrom 4, ChronZ 6, ELP3, LRCHl, SNWI or ERG nucleotide sequences or other nucleotide sequences referenced in Table A. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences, GUA, GUU and GUC. Once identified, short RNA sequences of between fifteen (15) and twenty (20) ribonucleotides corresponding to the region of the target gene containing the cleavage site may be evaluated for predicted structural features such as secondary structure that may render the oligonucleotide sequence unsuitable. The suitability of candidate targets may also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using ribonuclease protection assays.

[0045] Antisense RNA and DNA molecules, siRNA and ribozymes may be prepared by any method known in the art for the synthesis of RNA molecules. These include techniques for chemically synthesizing oligodeoxyribonucleotides well known in the art such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and ira vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA
sequences may be incorporated into a wide variety of vectors which incorporate suitable RNA
polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA
constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.

[0046] DNA encoding a polypeptide also may have a number of uses for the diagnosis of diseases, including osteoarthritis, resulting from aberrant expression of a target gene described herein. For example, the nucleic acid sequence may be used in hybridization assays of biopsies or autopsies to diagnose abnormalities of expression or function (e.g., Southern or Northern blot analysis, in situ hybridization assays).

[0047] In addition, the expression of a polypeptide during embryonic development may also be determined using nucleic acid encoding the polypeptide. As addressed, infra, production of functionally impaired polypeptide is the cause of various disease states, such as osteoarthritis. In situ hybridizations using polypeptide as a probe may be employed to predict problems related to osteoarthritis. Further, as indicated, infra, administration of human active polypeptide, recombinantly produced as described herein, may be used to treat disease states related to functionally impaired polypeptide. Alternatively, gene therapy approaches may be employed to remedy deficiencies of functional polypeptide or to replace or compete with dysfunctional polypeptide.
Expression Vectors Host Cells and Geneticall~gineered Cells [0048] Provided herein are nucleic acid vectors, often expression vectors, which contain a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A, or a substantially identical sequence thereof.
As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid, or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors may include replication defective retroviruses, adenoviruses and adeno-associated viruses for example.

[0049] A vector can include a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWl or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A in a form suitable for expression of an encoded target polypeptide or target nucleic acid in a host cell. A "target polypeptide"
is a polypeptide encoded by a KIAA0296, Chrom 4, Clarom 6, ELP3, LRCHl, SNWI
or ERG nucleotide sequence or other nucleotide sequence referenced in Table A, or a substantially identical nucleotide sequence thereof. The recombinant expression vector typically includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. The term "regulatory sequence" includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences.
The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, and the like. Expression vectors can be introduced into host cells to produce target polypeptides, including fusion polypeptides.

[0050] Recombinant expression vectors can be designed for expression of target polypeptides in prokaryotic or eukaryotic cells. For example, target polypeptides can be expressed in E, coli, insect cells (e.g., using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology.' Methods in Er~zy»aology 185, Academic Press, San Diego, CA (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0051] Expression of polypeptides in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion polypeptides. Fusion vectors add a number of amino acids to a polypeptide encoded therein, usually to the amino terminus of the recombinant polypeptide. Such fusion vectors typically serve three purposes:
1) to increase expression of recombinant polypeptide; 2) to increase the solubility of the recombinant polypeptide; and 3) to aid in the purification of the recombinant polypeptide by acting as a ligand in affinity purification. Often, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety subsequent to purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith & Johnson, Gene 67: 31-40 (1988)), pMAL (New England Biolabs, Beverly, MA) and pRITS (Pharmacia, Piscataway, NJ) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.

[0052] Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for target polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector is used to infect bone marrow cells that are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed (e.g., six (6) weeks).

[0053] Expressing the polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide is often used to maximize recombinant polypeptide expression (Gottesman, S., Gefze Expressioh Technology: Methods in EnzynZOlogy, Academic Press, San Diego, California 185: 119-128 (1990)). Another strategy is to alter the nucleotide sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., Nucleic Acids Res. 20: 2111-2118 (1992)). Such alteration of nucleotide sequences can be carried out by standard DNA
synthesis techniques.

[0054] When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. Recombinant mammalian expression vectors are often capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Non-limiting examples of suitable tissue-specific promoters include an albumin promoter (liver-specific; Pinkert et al., Genes Dev. 1: 268-277 (1987)), lymphoid-specific promoters (Calame ~ Eaton, Adv. Immunol. 43: 235-275 (1988)), promoters of T cell receptors (Winoto & Baltimore, EMBO J. 8: 729-733 (1989)) promoters of immunoglobulins (Banerji et al., Cell 33: 729-740 (1983); Queen & Baltimore, Cell 33: 741-748 (1983)), neuron-specific promoters (e.g., the neurofilament promoter; Byrne &
Ruddle, Proc. Natl.

Acad. Sci. USA 86: 5473-5477 (1989)), pancreas-specific promoters (Edlund et al., Science 230: 912-916 (1985)), and mammary gland-specific promoters (e.g., milk whey promoter;
U.S. Patent No.
4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (I~essel &
Gruss, Science 249: 374-379 (1990)) and the oc-fetopolypeptide promoter (Campes & Tilghman, Genes Dev. 3:
537-546 (1989)).

[0055] A KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A also may be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters andlor enhancers) operatively linked to a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHl, SNWl or ERG nucleic acid or other nucleic acid referenced in Table A cloned in the antisense orientation can be chosen for directing constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types. Antisense expression vectors can be in the form of a recombinant plasmid, phagemid or attenuated virus. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub et al., Antisense RNA as a molecular tool for genetic analysis, Reviews - Trends in Genetics, Vol. 1(1) (1986).

[0056] Also provided herein are host cells that include a KIAA0296, Ch~om 4, Chrona 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A within a recombinant expression vector or a fragment of such a nucleotide sequence which facilitate homologous recombination into a specific site of the host cell genome. The terms "host~cell" and "recombinant host cell" are used interchangeably herein. Such terms refer not only to the particular subject cell but rather also to the progeny or potential progeny of such a cell. Because certain ,:
modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, a target polypeptide can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0057] Vectors can be introduced into host cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transductiouinfection, DEAE-dextran-mediated transfection, lipofection, or electroporation.

[0058] A host cell provided herein can be used to produce (i. e., express) a target polypeptide or a substantially identical polypeptide thereof. Accordingly, further provided are methods for producing a target polypeptide using host cells described herein. In one embodiment, the method includes culturing host cells into which a recombinant expression vector encoding a target polypeptide has been introduced in a suitable medium such that a target polypeptide is produced. In another embodiment, the method further includes isolating a target polypeptide from the medium or the host cell.

[0059] Also provided are cells or purified preparations of cells which include a KIAA0296, Chrom 4, Chrona 6, ELP3, LRCHl, SNWI or ERG transgene, or other transgene in Table A, or which otherwise misexpress target polypeptide. Cell preparations can consist of human or non-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. In preferred embodiments, the cell or cells include a I~IIAA0296, Chrorn 4, Chrom 6, ELP3, LRCHl, SNWI or ERG transgene or other transgene referenced in Table A (e.g., a heterologous form of a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG gene or other gene referenced in Table A, such as a human gene expressed in non-human cells). The transgene can be misexpressed, e.g., overexpressed or underexpressed. In other preferred embodiments, the cell or cells include a gene which misexpress an endogenous target polypeptide (e.g., expression of a gene is disrupted, also known as a knockout). Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed alleles or for use in drug screening.
Also provided are human cells (e.g., a hematopoietic stem cells) transfected with a KI~1A0296, Chrona 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A.

[0060] Also provided are cells or a purified preparation thereof (e.g., human cells) in which an endogenous KIAA0296, Chronz 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene. The expression characteristics of an endogenous gene within a cell (e.g., a cell line or microorganism) can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the corresponding endogenous gene. For example, an endogenous corresponding gene (e.g., a gene which is "transcriptionally silent," not normally expressed, or expressed only at very low levels) may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, US
5,272,071; WO 91/06667, published on May 16, 1991.
Transgenic Animals [0061] Non-human transgenic animals that express a heterologous target polypeptide (e.g., expressed from a KIAA0296, Chrorrr 4, Chrorn 6, ELP3, LRCHl, SNWI or ERG
nucleic acid or other nucleic acid referenced in Table A, or substantially identical sequence thereof) can be generated. Such animals are useful for studying the function and/or activity of a target polypeptide and for identifying and/or evaluating modulators of the activity of KI~4A0296, ChronZ 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acids, other nucleic acids referenced in Table A, and encoded polypeptides. As used herein, a "transgenic animal" is a non-human animal such as a mammal (e.g., a non-human primate such as chimpanzee, baboon, or macaque; an ungulate such as an equine, bovine, or caprine; or a rodent such as a rat, a mouse, or an Israeli sand rat), a bird (e.g., a chicken or a turkey), an amphibian (e.g., a frog, salamander, or newt), or an insect (e.g., Drosophila rraelarcogaster), in which one or more of the cells of the animal includes a transgene. A transgene is exogenous DNA or a rearrangement (e.g., a deletion of endogenous chromosomal DNA) that is often integrated into or occurs in the genome of cells in a transgenic animal. A transgene can direct expression of an encoded gene product in one or more cell types or tissues of the transgenic animal, and other transgenes can reduce expression (e.g., a knockout).
Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a KIAA0296, Chrorn 4, Chf~om 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal (e.g., an embryonic cell of the animal) prior to development of the animal.

[0062] Intronic sequences and polyadenylation signals can also be included in the transgene to increase expression efficiency of the transgene. One or more tissue-specific regulatory sequences can be operably linked to a KI~1A0296, Chf°ona 4, Chf°om 6, ELP3, LRCHI, SNWl or ERG nucleotide sequence or other nucleotide sequence referenced in Table A to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of a KIAA0296, Chrom 4, Clzf~ona 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A in its genome and/or expression of encoded mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a KIAA0296, Chron2 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A can further be bred to other transgenic animals carrying other transgenes.

[0063] Target polypeptides can be expressed in transgenic animals or plants by introducing, for example, a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A into the genome of an animal that encodes the target polypeptide. In preferred embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a , milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Also included is a population of cells from a transgenic animal.
Tar-e~ t PolYpeptides [0064] Also featured herein are isolated target polypeptides, which are encoded by a KIAA0296, Chf°om 4, Ch~om 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or a nucleotide sequence referenced in Table A (e.g., SEQ ID NO: 8-17 or a sequence referenced in Table A), or a substantially identical nucleotide sequence thereof. Examples of KIf1A0296, Chrom 4, Cht~om 6, ELP3, LRCHl, SNWI or ERG polypeptides are set forth in SEQ ID NO: 18-27. The term "polypeptide" as used herein includes proteins and peptides. An "isolated" or "purified" polypeptide or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. In one embodiment, the language "substantially free" means preparation of a target polypeptide having less than about 30%, 20%, 10% and more preferably 5% (by dry weight), of non-target polypeptide (also referred to herein as a "contaminating protein"), or of chemical precursors or non-target chemicals. When the target polypeptide or a biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, specifically, where culture medium represents less than about 20%, sometimes less than about 10%, and often less than about 5% of the volume of the polypeptide preparation. Isolated or purified target polypeptide preparations are sometimes 0.01 milligrams or more or 0.1 milligrams or more, and often 1.0 milligrams or more and 10 milligrams or more in dry weight.

[0065] Further included herein are target polypeptide fragments. The polypeptide fragment may be a domain or part of a domain of a target polypeptide. The polypeptide fragment may have increased, decreased or unexpected biological activity. The polypeptide fragment is often 50 or fewer, 100 or fewer, or 200 or fewer amino acids in length, and is sometimes 300, 400, 500, 600, 700, or 900 or fewer amino acids in length. Specific embodiments are directed to a PTPNI polypeptide fragment (e.g., rs2282146 in Table A), such as a catalytic domain starting at about amino acid 3 and ending at about amino acid 279.
Other embodiments are directed to a KCNSl polypeptide fragment (e.g., rs734784 in Table A), such as a voltage gated postassium ion channel domain (e.g., starting at about amino acid 21 and ending at about amino acid 509), a postassium channel tetramerization domain (e.g., starting at about amino acid 52 and ending at about amino acid 155) or an ion transport protein domain (e.g., starting at about amino acid 271 and ending at about amino acid 456), for example. Certain embodiments are directed to PSMBI
polypeptide fragments (e.g., sequence accessed by NP_002784; rs756519 in Table A), such as a proteasome protease domain (e.g., starting at about amino acid 34 and ending at about amino acid 226) or a proteasome B domain (e.g., starting at about amino acid 41 and ending at about amino acid 88). Certain embodiments are directed to a ANXA6 polypeptide fragment (e.g., rs1012414 in Table A), such as an annexin domain starting at about amino acid 5 and ending at about amino acid 325, an annexin domain startuig at about amino acid 179 and ending at about amino acid 507, or an annexin domain starting at about .
amino acid 355 and ending at about amino acid 673 in isoform 1 or isoform 2 (e.g., an isoform 1 sequence can be accessed using accession number NP_001146 and an isoform 2 sequence can be accessed using accession number NP 004024; isoform 2 lacks exon 21 and encodes a protein isoform lacking the six amino acids VAAEIL,). Amino acid sequences can be accessed using information in Table A and in SEQ
117 NO: 18-27.

[0066] Substantially identical target polypeptides may depart from the amino acid sequences of target polypeptides in different manners. For example, conservative amino acid modifications may be introduced at one or more positions in the amino acid sequences of target polypeptides. A "conservative amino acid substitution" is one in which the amino acid is replaced by another amino acid having a similar structure and/or chemical function. Families of amino acid residues having similar structures and functions are well known. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Also, essential and non-essential amino acids may be replaced. A "non-essential" amino acid is one that can be altered without abolishing or substantially altering the biological function of a target polypeptide, whereas altering an "essential" amino acid abolishes or substantially alters the biological function of a target polypeptide. Amino acids that are conserved among target polypeptides are typically essential amino acids. In certain embodiments, the polypeptide includes one or more non-synonymous polymorphic variants associated with osteoarthritis, as described above (e.g., a valine encoded by rs734784, a valine encoded by rs1042164, a glutamate encoded by rs749670, a threonine encoded by rs955592, a glutamine encoded by rs241448, and a glycine encoded by rs 1040461 ).

[0067] Also, target polypeptides may exist as chimeric or fusion polypeptides.
As used herein, a target "chimeric polypeptide" or target "fusion polypeptide" includes a target polypeptide linked to a non-target polypeptide. A "non-target polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a polypeptide which is not substantially identical to the target polypeptide, which includes, for example, a polypeptide that is different from the target polypeptide and derived from the same or a different organism. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire target polypeptide or a fragment thereof. The non-target polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.

[0068] Fusion polypeptides can include a moiety having high affinity for a ligand. For example, the fusion polypeptide can be a GST-target fusion polypeptide in which the target sequences are fused to the C-terminus of the GST sequences, or a polyhistidine-target fusion polypeptide in which the target polypeptide is fused at the N- or C-terminus to a string of histidine residues. Such fusion polypeptides can facilitate purification of recombinant target polypeptide. Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide), and a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A, or a substantially identical nucleotide sequence thereof, can be cloned into an expression vector such that the fusion moiety is linked in-frame to the target polypeptide. Further, the fusion polypeptide can be a target polypeptide containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression, secretion, cellular internalization, and cellular localization of a target polypeptide can be increased through use of a heterologous signal sequence. Fusion polypeptides can also include all or a part of a serum polypeptide (e.g., an IgG constant region or human serum albumin).

[0069] Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these target polypeptides can be used to affect the bioavailability of a substrate of the target polypeptide and may effectively increase target polypeptide biological activity in a cell. Target fusion polypeptides may be useful therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a target polypeptide; (ii) mis-regulation of the gene encoding the target polypeptide;
and (iii) aberrant post-translational modification of a target polypeptide. Also, target p0lypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify target polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a target polypeptide with a substrate.

[0070] In addition, polypeptides can be chemically synthesized using techniques known in the art (See, e.g., Creighton, 1983 Proteins. New York, N.Y.: W. H. Freeman and Company; and Hunkapiller et al., (1984) Nature July 12 -18;310(5973):105-11). For example, a relative short fragment can be synthesized by use of a peptide synthesizer. Furthermore, if desired, non-classical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the fragment sequence.
Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoroamino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L
(levorotary).

[0071] Polypeptides and polypeptide fragments sometimes are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction;
metabolic synthesis in the presence of tunicamycin; and the like. Additional post-translational modifications include, for example, N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide.

[0072] Also provided are chemically modified derivatives of polypeptides that can provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see e.g., U.S. Pat. No: 4,179,337. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycollpropylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

[0073] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about" indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).

[0074] The polymers should be attached to the polypeptide with consideration of effects on functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art (e.g., EP 0 401 384 (coupling PEG to G-CSF) and Malik et al. (1992) Exp Hematol. September;20(8):1028-35 (pegylation of GM-CSF using tresyl chloride)). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. For therapeutic purposes, the attaclnnent sometimes is at an amino group, such as attachment at the N-terminus or lysine group.

[0075] Proteins can be chemically modified at the N-terminus. Using polyethylene glycol as an illustration of such a composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, and the like), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus may be accomplished by reductive alkylation, which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.
Substantially Identical Nucleic Acids and Polypeptides [0076] Nucleotide sequences and polypeptide sequences that are substantially identical to a KIAA0296, Chrom 4, CI2f'o3rZ 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A and the target polypeptide sequences encoded by those nucleotide sequences, respectively, are included herein. The term "substantially identical" as used herein refers to two or more nucleic acids or polypeptides sharing one or more identical nucleotide sequences or polypeptide sequences, respectively. Included are nucleotide sequences or polypeptide sequences that are 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more (each often within a 1%, 2%, 3% or 4% variability) identical to a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence, or other nucleotide sequence referenced in Table A, or the encoded target polypeptide amino acid sequences. One test for determining whether two nucleic acids are substantially identical is to determine the percent of identical nucleotide sequences or polypeptide sequences shared between the nucleic acids or polypeptides.

[0077] Calculations of sequence identity are often performed as follows.
Sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The length of a reference sequence aligned for comparison purposes is sometimes 30% or more, 40% or more, 50% or more, often 60% or more, and more often 70% or more, 80% or more, 90% or more, or 100% of the length of the reference sequence. The nucleotides or amino acids at corresponding nucleotide or polypeptide positions, respectively, are then compared among the two sequences. When a position in the first sequence is occupied by the same nucleotide or amino acid as the corresponding position in the second sequence, the nucleotides or amino acids are deemed to be identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, introduced for optimal alignment of the two sequences.

[0078] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers & Miller, CABIOS 4: 11-17 (1989), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. Also, percent identity between two amino acid sequences can be determined using the Needleman ~ Wunsch, J. Mol.
Biol. 4~: 444-453 (1970) algorithm which has been incorporated into the GAP program in the GCG
software package (available at the http address www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http address www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A set of parameters often used is a Blossum 62 scoring matrix with a gap open penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0079] Another manner for determining if two nucleic acids are substantially identical is to assess whether a polynucleotide homologous to one nucleic acid will hybridize to the other nucleic acid under stringent conditions. As use herein, the term "stringent conditions" refers to conditions for hybridization and washing. Stringent conditions are known to those skilled in the art and can be found in Cu~f~ent Protocols in Moleeular Biology, John Wiley & Sons, N.Y. , 6.3.1-6.3.6 (1989). Aqueous and non-aqueous methods are described in that reference and either can be used. An example of stringent hybridization conditions is hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 50°C. Another example of stringent hybridization conditions are hybridization in 6X sodium chloridelsodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 55°C. A further example of stringent hybridization conditions is hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C. Often, stringent hybridization conditions are hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C. More often, stringency conditions are 0.5M
sodium phosphate, 7% SDS at 65°C, followed by one or more washes at 0.2X SSC, 1% SDS at 65°C.

[0080] An example of a substantially identical nucleotide sequence to a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A is one that has a different nucleotide sequence but still encodes the same polypeptide sequence encoded by the nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A. Another example is a nucleotide sequence that encodes a polypeptide having a polypeptide sequence that is more than 70% or more identical to, sometimes more than 75% or more, 80% or more, or 85% or more identical to, and often more than 90% or more and 95% or more identical to a polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A.

[0081] Nucleotide sequences in SEQ ID NO: 1-7 or referenced in Table A and amino acid sequences of encoded polypeptides can be used as "query sequences" to perform a search against public databases to identify other family members or related sequences, for example.
Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al., J. Mol. Biol.
215: 403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST
program, score =
100, wordlength = 12 to obtain nucleotide sequences homologous to nucleotide sequences in SEQ ID
NO: 1-7, SEQ ID NO: 8-17 or referenced in Table A. BLAST polypeptide searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to polypeptides encoded by the nucleotide sequences of SEQ ID NO: 8-17 or referenced in Table A. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17): 3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, default parameters of the respective programs (e.g., XBLAST
and NBLAST) can be used (see the http address www.ncbi.nlm.nih.gov).

[0082] A nucleic acid that is substantially identical to a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A may include polymorphic sites at positions equivalent to those described herein when the sequences are aligned. For example, using the alignment procedures described herein, SNPs in a sequence substantially identical to a sequence in SEQ ID NO: 1-7 or referenced in Table A can be identified at nucleotide positions that match (i.e., align) with nucleotides at SNP positions in each nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A. Also, where a polymorphic variation results in an insertion or deletion, insertion or deletion of a nucleotide sequence from a reference sequence can change the relative positions of other polymorphic sites in the nucleotide sequence.

[0083] Substantially identical nucleotide and polypeptide sequences include those that are naturally occurring, such as allelic variants (same locus), splice variants, homologs (different locus), and orthologs (different organism) or can be non-naturally occurring. Non-naturally occurring variants can be generated by mutagenesis techniques, including those applied to polynucleotides, cells, or organisms.
The variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions (as compared in the encoded product).
Orthologs, homologs, allelic variants, and splice variants can be identified using methods known in the art. These variants normally comprise a nucleotide sequence encoding a polypeptide that is 50% or more, about 55% or more, often about 70-75% or more or about 80-85% or more, and sometimes about 90-95% or more identical to the amino acid sequences of target polypeptides or a fragment thereof.
Such nucleic acid molecules can readily be identified as being able to hybridize under stringent conditions to a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A
or a fragment of this sequence. Nucleic acid molecules corresponding to orthologs, homologs, and allelic variants of a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A can further be identified by mapping the sequence to the same chromosome or locus as the nucleotide sequence in SEQ
ID NO: 1-7 or referenced in Table A.

[0084] Also, substantially identical nucleotide sequences may include codons that are altered with respect to the naturally occurring sequence for enhancing expression of a target polypeptide in a particular expression system. For example, the nucleic acid can be one in which one or more codons are altered, and often 10% or more or 20% or more of the codons are altered for optimized expression in bacteria (e.g., E. coli.), yeast (e.g., S. cervesiae), human (e.g., 293 cells), insect, or rodent (e.g., hamster) cells.
Methods for Identif5ring Risk of Osteoarthritis [0085] Methods for prognosing and diagnosing osteoarthritis are included herein. These methods include detecting the presence or absence of one or more polymorphic variations in a nucleotide sequence associated with osteoarthritis, such as variants in or around the loci set forth herein, or a substantially identical sequence thereof, in a sample from a subject, where the presence of a polymorphic variant described herein is indicative of a risk of osteoarthritis. Determining a risk of osteoarthritis sometimes refers to determining whether an individual is at an increased risk of osteoarthritis (e.g., intermediate risk or higher risk).

[0086] Thus, featured herein is a method for identifying a subject who is at risk of osteoarthritis, which comprises detecting an aberration associated with osteoarthritis in a nucleic acid sample from the subject. An embodiment is a method for detecting a risk of osteoarthritis in a subject, which comprises detecting the presence or absence of a polymorphic variation associated with osteoarthritis at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of: (a) a nucleotide sequence of SEQ D7 NO: 1-7 or referenced in Table A; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID
NO: 1-7 or referenced in Table A, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID
NO: 1-7 or referenced in Table A; and (d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising the polymorphic site; whereby the presence of the polymorphic variation is indicative of a predisposition to osteoarthritis in the subject. In certain embodiments, polymorphic variants at the positions described herein are detected for determining a risk of osteoarthritis, and polymorphic variants at positions in linkage disequilibrium with these positions are detected for determining a risk of osteoarthritis. As used herein, the terms "SEQ ID NO: 1-7" and other nucleotide sequences "referenced in Table A" refers to individual sequences in SEQ ID NO: l, 2, 3, 4, 5, 6 or 7, or any individual sequence referenced in Table A, each sequence being separately applicable to embodiments described herein.

[0087] Risk of osteoarthritis sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. Risk often is based upon the presence or absence of one or more polymorphic variants described herein, and also may be based in part upon phenotypic traits of the individual being tested. Methods for calculating risk based upon patient data are well known (see, e.g., Agresti, Categorical Data Analysis, 2nd Ed. 2002. Wiley). Allelotyping and genotyping analyses may be carried out in populations other than those exemplified herein to enhance the predictive power of the prognostic method. These further analyses are executed in view of the exemplified procedures described herein, and may be based upon the same polymorphic variations or additional polymorphic variations.

[0088] In certain embodiments, determining the presence of a combination of two or more polymorphic variants associated with osteoarthritis in one or more genetic loci (e.g., one or more genes) of the sample is determined to identify, quantify and/or estimate, risk of osteoarthritis. The risk often is the probability of having or developing osteoarthritis. The risk sometimes is expressed as a relative risk with respect to a population average risk of osteoarthritis, and sometimes is expressed as a relative risk with respect to the lowest risk group. Such relative risk assessments often are based upon penetrance values determined by statistical methods, and are particularly useful to clinicians and insurance companies for assessing risk of osteoarthritis (e.g., a clinician can target appropriate detection, prevention and therapeutic regimens to a patient after determining the patient's risk of osteoarthritis, and an insurance company can fme tune actuarial tables based upon population genotype assessments of osteoarthritis risk). Risk of osteoarthritis sometimes is expressed as an odds ratio, which is the odds of a particular person having a genotype has or will develop osteoarthritis with respect to another genotype group (e.g., the most disease protective genotype or population average). In related embodiments, the determination is utilized to identify a subject at risk of osteoarthritis. In an embodiment, two or more polymorphic variations are detected in two or more regions in human genomic DNA associated with increased risk of osteoarthritis, such as a locus containing a KIAA0296, Chr~om 4, Chrom 6, ELP3, LRCHl, SNWI or ERG or other locus referenced in Table A, for example. In certain embodiments, 3 or more, or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100 or more polymorphic variants are detected in the sample. In specific embodiments, polymorphic variants are detected in a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG
region or other region referenced in Table A, for example. In another embodiment, polymorphic variants are detected at two or three positions in a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A. In certain embodiments, polymorphic variants are detected at other genetic loci (e.g., the polymorphic variants can be detected in a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHI, SlVWl or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A in addition to other loci or only in other loci), where the other loci include but are not limited to those described in patent applications 60/559,011; 60/559,202; 60/559,203; 60/559,042; 60/559,275; 60/559,040 and 60/559,225, each of which is entitled "Methods for Identifying Risk of Osteoarthritis and Treatments Thereof," each of which was filed on 1 April 2004 and each of which is incorporated herein by reference in its entirety in jurisdictions allowing incorporation by reference.

[0089] Results from prognostic tests may be combined with other test results to diagnose osteoarthritis. For example, prognostic results may be gathered, a patient sample may be ordered based on a determined predisposition to osteoarthritis, the patient sample is analyzed, and the results of the analysis may be utilized to diagnose osteoarthritis. Also osteoaxthritis diagnostic method can be developed from studies used to generate prognostic methods in which populations are stratified into subpopulations having different progressions of osteoarthritis. In another embodiment, prognostic results may be gathered, a patient's risk factors for developing osteoarthritis (e.g., age, weight, occupational history, race, diet) analyzed, and a patient sample may be ordered based on a determined predisposition to osteoarthritis.

[0090] The nucleic acid sample typically is isolated from a biological sample obtained from a subject. For example, nucleic acid can be isolated from blood, saliva, sputum, urine, cell scrapings, and biopsy tissue. The nucleic acid sample can be isolated from a biological sample using standard techniques, such as the technique described in Example 2. As used herein, the term "subject" refers primarily to humans but also refers to other mammals such as dogs, cats, and ungulates (e.g., cattle, sheep, and swine). Subjects also include avians (e.g., chickens and turkeys), reptiles, and fish (e.g., salmon), as embodiments described herein can be adapted to nucleic acid samples isolated from any of these organisms. The nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.

[0091] The presence or absence of a polymorphic variant is determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic acid sample from a subject having a copy of each chromosome is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample.
For example, primer extension methods, ligase sequence determination methods (e.g., U.S. Pat. Nos.
5,679,524 and 5,952,174, and WO 01/27326), mismatch sequence determination methods (e.g., U.S. Pat. Nos.
5,851,770; 5,958,692; 6,110,684; and 6,183,958), microarray sequence determination methods, restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499), PCR-based assays (e.g., TAQMAN~ PCR
System (Applied Biosystems)), and nucleotide sequencing methods may be used.

[0092] Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PCR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation.
One oligonucleotide primer is complementary to a region 3' of the polymorphism and the other is complementary to a region 5' of the polymorphism. A PCR primer pair may be used in methods disclosed in U.S. Pat. Nos. 4,683,195; 4,683,202, 4,965,188; 5,656,493;
5,998,143; 6,140,054; WO
01127327; and WO 01/27329 for example. PCR primer pairs may also be used in any commercially available machines that perform PCR, such as any of the GENEAMP~ Systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon a KIAA0296, Chrom 4, Chr~om 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A using knowledge available in the art.

[0093] Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. As used herein, the term "adjacent"
refers to the 3' end of the extension oligonucleotide being often 1 nucleotide from the 5' end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5' end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid. The extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present.
Oligonucleotide extension methods are disclosed, for example, in U.S. Pat.
Nos. 4,656,127; 4,851,331;
5,679,524; 5,834,189; 5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981,186;
6,004,744; 6,013,431;
6,017,702; 6,046,005; 6,087,095; 6,210,891; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos.
5,547,835; 5,605,798; 5,691,141;
5,849,542; 5,869,242; 5,928,906; 6,043,031; and 6,194,144, and a method often utilized is described herein in Example 2.

[0094] A microarray can be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A microarray may include any oligonucleotides described herein, and methods for making and using oligonucleotide microarrays suitable for diagnostic use are disclosed in U.S. Pat. Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940; 5,849,483;
6,018,041; 6,045,996;
6,136,541; 6,142,681; 6,156,501; 6,197,506; 6,223,127; 6,225,625; 6,229,911;
6,239,273; WO
00/52625; WO 01/25485; and WO 01/29259. The microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions. The oligonucleotides may also be linked to the solid support directly or by a spacer molecule. A microarray may comprise one or more oligonucleotides complementary to a polymorphic site set forth herein.

[0095] A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit often comprises one or more pairs of oligonucleotide primers useful for amplifying a fragment of a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A
or a substantially identical sequence thereof, where the fragment includes a polymorphic site. The kit sometimes comprises a polymerizing agent, for example, a thermostable nucleic acid polymerase such as one disclosed in U.S. Pat. Nos. 4,889,818 or 6,077,664. Also, the kit often comprises an elongation oligonucleotide that hybridizes to a KIAA0296, Chrom 4, Chr~om 6, ELP3, LRCHI, SlVYT~l or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it also often comprises chain elongating nucleotides, such as dATP, dTTP, dGTP, dCTP, and dITP, including analogs of dATP, dTTP, dGTP, dCTP and dITP, provided that such analogs are substrates for a thermostable nucleic acid polymerase and can be incorporated into a nucleic acid chain elongated from the extension oligonucleotide. Along with chain elongating nucleotides would be one or more chain terminating nucleotides such as ddATP, ddTTP, ddGTP, ddCTP, and the like. In an embodiment, the kit comprises one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides.
Fits optionally include buffers, vials, microtiter plates, and instructions for use.

[0096] An individual identified as being at risk of osteoarthritis may be heterozygous or homozygous with respect to the allele associated with a higher risk of osteoarthritis. A subject homozygous for an allele associated with an increased risk of osteoarthritis is at a comparatively high risk of osteoarthritis, a subject heterozygous for an allele associated with an increased risk of osteoarthritis is at a comparatively intermediate risk of osteoarthritis, and a subject homozygous for an allele associated with a decreased risk of osteoarthritis is at a comparatively low risk of osteoarthritis. A
genotype may be assessed for a complementary strand, such that the complementary nucleotide at a particular position is detected.

[0097] Also featured are methods for determining risk of osteoarthritis and/or identifying a subject at risk of osteoarthritis by contacting a polypeptide or protein encoded by a KIAA0296, Chf~om 4, Chrorra 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A from a subject with an antibody that specifically binds to an epitope associated with increased risk of osteoarthritis in the polypeptide.
Applications of Prognostic and Diagnostic Results to Pharmaco~;enomic Methods [0098] Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype as a particular treatment regimen may exert a differential effect depending upon the subject's genotype. For example, based upon the outcome of a prognostic test described herein, a clinician or physician may target pertinent information and preventative or therapeutic treatments to a subject who would be benefited by the information or treatment and avoid directing such information and treatments to a subject who would not be benefited (e.g., the treatment has no therapeutic effect and/or the subject experiences adverse side effects).

[0099] The following is an example of a pharmacogenomic embodiment. A
particular treatment regimen can exert a differential effect depending upon the subject's genotype.
Where a candidate therapeutic exhibits a significant interaction with a major allele and a comparatively weak interaction with a minor allele (e.g., an order of magnitude or greater difference in the interaction), such a therapeutic typically would not be administered to a subject genotyped as being homozygous for the minor allele, and sometimes not administered to a subject genotyped as being heterozygous for the minor allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a major allele but is comparatively toxic when administered to subjects heterozygous or homozygous for a minor allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the minor allele.

(0100] The methods described herein are applicable to pharmacogenomic methods for preventing, alleviating or treating osteoarthritis. For example, a nucleic acid sample from an individual may be subjected to a prognostic test described herein. Where one or more polymorphic variations associated with increased risk of osteoarthritis are identified in a subject, information for preventing or treating osteoarthritis and/or one or more osteoarthritis treatment regimens then may be prescribed to that subj ect.

[0101] In certain embodiments, a treatment or preventative regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing osteoarthritis assessed by the methods described herein. Thus, provided are methods for identifying a subject predisposed to osteoarthritis and then prescribing a therapeutic or preventative regimen to individuals identified as having a predisposition. Thus, certain embodiments are directed to a method for reducing osteoarthritis in a subject, which comprises: detecting the presence or absence of a polymorphic variant associated with osteoarthritis in a nucleotide sequence in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of (a) a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ 117 NO: 1-7 or referenced in Table A; and (d) a fragment of a polynucleotide sequence of (a), (b), or (c); and prescribing or administering a treatment regimen to a subject from whom the sample originated where the presence of a polymorphic variation associated with osteoarthritis is detected in the nucleotide sequence. In these methods, predisposition results may be utilized in combination with other test results to diagnose osteoarthritis.

[0102] Certain preventative treatments often are prescribed to subjects having a predisposition to osteoarthritis and where the subject is diagnosed with osteoarthritis or is diagnosed as having symptoms indicative of an early stage of osteoarthritis. The treatment sometimes is preventative (e.g., is prescribed or administered to reduce the probability that osteoarthritis arises or progresses), sometimes is therapeutic, and sometimes delays, alleviates or halts the progression of osteoarthritis. Any known preventative or therapeutic treatment for alleviating or preventing the occurrence of osteoarthritis is prescribed and/or administered. For example, the treatment often is directed to decreasing pain and improving joint movement. Examples of OA treatments include exercises to keep joints flexible and improve muscle strength. Different medications to control pain, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., Voltaren); cyclooxygenase-2 (COX-2) inhibitors (e.g., Celebrex, Vioxx, Mobic, and Bextra); monoclonal antibodies (e.g., Remicade); tumor necrosis factor inhibitors (e.g., Enbrel); or injections of glucocorticoids, hyaluronic acid or chondrotin sulfate into joints that are inflamed and not responsive to NSAIDS. Orally administered chondroitin sulfate also may be used as a therapeutic, as it may increase hyaluronic acid levels and viscosity of synovial fluid, and decrease collagenase levels in synovial fluid. Also, glucosamine can serve as an OA
therapeutic as delivering it into joints may inhibit enzymes involved in cartilage degradation and enhance the production of hyaluronic acid. For mild pain without inflammation, acetaminophen may be used. Other treatments include: heat/cold therapy for temporary pain relief;
joint protection to prevent strain or stress on painful joints; surgery to relieve chronic pain in damaged joints; and weight control to prevent extra stress on weight-bearing joints.

[0103] As therapeutic approaches for treating osteoarthritis continue to evolve and improve, the goal of treatments for osteoarthritis related disorders is to intervene even before clinical signs first manifest. Thus, genetic markers associated with susceptibility to osteoarthritis prove useful for early diagnosis, prevention and treatment of osteoarthritis.

[0104] As osteoarthritis preventative and treatment information can be specifically targeted to subjects in need thereof (e.g., those at risk of developing osteoarthritis or those in an early stage of osteoarthritis), provided herein is a method for preventing or reducing the risk of developing osteoarthritis in a subject, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with osteoarthritis at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying a subject with a predisposition to osteoarthritis, whereby the presence of the polymorphic variation is indicative of a predisposition to osteoarthritis in the subject;
and (c) if such a predisposition is identified, providing the subject with information about methods or products to prevent or reduce osteoarthritis or to delay the onset of osteoarthritis. Also provided is a method of targeting information or advertising to a subpopulation of a human population based on the subpopulation being genetically predisposed to a disease or condition, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with osteoarthritis at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying the subpopulation of subjects in which the polymorphic variation is associated with osteoarthritis;
and (c) providing information only to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition.

[0105] Pharmacogenomics methods also may be used to analyze and predict a response to osteoarthritis treatment or a drug. For example, if pharmacogenomics analysis indicates a likelihood that an individual will respond positively to osteoarthritis treatment with a particular drug, the drug may be administered to the individual. Conversely, if the analysis indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects. The response to a therapeutic treatment can be predicted in a background study in which subjects in any of the following populations are genotyped: a population that responds favorably to a treatment regimen, a population that does not respond significantly to a treatment regimen, and a population that responds adversely to a treatment regimen (e.g., exhibits one or more side effects). These populations are provided as examples and other populations and subpopulations may be analyzed. Based upon the results of these analyses, a subject is genotyped to predict whether he or she will respond favorably to a treatment regimen, not respond significantly to a treatment regimen, or respond adversely to a treatment regimen.

[0106] The tests described herein also are applicable to clinical drug trials.
One or more polymorphic variants indicative of response to an agent for treating osteoarthritis or to side effects to an agent for treating osteoarthritis may be identified using the methods described herein. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as a result of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems.

[0107] Thus, another embodiment is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of: (a) obtaining a nucleic acid sample from an individual; (b) determining the identity of a polymorphic variation which is associated with a positive response to the treatment or the drug, or at least one polymorphic variation which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and (c) including the individual in the clinical trial if the nucleic acid sample contains said polymorphic variation associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said polymorphic variation associated with a negative response to the treatment or the drug. In addition, the methods described herein for selecting an individual for inclusion in a clinical trial of a treatment or drug encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination. The polymorphic variation may be in a sequence selected individually or in any combination from the group consisting of (i) a nucleotide sequence of SEQ )D

NO: 1[-7ror referenced in Table A; (ii) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ B7 NO: 1-7 or referenced in Table A;
(iii) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ >D NO: 1-7 or referenced in Table A, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A; and (iv) a fragment of a polynucleotide sequence of (i), (ii), or (iii) comprising the polymorphic site. The including step (c) optionally comprises administering the drug or the treatment to the individual if the nucleic acid sample contains the polymorphic variation associated with a positive response to the treatment or the drug and the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug.

[0108] Also provided herein is a method of partnering between a diagnostic/prognostic testing provider and a provider of a consumable product, which comprises: (a) the diagnostic/prognostic testing provider detects the presence or absence of a polymorphic variation associated with osteoarthritis at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) the diagnostic/prognostic testing provider identifies the subpopulation of subjects in which the polymorphic variation is associated with osteoarthritis; (c) the diagnostic/prognostic testing provider forwards information to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition; and (d) the provider of a consumable product forwards to the diagnostic test provider a fee every time the diagnostic/prognostic test provider forwards information to the subject as set forth in step (c) above.
Compositions Comprising Osteoarthritis-Directed Molecules [0109] Featured herein is a composition comprising a cell from a subject having osteoarthritis or at risk of osteoarthritis and one or more molecules specifically directed and targeted to a nucleic acid comprising a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence, other nucleotide sequence referenced in Table A, or an encoded amino acid sequence.
Such directed molecules include, but are not limited to, a compound that binds to a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence, or other nucleotide sequence referenced in Table A, or encoded amino acid sequence; a RNAi or siRNA molecule having a strand complementary or substantially complementary to a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI
or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A (e.g., hybridizes to a KIAA0296, Chrona 4, Chr°om 6, ELP3, LRCHI, SNWl or ERG nucleotide sequence or other nucleotide sequence referenced in Table A under conditions of high stringency); an antisense nucleic acid complementary or substantially complementary to an RNA encoded by a KIAA0296, Cht~om 4, Chr~ona 6, ELP3, LRCHl, SNWl or ERG nucleotide sequence or other nucleotide sequence referenced in Table A (e.g., hybridizes to a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHI, SNWI or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A under conditions of high stringency); a ribozyme that hybridizes to a KIAA0296, ClZrom 4, Clar~om 6, ELP3, LRCHl, SNWI
or ERG nucleotide sequence or other nucleotide sequence referenced in Table A (e.g., hybridizes to a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A under conditions of high stringency); a nucleic acid aptamer that specifically binds a polypeptide encoded by a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHl, SNWl or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A; and an antibody that specifically binds to a polypeptide encoded by a KIAA0296, Ch~om 4, ChronZ 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A or binds to a nucleic acid having such a nucleotide sequence. In an embodiment, the antibody selectively binds to an epitope comprising an amino acid encoded by rs734784, rs1042164, rs749670, rs955592, rs241448 and rs1040461. In specific embodiments, the osteoarthritis directed molecule interacts with a nucleic acid or polypeptide variant associated with osteoarthritis, such as variants referenced herein. In other embodiments, the osteoarthritis directed molecule interacts with a polypeptide involved in a signal pathway of a polypeptide encoded by a KIAA0296, Ch~om 4, Chrof~a 6, ELP3, LRCHI, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A, or a nucleic acid comprising such a nucleotide sequence.

[0110] Compositions sometimes include an adjuvant known to stimulate an immune response, and in certain embodiments, an adjuvant that stimulates a T-cell lymphocyte response. Adjuvants are known, including but not limited to an aluminum adjuvant (e.g., aluminum hydroxide); a cytokine adjuvant or adjuvant that stimulates a cytokine response (e.g., interleukin (IL)-12 and/or gamma-interferon cytokines); a Freund-type mineral oil adjuvant emulsion (e.g., Freund's complete or incomplete adjuvant); a synthetic lipoid compound; a copolymer adjuvant (e.g., TitreMax); a saponin;
Quil A; a liposome; an oil-in-water emulsion (e.g., an emulsion stabilized by Tween 80 and pluronic polyoxyethlene/polyoxypropylene block copolymer (Syntex Adjuvant Formulation);
TitreMax;
detoxified endotoxin (MPL) and mycobacterial cell wall components (T1~W, CWS) in 2% squalene (Ribi Adjuvant System)); a muramyl dipeptide; an immune-stimulating complex (ISCOM, e.g., an Ag-modified saponin/cholesterol micelle that forms stable cage-like structure);
an aqueous phase adjuvant that does not have a depot effect (e.g., Gerbu adjuvant); a carbohydrate polymer (e.g., AdjuPrime); L-tyrosine; a manide-oleate compound (e.g., Montanide); an ethylene-vinyl acetate copolymer (e.g., Elvax 40W1,2); or lipid A, for example. Such compositions are useful for generating an immune response against osteoarthritis directed molecule (e.g., an HLA-binding subsequence within a polypeptide encoded by a KIAA0296, Ch~orn 4, Clarom 6, ELP3, LRCHI, SNWI or ERG nucleotide sequence). In such methods, a peptide having an amino acid subsequence of a polypeptide encoded by a KIAA0296, Chrom 4, Chf~om 6, ELP3, LRCHI, SNWI or ERG nucleotide sequence is delivered to a subject, where the subsequence binds to an HLA molecule and induces a CTL lymphocyte response. The peptide sometimes is delivered to the subject as an isolated peptide or as a minigene in a plasmid that encodes the peptide. Methods for identifying HLA-binding subsequences in such polypeptides are known (see e.g., publication W002/20616 and PCT application US98/01373 for methods of identifying such sequences).

[0111] The cell may be in a group of cells cultured in vitro or in a tissue maintained in vitt°o or present in an animal in vivo (e.g., a rat, mouse, ape or human). In certain embodiments, a composition comprises a component from a cell such as a nucleic acid molecule (e.g., genomic DNA), a protein mixture or isolated protein, for example. The aforementioned compositions have utility in diagnostic, prognostic and pharmacogenomic methods described previously and in therapeutics described hereafter.
Certain osteoarthritis directed molecules are described in greater detail below.
Compounds [0112] Compounds can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive (see, e.g., Zuckermann et al., J. Med. Chem.37:
2678-85 (1994)); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; "one-bead one-compound" library methods; and synthetic library methods using affinity chromatography selection. Biological library and peptoid library approaches are typically limited to peptide libraries, while the other approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, Anticancer Drug Des.
12: 145, (1997)).
Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al., Proc. Natl. Acad. Sci. U.S.A. 90: 6909 (1993); Erb et al., Proc. Natl. Acad.
Sci. USA 91: 11422 (1994);
Zuckermann et al., J. Med. Chem. 37: 2678 (1994); Cho et al., Science 261:
1303 (1993); Carrell et al., Angew. Chem. Int. Ed. Engl. 33: 2059 (1994); Carell et al., Angew. Chem. Int.
Ed. Engl. 33: 2061 (1994); and in Gallop et al., J. Med. Chem. 37: 1233 (1994).

[0113] Libraries of compounds may be presented in solution (e.g., Houghten, Biotechniques 13:
412-421 (1992)), or on beads (Lam, Nature 354: 82-84 (1991)), chips (Fodor, Nature 364: 555-556 (1993)), bacteria or spores (Ladner, United States Patent No. 5,223,409), plasmids (Cull et al., Proc.
Natl. Acad. Sci. USA 89: 1865-1869 (1992)) or on phage (Scott and Smith, Science 249: 386-390 (1990); Devlin, Science 249: 404-406 (1990); Cwirla et al., Proc. Natl. Acad.
Sci. 87: 6378-6382 (1990); Felici, J. Mol. Biol. 222: 301-310 (1991); Ladner supra.).

[0114] A compound sometimes alters expression and sometimes alters activity of a polypeptide target and may be a small molecule. Small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

Antisense Nucleic Acid Molecules, Riboz~nes. RNAi, siRNA and Modified Nucleic Acid Molecules [0115] An "antisense" nucleic acid refers to a nucleotide sequence complementary to a "sense"
nucleic acid encoding a polypeptide, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire coding strand, or to a portion thereof or a substantially identical sequence thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence (e.g., 5' and 3' untranslated regions in SEQ ID
NO: 1-7 or a nucleotide sequence referenced in Table A).

[0116] An antisense nucleic acid can be designed such that it is complementary to the entire coding region of an mRNA encoded by a nucleotide sequence (e.g., SEQ ID NO: 1-7, SEQ
ID NO: 8-17 or a nucleotide sequence referenced in Table A), and often the antisense nucleic acid is an oligonucleotide antisense to only a portion of a coding or noncoding region of the mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of the mRNA, e.g., between the -10 and +10 regions of the target gene nucleotide sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length. The antisense nucleic acids, which include the ribozymes described hereafter, can be designed to target a KIAA0296, Ch~om 4, Chr~om 6, ELP3, LRCHl, SNWI or ERG
nucleotide sequence, often a variant associated with osteoarthritis, or a substantially identical sequence thereof. Among the variants, minor alleles and major alleles can be targeted, and those associated with a higher risk of osteoarthritis are often designed, tested, and administered to subjects.

[0117] An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.
Antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0118] When utilized as therapeutics, antisense nucleic acids typically are administered to a subject (e.g., by direct injection at a tissue site) or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide and thereby inhibit expression of the polypeptide, for example, by inhibiting transcription and/or translation.
Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then are administered systemically. For systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. Antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. Sufficient intracellular concentrations of antisense molecules are achieved by incorporating a strong promoter, such as a pol II
or pol III promoter, in the vector construct.

[0119] Antisense nucleic acid molecules sometimes are alpha-anomeric nucleic acid molecules.
An alpha-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual beta-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids. Res. 15: 6625-6641 (1987)). Antisense nucleic acid molecules can also comprise a 2'-0-methylribonucleotide (moue et al., Nucleic Acids Res. 15: 6131-6148 (1987)) or a chimeric RNA-DNA
analogue (moue et al., FEBS Lett. 215: 327-330 (1987)). Antisense nucleic acids sometimes are composed of DNA or PNA or any other nucleic acid derivatives described previously.

[0120] In another embodiment, an antisense nucleic acid is a ribozyme. A
ribozyme having specificity for a KIAA0296, Ch~om 4, Ch~om 6, ELP3, LRCHI, SNWI or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A can include one or more sequences complementary to such a nucleotide sequence, and a sequence having a known catalytic region responsible for mRNA
cleavage (see e.g., U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach, Nature 334: 585-591 (1988)). For example, a derivative of a Tetrahymena L-19 IVS RNA is sometimes utilized in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA (see e.g., Cech et al. U.S. Patent No. 4,987,071; and Cech et al. U.S. Patent No.
5,116,742). Also, target mRNA sequences can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules (see e.g., Bartel & Szostak, Science 261: 1411-1418 (1993)).

[0121] Osteoarthritis directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a KIAA0296, Ch~om 4, Chrom 6, ELP3, LRCHI, SNWI or ERG
nucleotide sequence or other nucleotide sequence referenced in Table A, or a substantially identical sequence thereof, especially one that includes a regulatory region that controls expression of a polypeptide. Gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a nucleotide sequence referenced herein or a substantially identical sequence (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells (see e.g., Helene, Anticancer Drug Des. 6(6): 569-84 (1991); Helene et al., Ann. N.Y. Acad. Sci.
660: 27-36 (1992); and Maher, Bioassays 14(12): 807-15 (1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a so-called "switchback" nucleic acid molecule. Switchback molecules are synthesized in an alternating 5'-3', 3'-S' manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.

[0122] Osteoarthritis directed molecules include RNAi and siRNA nucleic acids.
Gene expression may be inhibited by the introduction of double-stranded RNA (dsRNA), which induces potent and specific gene silencing, a phenomenon called RNA interference or RNAi. See, e.g., Fire et al., US
Patent Number 6,506,559; Tuschl et al. PCT International Publication No. WO
01/75164; Kay et al.
PCT International Publication No. WO 03/010180A1; or Bosher JM, Labouesse, Nat Cell Biol 2000 Feb;2(2):E31-6. This process has been improved by decreasing the size of the double-stranded RNA to 20-24 base pairs (to create small-interfering RNAs or siRNAs) that "switched off' genes in mammalian cells without initiating an acute phase response, i.e., a host defense mechanism that often results in cell death (see, e.g., Caplen et al. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9742-7 and Elbashir et al.
Methods 2002 Feb;26(2):199-213). There is increasing evidence of post-transcriptional gene silencing by RNA interference (RNAi) for inhibiting targeted expression in mammalian cells at the mRNA level, in human cells. There is additional evidence of effective methods for inhibiting the proliferation and migration of tumor cells in human patients, and for inhibiting metastatic cancer development (see, e.g., U. S. Patent Application No. US2001000993183; Caplen et al. Proc Natl Acad Sci U S A; and Abderrahmani et al. Mol Cell Biol 2001 Nov21(21):7256-67).

[0123] An "siRNA" or "RNAi" refers to a nucleic acid that forms a double stranded RNA and has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is delivered to or expressed in the same cell as the gene or target gene. "siRNA" refers to short double-stranded RNA
formed by the complementary strands. Complementary portions of the siRNA that hybridize to form the double stranded molecule often have substantial or complete identity to the target molecule sequence. In one embodiment, an siRNA refers to a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA.

[0124] When designing the siRNA molecules, the targeted region often is selected from a given DNA sequence beginning 50 to 100 nucleotides downstream of the start codon.
See, e.g., Elbashir et al,. Methods 26:199-213 (2002). Initially, 5' or 3' UTrs and regions nearby the start codon were avoided assuming that UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. Sometimes regions of the target 23 nucleotides in length conforming to the sequence motif AA(N19)TT (N, an nucleotide), and regions with approximately 30% to 70% G/C-content (often about 50% G/C-content) often are selected. If no suitable sequences are found, the search often is extended using the motifNA(N21). The sequence of the sense siRNA sometimes corresponds to (N19) TT or N21 (position 3 to 23 of the 23-nt motif), respectively. In the latter case, the 3' end of the sense siRNA often is converted to TT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. The antisense siRNA is synthesized as the complement to position 1 to 21 of the 23-nt motif. Because position 1 of the 23-nt motif is not recognized sequence-specifically by the antisense siRNA, the 3'-most nucleotide residue of the antisense siRNA can be chosen deliberately. However, the penultimate nucleotide of the antisense siRNA (complementary to position 2 of the 23-nt motif) often is complementary to the targeted sequence. For simplifying chemical synthesis, TT often is utilized. siRNAs corresponding to the target motifNAR(N17)YNN, where R is purine (A,G) and Y is pyrimidine (C,U), often are selected.
Respective 21 nucleotide sense and antisense siRNAs often begin with a purine nucleotide and can also be expressed from pol III
expression vectors without a change in targeting site. Expression of RNAs from pol III promoters often is efficient when the first transcribed nucleotide is a purine.

[0125] The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof. Often, the siRNA is about 15 to about 50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15-50 nucleotides in length, and the double stranded siRNA
is about 15-50 base pairs in length, sometimes about 20-30 nucleotides in length or about 20-25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. The siRNA
sometimes is about 21 nucleotides in length. Methods of using siRNA are well known in the art, and specific siRNA molecules may be purchased from a number of companies including Dharmacon Research, Inc.

[0126] Antisense, ribozyme, RNAi and siRNA nucleic acids can be altered to form modified nucleic acid molecules. The nucleic acids can be altered at base moieties, sugar moieties or phosphate backbone moieties to improve stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of nucleic acid molecules can be modified to generate peptide nucleic acids (see Hyrup et al., Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)).
As used herein, the terms "peptide nucleic acid" or "PNA" refers to a nucleic acid mimic such as a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can allow for specific hybridization to DNA
and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described, for example, in Hyrup et al., (1996) supra and Perry-O'Keefe et al., Proc. Natl. Acad. Sci. 93: 14670-675 (1996).

[0127] PNA nucleic acids can be used in prognostic, diagnostic, and therapeutic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, for example, inducing transcription or translation arrest or inhibiting replication. PNA
nucleic acid molecules can also be used in the analysis of single base pair mutations in a gene, (e.g., by PNA-directed PCR clamping); as "artificial restriction enzymes" when used in combination with other enzymes, (e.g., S1 nucleases (Hyrup (1996) supra)); or as probes or primers for DNA sequencing or hybridization (Hyrup et al., (1996) supra; Perry-O'Keefe supra).

[0128] In other embodiments, oligonucleotides may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across cell membranes (see e.g., Letsinger et al., Proc. Natl. Acad. Sci. USA 86: 6553-6556 (1989); Lemaitre et al., Proc. Natl. Acad. Sci. USA 84: 648-652 (1987); PCT Publication No. W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No. W089/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (See, e.g., Krol et al., Bio-Techniques 6: 958-976 (1988)) or intercalating agents. (See, e.g., Zon, Pharm. Res. 5: 539-549 (1988) ).
To.this end, the oligonucleotide may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).

[0129] Also included herein are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a KIAA0296, Clarom 4, Chrorra 6, ELP3, LRCHl, SNWI
or ERG nucleotide sequence or other nucleotide sequence referenced in Table A, or a substantially identical sequence thereof, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantifying the presence of the nucleic acid in a sample.
Molecular beacon nucleic acids are described, for example, in Lizardi et al., U.S. Patent No. 5,854,033;
Nazarenko et al., U.S. Patent No. 5,866,336, and Livak et al., U.S. Patent 5,876,930.
Antibodies [0130] The term "antibody" as used herein refers to an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion.
Examples of immunologically active portions of immunoglobulin molecules include Flab) and F(ab')z fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody sometimes is a polyclonal, monoclonal, recombinant (e.g., a chimeric or humanized), fully human, non-human (e.g., murine), or a single chain antibody. An antibody may have effector function and can fix complement, and is sometimes coupled to a toxin or imaging agent.

[0131] A full-length polypeptide or antigenic peptide fragment encoded by a nucleotide sequence referenced herein can be used as an immunogen or can be used to identify antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. An antigenic peptide often includes at least 8 amino acid residues of the amino acid sequences encoded by a nucleotide sequence referenced herein, or substantially identical sequence thereof, and encompasses an epitope. Antigenic peptides sometimes include 10 or more amino acids, 15 or more amino acids, 20 or more amino acids, or 30 or more amino acids. Hydrophilic and hydrophobic fragments of polypeptides sometimes are used as immunogens.

[0132] Epitopes encompassed by the antigenic peptide are regions located on the surface of the polypeptide (e.g., hydrophilic regions) as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human polypeptide sequence can be used to indicate the regions that have a particularly high probability of being localized to the surface of the polypeptide and are thus likely to constitute surface residues useful for targeting antibody production. The antibody may bind an epitope on any domain or region on polypeptides described herein.

[0133] Also, chimeric, humanized, and completely human antibodies are useful for applications which include repeated administration to subjects. Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA
techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al International Application No. PCT/LJS86/02269; Akira, et al European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al European Patent Application 173,494; Neuberger et al PCT International Publication No. WO 86/01533; Cabilly et al U.S. Patent No. 4,816,567; Cabilly et al European Patent Application 125,023; Better et al., Science 240: 1041-1043 (1988); Liu et al., Proc. Natl. Acad. Sci. USA 84: 3439-3443 (1987); Liu et al., J. Immunol. 139:
3521-3526 (1987); Sun et al., Proc. Natl. Acad. Sci. USA 84: 214-218 (1987); Nishimura et al., Canc.
Res. 47: 999-1005 (1987); Wood et al., Nature 314: 446-449 (1985); and Shaw et al., J. Natl.
Cancer Inst. 80: 1553-1559 (1988); Morrison, S. L., Science 229: 1202-1207 (1985); Oi et al., BioTechniques 4: 214 (1986);
Winter U.S. Patent 5,225,539; Jones et al., Nature 321: 552-525 (1986);
Verhoeyan et al., Science 239:
1534; and Beidler et al., J. Immunol. 141: 4053-4060 (1988).

[0134] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar, Int. Rev. Immunol.
13: 65-93 (1995); and U.S. Patent Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Fremont, CA) and Medarex, Inc. (Princeton, NJ), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.
Completely human antibodies that recognize a selected epitope also can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody (e.g., a murine antibody) is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described for example by Jespers et al., Bio/Technology 12: 899-903 ( 1994).

[0135] An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al., Ann. N Y Acad. Sci. 880: 263-80 (1999);
and Reiter, Clin. Cancer Res. 2: 245-52 (1996)). Single chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.

[0136] Antibodies also may be selected or modified so that they exhibit reduced or no ability to bind an Fc receptor. For example, an antibody may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor (e.g., it has a mutagenized or deleted Fc receptor binding region).

[0137] Also, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1 dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

[0138] Antibody conjugates can be used for modifying a given biological response. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, gamma-interferon, alpha-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Also, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No.
4,676,980, for example.

[0139] An antibody (e.g., monoclonal antibody) can be used to isolate target polypeptides by standard techniques, such as affinity chromatography or immunoprecipitation.
Moreover, an antibody can be used to detect a target polypeptide (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide.
Antibodies can be used diagnostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance (i.e., antibody labeling). Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, allealine phosphatase, (3-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include lzsh i3ih 3sS
or 3H. Also, an antibody can be utilized as a test molecule for determining whether it can treat osteoarthritis, and as a therapeutic for administration to a subject for treating osteoarthritis.

[0140] An antibody can be made by immunizing with a purified antigen, or a fragment thereof, e.g., a fragment described herein, a membrane associated antigen, tissues, e.g., crude tissue preparations, whole cells, preferably living cells, lysed cells, or cell fractions.

[0141] Included herein are antibodies which bind only a native polypeptide, only denatured or otherwise non-native polypeptide, or which bind both, as well as those having linear or conformational epitopes. Conformational epitopes sometimes can be identified by selecting antibodies that bind to native but not denatured polypeptide. Also featured are antibodies that specifically bind to a polypeptide variant associated with osteoarthritis.
Methods for Identi , ink Candidate Therapeutics for Treating Osteoarthritis [0142] Current therapies for the treatment of osteoarthritis have limited efficacy, limited tolerability and significant mechanism-based side effects, and few of the available therapies adequately address underlying defects. Current therapeutic approaches were largely developed in the absence of defined molecular targets or even a solid understanding of disease pathogenesis. Therefore, provided are methods of identifying candidate therapeutics that target biochemical pathways related to the development of osteoarthritis.

[0143] Thus, featured herein are methods for identifying a candidate therapeutic for treating osteoarthritis. The methods comprise contacting a test molecule with a target molecule in a system. A
"target molecule" as used herein refers to a KIAA0296, Cla~om 4, Chrom 6, ELP3, LRCHI, SNWI or ERG nucleic acid or other nucleotide sequence referenced in Table A, a substantially identical nucleic acid thereof, or a fragment thereof, and an encoded polypeptide of the foregoing. The methods also comprise determining the presence or absence of an interaction between the test molecule and the target molecule, where the presence of an interaction between the test molecule and the nucleic acid or polypeptide identifies the test molecule as a candidate osteoarthritis therapeutic. The interaction between the test molecule and the target molecule may be quantified.

[0144] Test molecules and candidate therapeutics include, but are not limited to, compounds, antisense nucleic acids, siRNA molecules, ribozymes, polypeptides or proteins encoded by a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleotide sequence or other nucleotide sequence referenced in Table A , or a substantially identical sequence or fragment thereof, and immunotherapeutics (e.g., antibodies and HLA-presented polypeptide fragments).
A test molecule or candidate therapeutic may act as a modulator of target molecule concentration or target molecule function in a system. A "modulator" may agonize (i.e., up-regulates) or antagonize (i.e., down-regulates) a target molecule concentration partially or completely in a system by affecting such cellular functions as DNA replication and/or DNA processing (e.g., DNA methylation or DNA repair), RNA
transcription and/or RNA processing (e.g., removal of intronic sequences and/or translocation of spliced mRNA from the nucleus), polypeptide production (e.g., translation of the polypeptide from mRNA), and/or polypeptide post-translational modification (e.g., glycosylation, phosphorylation, and proteolysis of pro-polypeptides). A modulator may also agonize or antagonize a biological function of a target molecule partially or completely, where the function may include adopting a certain structural conformation, interacting with one or more binding partners, ligand binding, catalysis (e.g., phosphorylation, dephosphorylation, hydrolysis, methylation, and isomerization), and an effect upon a cellular event (e.g., effecting progression of osteoarthritis).

[0145] As used herein, the term "system" refers to a cell free in vitro environment and a cell-based environment such as a collection of cells, a tissue, an organ, or an organism.
A system is "contacted"
with a test molecule in a variety of manners, including adding molecules in solution and allowing them to interact with one another by diffusion, cell injection, and any administration routes in an animal. As used herein, the term "interaction" refers to an effect of a test molecule on test molecule, where the effect sometimes is binding between the test molecule and the target molecule, and sometimes is an observable change in cells, tissue, or organism.

[0146] There are many standard methods for detecting the presence or absence of interaction between a test molecule and a target molecule. For example, titrametric, acidimetric, radiometric, NMR, monolayer, polarographic, spectrophotometric, fluorescent, and ESR assays probative of a target molecule interaction may be utilized. Any modulator can be tested in such methods and modulators for certain targets described in Table A are known. For example, modulators of protein tyrosine phosphatases (e.g., PTPNI includes a protein phosphatase domain) are described in WO-03072537, WO-03020688, WO-00218321, WO-00218323, WO-03055883, WO-03041729, WO-00226707, WO-00226743 and WO-03037328; modulators of potassium channels (e.g., KCNSI
includes a potassium channel domain) are described in WO-09962891, WO-09716437, WO-09521813, WO-09521823, WO-09521824, WO-09521825 and WO-03088908; modulators of annexin (e.g., AN~YA6 includes an annexin domain) are described in WO-2004018670, WO-02067857, WO-2004013303 and WO-00147510;
proteasome modulators (e.g., PSMBI includes a proteasome domain) are described in WO-2004014882 and Roesel et al. Proceedings of the American Association of Cancer Research 2003, 44:1 st Ed (Abs 1769), and bortezomib (Velcade, MLN-341, LDP-341 and PS-341), a ubiquitin proteosome inhibitor, is used for the treatment of multiple myeloma; and modulators of protein kinases (e.g., FYN is a protein kinase) are described in WO-03081210, WO-02080926, WO-02076986, WO-03077921, W003026666, W003026665 and W003026664.

[0147] Test molecule/target molecule interactions can be detected and/or quantified using assays known in the art. For example, an interaction can be determined by labeling the test molecule and/or the target molecule, where the label is covalently or non-covalently attached to the test molecule or target molecule. The label is sometimes a radioactive molecule such as lzslysih ssS or 3H, which can be detected by direct counting of radioemission or by scintillation counting.
Also, enzymatic labels such as horseradish peroxidase, alkaline phosphatase, or luciferase may be utilized where the enzymatic label can be detected by determining conversion of an appropriate substrate to product. In addition, presence or absence of an interaction can be determined without labeling. For example, a microphysiometer (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indication of an interaction between a test molecule and target molecule (McConnell, H. M. et al., Science 257: 1906-1912 (1992)).

[0148] In cell-based systems, cells typically include a KIAA0296, Chrona 4, Chrom 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleotide sequence referenced in Table A, an encoded polypeptide, or substantially identical nucleic acid or polypeptide thereof, and are often of mammalian origin, although the cell can be of any origin. Whole cells, cell homogenates, and cell fractions (e.g., cell membrane fractions) can be subjected to analysis. Where interactions between a test molecule with a target polypeptide are monitored, soluble and/or membrane bound forms of the polypeptide may be utilized. Where membrane-bound forms of the polypeptide are used, it may be desirable to utilize a solubilizing agent. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton~ X-100, Triton~ X-114, Thesit~, Isotridecypoly(ethylene glycol ether)n, 3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS), 3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate (CHAPSO), or N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate.

[0149] An interaction between a test molecule and target molecule also can be detected by monitoring fluorescence energy transfer (FET) (see, e.g., Lakowicz et al., U.S. Patent No. 5,631,169;
Stavrianopoulos et al. U.S. Patent No. 4,868,103). A fluorophore label on a first, "donor" molecule is selected such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, "acceptor" molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the "donor" polypeptide molecule may simply utilize the natural fluorescent energy of tryptophan residues.
Labels are chosen that emit different wavelengths of light, such that the "acceptor" molecule label may be differentiated from that of the "donor". Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the "acceptor" molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

[0150] In another embodiment, determining the presence or absence of an interaction between a test molecule and a target molecule can be effected by monitoring surface plasmon resonance (see, e.g., Sjolander & Urbaniczk, Afzal. Chem. 63: 2338-2345 (1991) and Szabo et al., Cur. Opin. Struct. Biol. S:
699-705 (1995)). "Surface plasmon resonance" or "biomolecular interaction analysis (BIA)" can be utilized to detect biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

[0151] In another embodiment, the target molecule or test molecules are anchored to a solid phase, facilitating the detection of target molecule/test molecule complexes and separation of the complexes from free, uncomplexed molecules. The target molecule or test molecule is immobilized to the solid support. In an embodiment, the target molecule is anchored to a solid surface, and the test molecule, which is not anchored, can be labeled, either directly or indirectly, with detectable labels discussed herein.

[0152] It may be desirable to immobilize a target molecule, an anti-target molecule antibody, and/or test molecules to facilitate separation of target molecule/test molecule complexes from uncomplexed forms, as well as to accommodate automation of the assay. The attachment between a test molecule and/or target molecule and the solid support may be covalent or non-covalent (see, e.g., U.S.
Patent No. 6,022,688 for non-covalent attachments). The solid support may be one or more surfaces of the system, such as one or more surfaces in each well of a microtiter plate, a surface of a silicon wafer, a surface of a bead (see, e.g., Lam, Nature 354: 82-84 (1991)) that is optionally linked to another solid support, or a channel in a microfluidic device, for example. Types of solid supports, linker molecules for covalent and non-covalent attaclunents to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are well known (see, e.g., U.S.
Patent Nos. 6,261,776;
5,900,481; 6,133,436; and 6,022,688; and WIPO publication WO 01/18234).

[0153] In an embodiment, target molecule may be immobilized to surfaces via biotin and streptavidin. For example, biotinylated target polypeptide can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, IL), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In another embodiment, a target polypeptide can be prepared as a fusion polypeptide. For example, glutathione-S-transferase/target polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivitized microtiter plates, which are then combined with a test molecule under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, or the matrix is immobilized in the case of beads, and complex formation is determined directly or indirectly as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of target molecule binding or activity is determined using standard techniques.

[0154] In an embodiment, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that a significant percentage of complexes formed will remain immobilized to the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of manners. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface, e.g., by adding a labeled antibody specific for the immobilized component, where the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody.

[0155] In another embodiment, an assay is performed utilizing antibodies that specifically bind target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule. Such antibodies can be derivitized to a solid support, and unbound target molecule may be immobilized by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

[0156] Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by any of a number of standard techniques, including but not limited to: differential centrifugation (see, e.g., Rivas, G., and Minton, Trends Biochem Sci Aug;18(8):
284-7 (1993)); chromatography (gel filtration chromatography, ion-exchange chromatography);
electrophoresis (see, e.g., Ausubel et al., eds. Current Protocols in Molecular Biology , J. Wiley: New York (1999)); and immunoprecipitation (see, e.g., Ausubel et al., eds., supra). Media and chromatographic techniques are known to one skilled in the art (see, e.g., Heegaard, JMoI. Recognit.
Winter; 1l (I-6): 141-8 (1998); Hage & Tweed, J. Chromatogr. B Biomed. Sci.
Appl. Oct 10; 699 (1-2):
499-525 (1997)). Further, fluorescence energy transfer may also be conveniently utilized, as described herein, to detect binding without further purification of the complex from solution.

[0157] In another embodiment, modulators of target molecule expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of target mRNA or target polypeptide is evaluated relative to the level of expression of target mRNA or target polypeptide in the absence of the candidate compound. When expression of target mRNA or target polypeptide is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as an agonist of target mRNA or target polypeptide expression. Alternatively, when expression of target mRNA or target polypeptide is less (e.g., less with statistical significance) in the presence of the candidate compound than in its absence, the candidate compound is identified as an antagonist or inhibitor of target mRNA or target polypeptide expression. The level of target mRNA or target polypeptide expression can be determined by methods described herein.

[0158] In another embodiment, binding partners that interact with a target molecule are detected.
The target molecules can interact with one or more cellular or extracellular macromolecules, such as polypeptides in vivo, and these interacting molecules are referred to herein as "binding partners."
Binding partners can agonize or antagonize target molecule biological activity. Also, test molecules that agonize or antagonize interactions between target molecules and binding partners can be ,useful as therapeutic molecules as they can up-regulate or down-regulated target molecule activity in vivo and thereby treat osteoarthritis.

[0159] Binding partners of target molecules can be identified by methods known in the art. For example, binding partners may be identified by lysing cells and analyzing cell lysates by electrophoretic techniques. Alternatively, a two-hybrid assay or three-hybrid assay can be utilized (see, e.g., U.S.
Patent No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J.
Biol. Chem. 268: 12046-12054 (1993); Bartel et al., BiotechrZiques 14: 920-924 (1993); Iwabuchi et al., Oncogerae 8: 1693-1696 (1993); and Brent W094/10300). A two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. The assay often utilizes two different DNA constructs. In one construct, a KIAA0296, Chrom 4, Chrom 6, ELP3, LRCHI, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A
(sometimes referred to as the "bait") is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In another construct, a DNA sequence from a library of DNA sequences that encodes a potential binding partner (sometimes referred to as the "prey") is fused to a gene that encodes an activation domain of the known transcription factor. Sometimes, a KIAA0296, Chrom 4, Chrona 6, ELP3, LRCHl, SNWI or ERG nucleic acid or other nucleic acid referenced in Table A can be fused to the activation domain. If the "bait" and the "prey" molecules interact in vivo, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to identify the potential binding partner.

[0160] In an embodiment for identifying test molecules that antagonize or agonize complex formation between target molecules and binding partners, a reaction mixture containing the target molecule and the binding partner is prepared, under conditions and for a time sufficient to allow complex formation. The reaction mixture often is provided in the presence or absence of the test molecule. The test molecule can be included initially in the reaction mixture, or can be added at a time subsequent to the addition of the target molecule and its binding partner.
Control reaction mixtures are incubated without the test molecule or with a placebo. Formation of any complexes between the target molecule and the binding partner then is detected. Decreased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule antagonizes target molecule/binding partner complex formation.
Alternatively, increased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule agonizes target molecule/binding partner complex formation. In another embodiment, complex formation of target molecule/binding partner can be compared to complex formation of mutant target molecule/binding partner (e.g., amino acid modifications in a target polypeptide). Such a comparison can be important in those cases where it is desirable to identify test molecules that modulate interactions of mutant but not non-mutated.target gene products.

[0161] The assays can be conducted in a heterogeneous or homogeneous format.
In heterogeneous assays, target molecule and/or the binding partner are immobilized to a solid phase, and complexes are detected on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the molecules being tested. For example, test compounds that agonize target molecule/binding partner interactions can be identified by conducting the reaction in the presence of the test molecule in a competition format. Alternatively, test molecules that agonize preformed complexes, e.g., molecules with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed.

(0162] In a heterogeneous assay embodiment, the target molecule or the binding partner is anchored onto a solid surface (e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored molecule can be immobilized by non-covalent or covalent attachments. Alternatively, an immobilized antibody specific for the molecule to be anchored can be 4~

used to anchor the molecule to the solid surface. The partner of the immobilized species is exposed to the coated surface with or without the test molecule. After the reaction is complete, unreacted components are removed (e.g., by washing) such that a significant portion of any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface is indicative of complex. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored to the surface;
e.g., by using a labeled antibody specific for the initially non-immobilized species. Depending upon the order of addition of reaction components, test compounds that inhibit complex formation or that disrupt preformed complexes can be detected.

[0163] In another embodiment, the reaction can be conducted in a liquid phase in the presence or absence of test molecule, where the reaction products are separated from unreacted components, and the complexes are detected (e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes). Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.

[0164] In an alternate embodiment, a homogeneous assay can be utilized. For example, a preformed complex of the target gene product and the interactive cellular or extracellular binding partner product is prepared. One or both of the target molecule or binding partner is labeled, and the signal generated by the labels) is quenched upon complex formation (e.g., U.S.
Patent No. 4,109,496 that utilizes this approach for immunoassays). Addition of a test molecule that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target molecule/binding partner complexes can be identified.

[0165] Candidate therapeutics for treating osteoarthritis are identified from a group of test molecules that interact with a target molecule. Test molecules are normally ranked according to the degree with which they modulate (e.g., agonize or antagonize) a function associated with the target molecule (e.g., DNA replication and/or processing, RNA transcription and/or processing, polypeptide production and/or processing, and/or biological function/activity), and then top ranleing modulators are selected. Also, pharmacogenomic information described herein can determine the rank of a modulator.
The top 10% of ranked test molecules often are selected for further testing as candidate therapeutics, and sometimes the top 1 S%, 20%, or 25% of ranked test molecules are selected for further testing as candidate therapeutics. Candidate therapeutics typically are formulated for administration to a subject.
Therapeutic Formulations [0166] Formulations and pharmaceutical compositions typically include in combination with a pharmaceutically acceptable carrier one or more target molecule modulators.
The modulator often is a test molecule identified as having an interaction with a target molecule by a screening method described above. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner. Also, formulations may comprise a target polypeptide or fragment thereof in combination with a pharmaceutically acceptable carrier.

[0167] As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0168] A pharmaceutical composition typically is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate;
chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0169] Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
/[0170] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
[0171] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0172] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
[0173] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. Molecules can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
[0174] In one embodiment, active molecules are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers.
These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4, 522, 811.
[0175] It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
[0176] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LDso/EDso. Molecules which exhibit high therapeutic indices are preferred.
While molecules that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
[0177] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such molecules lies preferably within a range of circulating concentrations that include the EDSO with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
For any molecules used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the ICSO (i.e., the concentration of the test compound which achieves a half maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
Levels in plasma may be measured, for example, by high performance liquid chromatography.
[0178] As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, sometimes about 0.01 to 25 mg/kg body weight, often about 0.1 to 20 mg/kg body weight, and more often about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, sometimes between 2 to 8 weeks, often between about 3 to 7 weeks, and more often for about 4, 5, or 6 weeks.
The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.
[0179] With regard to polypeptide formulations, featured herein is a method for treating osteoarthritis in a subject, which comprises contacting one or more cells in the subject with a first polypeptide, where the subject comprises a second polypeptide having one or more polymorphic variations associated with cancer, and where the first polypeptide comprises fewer polymorphic variations associated with cancer than the second polypeptide. The first and second polypeptides are encoded by a nucleic acid which comprises a nucleotide sequence in SEQ ID NO:
1-7 or referenced in Table A; a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence referenced in SEQ ID NO: 1-7 or referenced in Table A; a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-7 or referenced in Table A and a nucleotide sequence 90%
or more identical to a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A. The subject often is a human.
[0180] For antibodies, a dosage of 0.1 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg) is often utilized. If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is often appropriate. Generally, partially human antibodies and fully human antibodies have a longer half life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g., into the brain). A method for lipidation of antibodies is described by Cruikshank et al., J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193 (1997).
[0181] Antibody conjugates can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL,-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No.
4,676,980.
[0182] For compounds, exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight, for example, about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid described herein, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0183] With regard to nucleic acid formulations, gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S.
Patent 5,328,470) or by stereotactic injection (see e.g., Chen et al., (1994) Proc. Natl. Acad. Sei.
USA 91:3054-3057).
Pharmaceutical preparations of gene therapy vectors can include a gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded.
Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells (e.g., retroviral vectors) the pharmaceutical preparation can include one or more cells which produce the gene delivery system. Examples of gene delivery vectors are described herein.
Therapeutic Methods [0184] A therapeutic formulation described above can be administered to a subject in need of a therapeutic for inducing a desired biological response. Therapeutic formulations can be administered by any of the paths described herein. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from pharmacogenomic analyses described herein.
[0185] As used herein, the term "treatment" is defined as the application or administration of a therapeutic formulation to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect osteoarthritis, symptoms of osteoarthritis or a predisposition towards osteoarthritis. A therapeutic formulation includes, but is not limited to, small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides. Administration of a therapeutic formulation can occur prior to the manifestation of symptoms characteristic of osteoarthritis, such that osteoarthritis is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.
[0186] As discussed, successful treatment of osteoarthritis can be brought about by techniques that serve to agonize target molecule expression or function, or alternatively, antagonize target molecule expression or function. These techniques include administration of modulators that include, but are not limited to, small organic or inorganic molecules; antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab')Z and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.
[0187] Further, antisense and ribozyme molecules that inhibit expression of the target gene can also be used to reduce the level of target gene expression, thus effectively reducing the level of target gene activity. Still further, triple helix molecules can be utilized in reducing the level of target gene activity. Antisense, ribozyme and triple helix molecules are discussed above.
It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA
produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extracellular polypeptide, it can be preferable to co-administer normal target gene polypeptide into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.
[0188] Another method by which nucleic acid molecules may be utilized in treating or preventing osteoarthritis is use of aptamer molecules specific for target molecules.
Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to ligands (see, e.g., Osborne, et al., Curr. Opin. Chem. Biol. l (1): 5-9 (1997); and Patel, D. J., Curr. Opira. Claem. Biol.
Jun; I (1): 32-46 (1997)).
[0189] Yet another method of utilizing nucleic acid molecules for osteoarthritis treatment is gene therapy, which can also be referred to as allele therapy. Provided herein is a gene therapy method for treating osteoarthritis in a subject, which comprises contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence (e.g., the first nucleotide sequence is identical to or substantially identical to a nucleotide sequence of SEQ ID NO:
1-7 or other nucleotide sequence referenced in Table A). Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with osteoarthritis (e.g., the second nucleotide sequence is identical to or substantially identical to a nucleotide sequence of SEQ ID NO: 1-7 or other nucleotide sequence referenced in Table A). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with osteoarthritis than the second nucleotide sequence.
The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof.
The subject is often a human. Allele therapy methods often are utilized in conjunction with a method of first determining whether a subject has genomic DNA that includes polymorphic variants associated with osteoarthritis.
[0190] In another allele therapy embodiment, provided herein is a method which comprises contacting one or more cells in the subject or from the subject with a polypeptide encoded by a nucleic acid having a first nucleotide sequence (e.g., the first nucleotide sequence is identical to or substantially identical to the nucleotide sequence of SEQ ID NO: 1-7 or other nucleotide sequence referenced in Table A). Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with osteoarthritis (e.g., the second nucleotide sequence is identical to or substantially identical to a nucleotide sequence of SEQ ID NO: 1-7 or other nucleotide sequence referenced in Table A). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with osteoarthritis than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof.
The subject is often a human.

[0191] For antibody-based therapies, antibodies can be generated that are both specific for target molecules and that reduce target molecule activity. Such antibodies may be administered in instances where antagonizing a target molecule function is appropriate for the treatment of osteoarthritis.
[0192] In circumstances where stimulating antibody production in an animal or a human subject by injection with a target molecule is harmful to the subject, it is possible to generate an immune response against the target molecule by use of anti-idiotypic antibodies (see, e.g., Herlyn, Anfa. Med.; 31 (1): 66-78 (1999); and Bhattacharya-Chatterjee & Foon, Cancer Treat. Res.; 94: 51-68 (1998)). Introducing an anti-idiotypic antibody to a mammal or human subject often stimulates production of anti-anti-idiotypic antibodies, which typically are specific to the target molecule. Vaccines directed to osteoarthritis also may be generated in this fashion.
[0193] In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies may be preferred. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells.
Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen is preferred. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used. Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (see, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA 90: 7889-7893 (1993)).
[0194] Modulators can be administered to a patient at therapeutically effective doses to treat osteoarthritis. A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of osteoarthritis. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDSO (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LDSO/EDso. Modulators that exhibit large therapeutic indices are preferred. While modulators that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such molecules to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.
[0195] Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDSO with little or no toxicity.
The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the ICSO (i. e., the concentration of the test compound that achieves a half maximal inhibition of symptoms) as determined in cell culture.
Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.
[0196] Another example of effective dose determination for an individual is the ability to directly assay levels of "free" and "bound" compound in the serum of the test subject.
Such assays may utilize antibody mimics and/or "biosensors" that have been created through molecular imprinting techniques.
Molecules that modulate target molecule activity are used as a template, or "imprinting molecule", to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated "negative image" of the compound and is able to selectively rebind the molecule under biological assay conditions. A detailed review of this technique can be seen in Ansell et al., Cu~~ent Opinion in Biotechnology 7: 89-94 (1996) and in Shea, Trends in Polymer Science 2: 166-173 (1994). Such "imprinted" affinity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrixes in this way can be seen in Vlatakis, et al., Nature 361:
645-647 (1993). Through the use of isotope-labeling, the "free" concentration of compound which modulates target molecule expression or activity readily can be monitored and used in calculations of ICSO. Such "imprinted"
affinity matrixes can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes readily can be assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual ICSO. An example of such a "biosensor" is discussed in Kriz et al., Analytical Chemistry 67.' 2142-2144 (1995).
[0197] The examples set forth below illustrate but not limit the invention.
Examples [0198] In the following studies a group of subjects was selected according to specific parameters pertaining to osteoarthritis. Nucleic acid samples obtained from individuals in the study group were subjected to genetic analyses that identified associations between osteoarthritis and certain polymorphic variants in human genomic DNA. The polymorphisms were genotyped again in two replication cohorts consisting of individuals selected for OA. In addition, SNPs proximal to the incident polymorphism in the KIAA0296 region, the Cla~~om 4 region, the Ch~om 6 region, the ELP3 region, the LRCHI region, the SNWI region and in the ERG region were identified and allelotyped in OA case and control pools.
Methods are described for producing target polypeptides encoded by the nucleic acids of Table A in vitf~o or in vivo, which can be utilized in methods that screen test molecules for those that interact with target polypeptides. Test molecules identified as being interactors with target polypeptides can be screened further as osteoarthritis therapeutics.

Example 1 Samples and Poolin S~ trategies Sample Selection [0199] Blood samples were collected from individuals diagnosed with knee osteoarthritis, which were referred to as case samples. Also, blood samples were collected from individuals not diagnosed with knee osteoarthritis as gender and age-matched controls. A database was created that listed all phenotypic trait information gathered from individuals for each case and control sample. Genomic DNA was extracted from each of the blood samples for genetic analyses.
DNA Extraction from Blood Samples [0200] Six to ten milliliters of whole blood was transferred to a 50 ml tube containing 27 ml of red cell lysis solution (RCL). The tube was inverted until the contents were mixed. Each tube was incubated for 10 minutes at room temperature and inverted once during the incubation. The tubes were then centrifuged for 20 minutes at 3000 x g and the supernatant was carefully poured off. 100-200 w1 of residual liquid was left in the tube and was pipetted repeatedly to resuspend the pellet in the residual supernatant. White cell lysis solution (WCL) was added to the tube and pipetted repeatedly until completely mixed. While no incubation was normally required, the solution was incubated at 37°C or room temperature if cell clumps were visible after mixing until the solution was homogeneous. 2 ml of protein precipitation was added to the cell lysate. The mixtures were vortexed vigorously at high speed for 20 sec to mix the protein precipitation solution uniformly with the cell lysate, and then centrifuged for 10 minutes at 3000 x g. The supernatant containing the DNA was then poured into a clean 15 ml tube, which contained 7 ml of 100% isopropanol. The samples were mixed by inverting the tubes gently until white threads of DNA were visible. Samples were centrifuged for 3 minutes at 2000 x g and the DNA was visible as a small white pellet. The supernatant was decanted and 5 ml of 70% ethanol was added to each tube. Each tube was inverted several times to wash the DNA
pellet, and then centrifuged for 1 minute at 2000 x g. The ethanol was decanted and each tube was drained on clean absorbent paper. The DNA was dried in the tube by inversion for 10 minutes, and then 1000 ~,1 of 1X TE was added. The size of each sample was estimated, and less TE buffer was added during the following DNA
hydration step if the sample was smaller. The DNA was allowed to rehydrate overnight at room temperature, and DNA samples were stored at 2-8°C.
[0201] DNA was quantified by placing samples on a hematology mixer for at least 1 hour. DNA
was serially diluted (typically 1:80, 1:160, 1:320, and 1:640 dilutions) so that it would be within the measurable range of standards. 125 p,1 of diluted DNA was transferred to a clear U-bottom microtitre plate, and 125 ~,1 of 1X TE buffer was transferred into each well using a multichannel pipette. The DNA and 1X TE were mixed by repeated pipetting at least 15 times, and then the plates were sealed. 50 p1 of diluted DNA was added to wells AS-H12 of a black flat bottom microtitre plate. Standards were inverted six times to mix them, and then 50 ~,1 of 1X TE buffer was pipetted into well A1, 1000 ng/ml of standard was pipetted into well A2, 500 ng/ml of standard was pipetted into well A3, and 250 ng/ml of standard was pipetted into well A4. PicoGreen (Molecular Probes, Eugene, Oregon) was thawed and freshly diluted 1:200 according to the number of plates that were being measured. PicoGreen was vortexed and then 501 was pipetted into all wells of the black plate with the diluted DNA. DNA and PicoGreen were mixed by pipetting repeatedly at least 10 times with the multichannel pipette. The plate was placed into a Fluoroskan Ascent Machine (microplate fluorometer produced by Labsystems) and the samples were allowed to incubate for 3 minutes before the machine was run using filter pairs 485 nm excitation and 538 nm emission wavelengths. Samples having measured DNA
concentrations of greater than 450 ng/~,1 were re-measured for conformation. Samples having measured DNA
concentrations of 20 ng/~,1 or less were re-measured for confirmation.
Poolin S~trate-dies - Discovery Cohort [0202] Samples were derived from the Nottingham knee OA family study (UK) where index cases were identified through a knee replacement registry. Siblings were approached and assessed with knee x-rays and assigned status as affected or unaffected. In all 1,157 individuals were available. In order to create same-sex pools of appropriate sizes, 335 unrelated female individuals with OA from the Nottingham OA sample were selected for the case pool. The control pool was made up of unrelated female individuals from the St. Thomas twin study (England) with normal knee x-rays and without other indications of OA, regardless of anatomical location, as well as lacking family history of OA. The St. Thomas twin study consists of Caucasian, female participants from the St.
Thomas' Hospital, London, adult-twin registry, which is a voluntary registry of >4,000 twin pairs ranging from 18 to 76 years of age. The female case samples and female control samples are described further in Table 1 below.
[0203] A select set of samples from each group were utilized to generate pools, and one pool was created for each group. Each individual sample in a pool was represented by an equal amount of genomic DNA. For example, where 25 ng of genomic DNA was utilized in each PCR
reaction and there were 200 individuals in each pool, each individual would provide 125 pg of genomic DNA.
Inclusion or exclusion of samples for a pool was based upon the following criteria: the sample was derived from an individual characterized as Caucasian; the sample was derived from an individual of British paternal and maternal descent; case samples were derived from individuals diagnosed with specific knee osteoarthritis (OA) and were recruited from an OA knee replacement clinic. Control samples were derived from individuals free of OA, family history of OA, and rheumatoid arthritis.
Also, sufficient genomic DNA was extracted from each blood sample for all allelotyping and genotyping reactions performed during the study. Phenotype information from each individual was collected and included age of the individual, gender, family history of OA, general medical information (e.g., height, weight, thyroid disease, diabetes, psoriasis, hysterectomy), joint history (previous and current symptoms, joint-related operations, age at onset of symptoms, date of primary diagnosis, age of individual as of primary diagnosis and order of involvement), and knee-related findings (crepitus, restricted passive movement, bony swelling/deformity). Additional knee information included knee history, current symptoms, any major knee injury, menisectomy, knee replacement surgery, age of surgery, and treatment history (including hormone replace therapy (HRT)).
Samples that met these criteria were added to appropriate pools based on disease status.
[0204] The selection process yielded the pools set forth in Table 1, which were used in the studies that follow:

Female case Female control Pool size 335 335 umber) Pool Criteria ntr case l (ex: case/control)co o Mean Age 5'7,21 69.95 (ex: years) Example 2 Association of Polymorphic Variants with Osteoarthritis [0205] A whole-genome screen was performed to identify particular SNPs associated with occurrence of osteoarthritis. As described in Example 1, two sets of samples were utilized, which included samples from female individuals having knee osteoarthritis (osteoarthritis cases), and samples from female individuals not having knee osteoarthritis (female controls). The initial screen of each pool was performed in an allelotyping study, in which certain samples in each group were pooled. By pooling DNA from each group, an allele frequency for each SNP in each group was calculated. These allele frequencies were then compared to one another. Particular SNPs were considered as being associated with osteoarthritis when allele frequency differences calculated between case and control pools were statistically significant. SNP disease association results obtained from the allelotyping study were then validated by genotyping each associated SNP across all samples from each pool. The results of the genotyping then were analyzed, allele frequencies for each group were calculated from the individual genotyping results, and a p-value was calculated to determine whether the case and control groups had statistically significant differences in allele frequencies for a particular SNP. When the genotyping results agreed with the original allelotyping results, the SNP
disease association was considered validated at the genetic level.
SNP Panel Used for Genetic Anal'tses [0206] A whole-genome SNP screen began with an initial screen of approximately 25,000 SNPs over each set of disease and control samples using a pooling approach. The pools studied in the screen are described in Example 1. The SNPs analyzed in this study were part of a set of 25,488 SNPs confirmed as being statistically polymorphic as each is characterized as having a minor allele frequency of greater than 10%. The SNPs in the set reside in genes or in close proximity to genes, and many reside in gene exons. Specifically, SNPs in the set are located in exons, introns, and within 5,000 base-pairs upstream of a transcription start site of a gene. In addition, SNPs were selected according to the following criteria: they are located in ESTs; they are located in Locuslink or Ensembl genes; and they are located in Genomatix promoter predictions. SNPs in the set were also selected on the basis of even spacing across the genome, as depicted in Table 2.
[0207] A case-control study design using a whole genome association strategy involving approximately 28,000 single nucleotide polymorphisms (SNPs) was employed.
Approximately 25,000 SNPs were evenly spaced in gene-based regions of the human genome with a median inter-marker distance of about 40,000 base pairs. Additionally, approximately 3,000 SNPs causing amino acid substitutions in genes described in the literature as candidates for various diseases were used. The case-control study samples were of female Caucasian origin (British paternal and maternal descent) 670 individuals were equally distributed in two groups: female controls and female cases. The whole genome association approach was first conducted on 2 DNA pools representing the 2 groups.
Significant markers were confirmed by individual genotyping.

General Statistics Spacing Statistics Total # of SNPs 25,488 Median 37,058 by # of Exonic SNPs>4,335 (17%) Minimum* 1,000 by # SNPs with refSNP20,776 (81%) Maximum* 3,000,000 ID by Gene Coverage >10,000 Mean 122,412 by Chromosome CoverageAll Std Deviation 373,325 by *Excludes outliers Alleloty~ing and Genoty~ing Results [0208] The genetic studies summarized above and described in more detail below identified allelic variants associated with osteoarthritis, which are summarized in Table A.
Assay for Verifying, Alleloty~ing, and Genotypin~ SNPs [0209] A MassARRAYTM system (Sequenom, Inc.) was utilized to perform SNP
genotyping in a high-throughput fashion. This genotyping platform was complemented by a homogeneous, single-tube assay method (hMETM or homogeneous MassEXTENDTM (Sequenom, Inc.)) in which two genotyping primers anneal to and amplify a genomic target surrounding a polymorphic site of interest. A third primer (the MassEXTENDTM primer), which is complementary to the amplified target up to but not including the polymorphism, was then enzymatically extended one or a few bases through the polymorphic site and then terminated.

[0210] For each polymorphism, SpectroDESIGNERTM software (Sequenom, Inc.) was used to generate a set of PCR primers and a MassEXTENDTM primer which where used to genotype the polymorphism. Other primer design software could be used or one of ordinary skill in the art could manually design primers based on his or her knowledge of the relevant factors and considerations in designing such primers. Table 3 shows PCR primers and Table 4 shows extension primers used for analyzing polymorphisms. The initial PCR amplification reaction was performed in a 5 ~,l total volume containing 1X PCR buffer with 1.5 mM MgCl2 (Qiagen), 200 p,M each of dATP, dGTP, dCTP, dTTP
(Gibco-BRL), 2.5 ng of genomic DNA, 0.1 units of HotStar DNA polymerase (Qiagen), and 200 nM
each of forward and reverse PCR primers specific for the polymorphic region of interest.
TABLE 3: PCR Primers SNP

Forward PCR primer Reverse PCR primer Reference rs552 ACGTTGGATGGACTGAGGTAGATGATGCACGTTGGATGGCTTTCTTTCCCTTGGTTTC

rs12904 ACGTTGGATGGAACCACTCCCACCACAGACGTTGGATGGGTGGGGATGGCACTGTC

rs2282146ACGTTGGATGTCCCACGAGGACCTGGAGACGTTGGATGTTCGTTTGGGTGGCCGGG

rs734784ACGTTGGATGTCGGGATGTCTCCAGAGATGACGTTGGATGGCAACCACCAAGAGTTTGAG

rs1042164ACGTTGGATGTTTCTTCCAGACGGGCTTTCACGTTGGATGCAAAGTCAGCCGCAAACGAC

rs749670ACGTTGGATGTCTCATCTGTGTGCCCATTGACGTTGGATGATGAGGGTGAAAGGCAGGAG

rs955592ACGTTGGATGTTCCCATTCTTCTTGGGCTCACGTTGGATGTCTCAGAGGGTCTCCTTTTC

rs1143016ACGTTGGATGTTGTCCAGCAGGTAGGGCAGACGTTGGATGACCCATCGCGGATACATGTG

rs755248ACGTTGGATGGGTCTCTGCTGAGGAAGTGGACGTTGGATGACACTCACTACGGGGCCAG

rs1055055ACGTTGGATGTTGTGCTTGCTGAGGAATCCACGTTGGATGGTTGCAGAGAGCGTCTATAC

rs835409ACGTTGGATGTCCTGTTGGCTTTTGCAGACACGTTGGATGACTGCTCATGGTGGTTGAAC

rs927663ACGTTGGATGTTTGACTGGTTGCCCCAAACACGTTGGATGAAGAATCTTCAGTGCCAGCC

rs8162 ACGTTGGATGCTTCATCCAGAACCTCCAGGACGTTGGATGTGCATATGGCTTGTCAGAGC

rs831038ACGTTGGATGTGAAAGAGCTGCCTTCTTTCACGTTGGATGAAATGACACTCACGGTAAGC

rs33079 ACGTTGGATGTTATTTCATTGGCCAAGCCCACGTTGGATGGTGTTCACTTGTTCATGCAC

rs1710880ACGTTGGATGCGAAGGCAGAGAATAAACTGACGTTGGATGAACTCTGTGGTTTAAGAAAG

rs1078153ACGTTGGATGTCCTGCGTGTAACTGAGAGGACGTTGGATGAACATACACACAGTGCGAGC

rs799570ACGTTGGATGATGCATATGGGCAGGTTGCCACGTTGGATGCCAGGAAAGCATCCTCAGAC

rs1282730ACGTTGGATGTCCTTTGACTTACTGTGCTGACGTTGGATGAGAAAAGAGGTTGTGTACAG

rs1518875ACGTTGGATGAGAATGCGTTCAATGCCTGCACGTTGGATGAGCGAAAAGCTCTGCCATTG

rs1568694ACGTTGGATGGTTCATTCAGTTATGGACGGACGTTGGATGTGATAGGAGGGAGCCATCTC

rs905042ACGTTGGATGTAACAATGGTAAGGGCCAAGACGTTGGATGGGTCCATAATGGTCATTGTG

rs1957723ACGTTGGATGTACTCACTTGTGTACTGCTCACGTTGGATGGCTGCAGCGTCACATTAATC

rs794018ACGTTGGATGGGATGATGATGAAATGACTGACGTTGGATGGCTCTAGTTAGATGAGTCTC

rs707723ACGTTGGATGTGTGGCTGAAGTTTGCTCTGACGTTGGATGCACACACAAACCTTGAAGAG

rs893861ACGTTGGATGGAGGCATGTACACAAAACTGACGTTGGATGGCTCACGACTGTAATAGTTG

rs1914903ACGTTGGATGTGCGTCAAGT1'GAAGTCCTCACGTTGGATGAGGGTAGTGAGTTCACATGC

rs2062232ACGTTGGATGTCCTGCTCAGATAACTGCTGACGTTGGATGGCGGTAGTTTTCCCTAAACC

rs26609 ACGTTGGATGCAAGGGAGATCAGAAACATCACGTTGGATGAATTCATTGTTCTTGATGGC

rs1370987ACGTTGGATGATACTTTGGATGTCTGGTGGACGTTGGATGGGTCTTTGGTCACAACTATC

rs1012414ACGTTGGATGACTTGGAAAGTCAGTCTGGGACGTTGGATGGAAACCGAGAAATGGCTATG

rs435903ACGTTGGATGGGCATAAGTTAGAGACAACCACGTTGGATGGGCTATGTTATGCTGCTGTG

rs1248 ACGTTGGATGGAGATTGTGCATTTTGGCAAGACGTTGGATGCAGACACCATCTTAACCAAG

rs703508ACGTTGGATGAGCTCTGTGGCCTCTTTTGGACGTTGGATGTACTCACAGTCTTCCCGGCG

rs226465ACGTTGGATGAATTTTGACCCCTGCCAACCACGTTGGATGTATGTGAAAGAGGCGTGAAG

rs241448ACGTTGGATGCAAGCTGCAGAAGCTTGCCACGTTGGATGTGAGAAGAGGGCCCAGTATC

rs763155ACGTTGGATGGGGAAACCCAAAATAGTGTCACGTTGGATGTCACAGGAGAGTAATGCCTC

rs1040461ACGTTGGATGACATCTGGTGGAAGTCACTCACGTTGGATGGGTCCTTTGTTTGTTGGGTC

rs462832~ ACGTTGGATGCACTTTCTCTGTAATATTTGACGTTGGATGTGAGACAACAAAAATTTGCC
~

SNP Forward PCR primer Reverse PCR primer Reference rs804194ACGTTGGATGTAATCCGGTGGCAGATCAAGACGTTGGATGGAAATTCATGTGCTGACGGG

rs1022646ACGTTGGATGACTGTCACCTAATCATCCTGACGTTGGATGGACTATGTTGGAGTTCAGAG

rs1569112ACGTTGGATGTCATGATCTGCCTGTGGAGAACGTTGGATGACCATCCTCACACCCATCCA

rs805623ACGTTGGATGATCAACCACTCATACACTGCACGTTGGATGCACAGAAACAGCTGGATTGC

rs1019850ACGTTGGATGTTTTACTCCAGGAAGCCACCACGTTGGATGAGCAGGGAGAATTGTTCCAG

rs1599931ACGTTGGATGTCAAACCCTTCCTGTAGACGACGTTGGATGTGAACATAGTAGGCGCTCAG

AA ACGTTGGATGTAGGAGTGCTCGTATTTTGGACGTTGGATGCTGGGAACAGCTTTTGATCC

rs279941ACGTTGGATGCATAGGGAACACCGAGAATGACGTTGGATGGGTTGTCATCTATGGGCTAG

rs1062230ACGTTGGATGAAACTCCTTTCCCTCTCAAGACGTTGGATGGGCCCATCAGTCTATAGTTT

rs1859911ACGTTGGATGCTGTITfTCCGAGCATCTACACGTTGGATGCCTCTTGCATATGAGATAGG

rs1477261ACGTTGGATGCAGGGTTATGTGGTATTATCACGTTGGATGGGGAAAGTAAAAGATAAGAG

rs1191119ACGTTGGATGACTCTCAGGGTGATTATCTGACGTTGGATGTGTAAGATTCTGGCACTGTC

rs657780ACGTTGGATGTTTAAGAAGCCGCCAAGGAGACGTTGGATGCCCATTTTCAGACCACTTGG

rs1393890ACGTTGGATGGTCTGATTATCTTTCTGCCGACGTTGGATGGGTACCTTTATCCTTGCTTC

rs1478714ACGTTGGATGAATAATTTGCTGACACCCCCACGTTGGATGGGAGTCCAGAGGTTAAACAG

rs868213ACGTTGGATGTGTCAGAACTGGGCACATTCACGTTGGATGAGGGATAGGGATCAGGAATG

rs690115ACGTTGGATGAATAGCCAAGGCCGTGTGGGACGTTGGATGCACCTGGGAGATAGCAGGG

rs1465501ACGTTGGATGTCAGGAATTGTTACCTGGACACGTTGGATGCCCTCATCTAGACACTTTTG

rs899173ACGTTGGATGAGTGCCACATCACTCTTGTGACGTTGGATGTTCTGCTCCACTACAGTCTC

rs10477 ACGTTGGATGGGGGCTACGTGGAAGTTACCACGTTGGATGATGGCAATCAAGAGAGTCTAA

rs926393ACGTTGGATGAGATCAGCCCAGGAAATGTGACGTTGGATGTGTTGGAGAAGGTTTCCACC

rs465271ACGTTGGATGAATCACAGCTCATGGCTCACACGTTGGATGATGGTAGTGTGCACCTATGG

rs13847 ACGTTGGATGCGCCCGTAGTGATAAGCACACGTTGGATGCAGGACAGGGCAGAGTGAG

rs738658ACGTTGGATGGATGGTATGTGTGCATCAGGACGTTGGATGCTTTCCAAGAGATGGCGTTC

rs756519ACGTTGGATGTCTAGAGACACCTGAGGTTGACGTTGGATGTGTTTCACTTCAGAGCCCTG

rs1042327ACGTTGGATGAACTTCACATCACAGCTCCCACGTTGGATGCAGAAGTTGGGTTTTCCAGC

rs8770 ACGTTGGATGCTGTCACTGGACACTTTTGACGTTGGATGAAAATAGAGGTGCAGAGATG

rs1563055ACGTTGGATGAGTTCTTTCTCCTCACATTGACGTTGGATGCCCTTTAGAAGCACATACTC

rs912428ACGTTGGATGACTACATCCATTCCAGGGAGACGTTGGATGTCAGATCAGAGTGAGTTTAG

rs1888475ACGTTGGATGACCCCTGGCAAGTGAATTACACGTTGGATGGGGAGGTGGATGTTCTTATC

[0211] Samples were incubated at 95°C for 15 minutes, followed by 45 cycles of 95°C for 20 seconds, 56°C for 30 seconds, and 72°C for 1 minute, finishing with a 3 minute final extension at 72°C.
Following amplification, shrimp alkaline phosphatase (SAP) (0.3 units in a 2 ~l volume) (Amersham Pharmacia) was added to each reaction (total reaction volume was 7 ~1) to remove any residual dNTPs that were not consumed in the PCR step. Samples were incubated for 20 minutes at 37°C, followed by minutes at 85°C to denature the SAP.
[0212] Once the SAP reaction was complete, a primer extension reaction was initiated by adding a polymorphism-specific MassEXTENDTM primer cocktail to each sample. Each MassEXTENDTM
cocktail included a specific combination of dideoxynucleotides (ddNTPs) and deoxynucleotides (dNTPs) used to distinguish polymorphic alleles from one another. Methods for verifying, allelotyping and genotyping SNPs are disclosed, for example, in U.S. Pat. No. 6,258,538, the content of which is hereby incorporated by reference. In Table 4, ddNTPs are shown and the fourth nucleotide not shown is the dNTP.

TABLE 4: Extension Primers SNP Termination ReferenceExtend Probe Mix rs552 TGATGCTGTTGTCAGATACC ACT

rs12904 AGCCTCAAAACGGGTCA ACT

rs2282146GGACCTGGAGCCCCCACC ACG

rs734784GCCTCCGACACCCCATCAA ACG

rs1042164CTTGCTCGGGACCAGTCCA ACT

rs749670GGTGGTGGGCATCCCTTTC ACG

rs955592TTGGGCTCTGACCACCTCT ACT

rs1143016ATGCAGCGTCACCAGCAC ACT

rs755248TGAGGAAGTGGCAGGTGTG ACG

rs1055055CCCAGTTCAGGCTCACTTTC ACT

rs835409TTGCAGACCAGCCAATTAAGAA ACT

rs927663GGTTGCCCCAAACTCCCTT ACT

rs8162 AACACAGAGCAAAGCACC ACT

rs831038CGTTATAGTAAAGGAAAGGCAG ACG

rs33079 CCCATCACCTGGAGCTTTG ACG

rs1710880CTGTATTATGTTTCCCCTTGG CGT

rs1078153GCCGGCACCGTCAGAAAC CGT

rs799570GCAGTTCCTAGAAGACAGCT ACT

rs1282730TGCTGGCCCAACTTTTGTCT ACG

rs1518875CTGCAATGTTTCCAAACCCC ACT

rs1568694AGTTATGGACGGAAGAAGGG ACG

rs905042GGTAAGGGCCAAGTGAGTG CGT

rs1957723AGCATGGCATAGGCACTGG ACG

rs794018AAATGACTGAAAATGTGTACTATA ACG

rs707723CCTGAGGTATATTCAATA ACG

rs893861CATGTACACAAAACTGTTAAGTAA ACG

rs1914903TCCCCATAGATGGACCTGC ACG

rs2062232GCTGAAGACAAGGATTAGGTT ACG

rs26609 GAGATCAGAAACATCACCTTG CGT

rs1370987TTTGGGAGTTACTGCCTTAGAA ACT

rs1012414ACTAGGAACCAGAATATGAGCATC ACG

rs435903AAGCTAACAATGGAATAATGGC ACG

rs1248 GTGCATTTTGGCAAGAATATATG CGT

rs703508GGGGTCCAGGCAGAAAGAAAC ACG

rs226465CCTCTTCCCCTCCTCCCT ACT

rs241448GCAGAAGCTTGCCCAGCTC ACG

rs763155GCAGCCTGCAAGTGAGTGA ACT

rs 1040461AAGTCACTCCGGTCAGAATTCA ACT

rs462832ATAAGAATCTTTTAGATCCCAACA CGT

rs804194GATCAAGGCTGATCTCGCC ACT

rs1022646CCTAATCATCCTGCCACCC ACT

rs1569112ACCAGGCCGCATGGGCTG ACG

rs805623CTGTGTTCAAATAAGGCAACC ACT

rs1019850AGGAAGCCACCAGCTAATAC CGT

rs1599931CTGAGGCCGGGAGGGATT ACT

AA TAGTTTTAAATTCTGCACA ACT

rs279941AACACCGAGAATGAAAACATC ACT

rs1062230ATGCTGGTTCTGTCCAA ACG

rs1859911TCCGAGCATCTACATGCTCA ACT

rs1477261AGGAGGAGCCCAAATATGAAA CGT

rs1191119GTCTTTTTGTTAACTGGGGAACCC ACG

rs657780CGCCAAGGAGTTTCCCACA ACT

rs1393890CTGCCGTACCTGGCAAGC ACT

rs147871~CCCCGAGGGGACAGTCCA ~ ACG

SNP Extend Probe Termination Reference Mix rs868213GGGCACATTCTTGAGGAGGT ACG

rs690115AGCCGAGGGAGCTGACCCTG ACG

rs1465501TCCAGGAGCCCTCAGAATG ACT

rs899173CCTCTGGCAAAGTGTGGAGC ACG

rs10477 AGTACGATATCAAAGATC ACG

rs926393CAGGAAATGTGCTTTCGAGTTCC ACG

rs465271GGCTCAAGGGATCCTCCCA ACG

rs13847 AAGCACACCGGCACGAAC ACT

rs738658GAGGCATTTTCATTAATGCATG CGT

rs756519CAGAGCCCTGTTCTTTGATTT ACG

rs1042327CATCACAGCTCCCCACCAT ACT

rs8770 TAGACACTGTGTAAGCAATC ACG

rs 1563055TTCTCCTCACATTGTTTCTACT ACG

rs912428CCATTCCAGGGAGACTCCCA ACT

rs1888475GACATCAAATGATTCCCCTGT ~ ACT

[0213] The MassEXTENDTM reaction was performed in a total volume of 9 ~,1, with the addition of 1X ThermoSequenase buffer, 0.576 units of ThermoSequenase (Amersham Pharmacia), 600 nM
MassEXTENDTM primer, 2 mM of ddATP and/or ddCTP and/or ddGTP and/or ddTTP, and 2 mM of dATP or dCTP or dGTP or dTTP. The deoxy nucleotide (dNTP) used in the assay normally was complementary to the nucleotide at the polymorphic site in the amplicon.
Samples were incubated at 94°C for 2 minutes, followed by 55 cycles of 5 seconds at 94°C, 5 seconds at 52°C, and 5 seconds at 72°C.
[0214] Following incubation, samples were desalted by adding 16 ~1 of water (total reaction volume was 25 ~l), 3 mg of SpectroCLEANTM sample cleaning beads (Sequenom, Inc.) and allowed to incubate for 3 minutes with rotation. Samples were then robotically dispensed using a piezoelectric dispensing device (SpectroJETTM (Sequenom, Inc.)) onto either 96-spot or 384-spot silicon chips containing a matrix that crystallized each sample (SpectroCHIPTM (Sequenom, Inc.)). Subsequently, MALDI-TOF mass spectrometry (Biflex and Autoflex MALDI-TOF mass spectrometers (Bruker Daltonics) can be used) and SpectroTYPER RTTM software (Sequenom, Inc.) were used to analyze and interpret the SNP genotype for each sample.
Genetic Anal [0215] Minor allelic frequencies for the polymorphisms set forth in Table A
were verified as being 10% or greater using the extension assay described above in a group of samples isolated from 92 individuals originating from the state of Utah in the United States, Venezuela and France (Coriell cell repositories).
[0216] Genotyping results are shown for female pools in Table 5. In Table 5, "AF" refers to allelic frequency; and "F case" and "F control" refer to female case and female control groups, respectively.

TABLE 5: Genotyping Results SNP Reference p-~alue F c se F control A=0.190 A=0.123 rs552 G = 0.810 G = 0.877 0.0011 A = 0.455 A = 0.375 rs12904 G = 0,545 G = 0.625 0.0012 C = 0.906 C = 0.939 rs2282146 T = 0.094 T = 0.061 0.0105 G=0.483 G=0.416 rs734784 A = 0.517 A = 0.584 0.0052 T=0.233 T=0.159 rs1042164 C = 0.767 C = 0.841 0.0002 C=0.342 C=0.419 rs749670 T = 0.658 T = 0.581 0.0038 T = 0.045 T = 0.076 rs955592 C = 0.955 ' C = 0.924 0.0177 T = 0.093 T = 0.054 rs1143016 C = 0.907 C = 0.946 0.0071 G=0.146 G=0.069 rs755248 A = 0.854 A = 0.931 0.0000 A = 0.432 A = 0.355 rs 1055055 G = 0.568 G = 0.645 0.0046 T=0.620 T=0.681 rs835409 G = 0.380 G = 0.319 0.0222 T=0.301 T=0.358 rs927663 G = 0.699 G = 0.642 0.0289 A=0.591 A=0.657 rs8162 G = 0.409 G = 0.343 0.0149 C=0.617 C=0.666 rs831038 T = 0.383 T = 0.334 0.0359 G=0.823 G=0.881 rs33079 A = 0.177 A = 0.119 0.0013 C=0.303 C=0.371 rs1710880 A = 0.697 A = 0.629 0.0129 T=0.818 T=0.875 rs1078153 A = 0.182 A = 0.125 0.0039 A=0.675 A=0.740 rs799570 G = 0.325 G = 0.260 0.0100 G=0.086 G=0.127 rs1282730 A = 0.914 A = 0.873 0.0150 T = 0.033 T = 0.055 rs1518875 C = 0.967 C = 0.945 0.0508 G=0.045 G=0.081 rs1568694 A = 0.955 A = 0.919 0.0064 A = 0.832 A = 0.769 rs905042 T = 0.168 T = 0.231 0.0047 G = 0.778 G = 0.839 rs1957723 A = 0.222 A = 0.161 0.0048 G = 0.273 G = 0.220 rs794018 A = 0.727 A = 0.780 0.0034 C=0.759 C=0.811 rs707723 T = 0.241 T = 0.189 0.0195 G=0.246 G=0.196 rs893861 A = 0.754 A = 0.804 0.0251 G=0.861 G=0.910 rs1914903 A = 0.139 A = 0.090 0.0055 C=0.064 C=0.117 rs2062232 T = 0.936 T = 0.883 0.0012 A = 0.777 A = 0.840 rs26609 T = 0.223 T = 0.160 0.0039 A=0.422 A=0.341 rs1370987 G = 0.578 G = 0.659 0.0007 G=0.876 G=0.833 rs1012414 A = 0.124 A = 0.167 0.0289 rs435903 G = 0.766 G = 0.685 0.0013 SNP ReferenceF case F co trol p-value A=0.234 A=0.315 T = 0.668 T = 0.593 rs1248 A = 0.332 A = 0.407 0.0014 G=0.875 G=0.910 rs703508 A = 0.125 A = 0.090 0.0375 G=0.094 G=0.129 rs226465 C = 0.906 C = 0.871 0.0454 C=0.294 C=0.212 rs241448 T = 0.706 T = 0.788 0.0010 A=0.160 A=0.114 rs763155 C = 0.840 C = 0.886 0.0140 T = 0.069 T = 0.098 rs1040461 C = 0.931 C = 0.902 0.0281 A=0.218 A=0.145 rs462832 T = 0.782 T = 0.855 0.0008 T=0.583 T=0.679 rs804194 C = 0.417 C = 0.321 0.0004 A=0.169 A=0.103 rs1022646 G = 0.831 G = 0.897 0.0007 G=0.853 G=0.812 rs1569112 A = 0.147 A = 0.188 0.0468 A=0.097 A=0.140 rs805623 G = 0.903 G = 0.860 0.0143 A = 0.330 A = 0.240 rs 1019850 T = 0.670 T = 0.760 0.0005 A = 0.581 A = 0.659 rs1599931 G = 0.419 G = 0.341 0.0037 A = 0.506 A = 0.577 AA G = 0.494 G = 0.423 0.0102 T=0.100 T=0.138 rs279941 G = 0.900 G = 0.862 0.0324 C=0.778 C=0.717 rs1062230 T = 0.222 T = 0.283 0.0109 T = 0.295 T = 0.243 rs1859911 C = 0.705 C = 0.757 0.0328 T=0.861 T=0.809 rs1477261 A = 0.139 A = 0.191 0.0105 G=0.121 G=0.078 rs1191119 A = 0.879 A = 0.922 0.0079 A = 0.674 A = 0.583 rs657780 G = 0.326 G = 0.417 0.0009 G = 0.639 G = 0.724 rs1393890 C = 0.361 C = 0.276 0.0014 G=0.331 G=0.269 rs 1478714 A = 0.669 A = 0.731 0.0136 C=0.078 C=0.044 rs868213 T = 0.922 T = 0.956 0.0083 G = 0.839 G = 0.784 rs690115 A = 0.161 A = 0.216 0.0111 A = 0.846 A = 0.903 rs1465501 G = 0.154 G = 0.097 0.0020 C = 0.895 C = 0.858 rs899173 T = 0.105 T = 0.142 0.0408 C=0.087 C=0.146 rs 10477 T = 0.913 T = 0.854 0.0010 C=0.715 C=0.647 rs926393 T = 0.285 T = 0.353 0.0082 C=0.194 C=0.130 rs465271 T = 0.806 T = 0.870 0.0019 A=0.111 A=0.163 rs13847 G = 0.889 G = 0.837 0.0056 C = 0.898 C = 0.855 rs738658 A = 0.102 A = 0.145 0.0183 rs756519 C = 0.581 C = 0.656 0.0055 T=0.419 T=0.344 SNP Reference p-~alue F c se F control rs1042327 T = 0.472 T = 0.563 0 C=0.528 C=0.437 .

rs8770 C = 0.529 C = 0.432 0 T = 0.471 T = 0.568 .

rs1563055 C = 0.653 C = 0.736 0 T = 0.347 T = 0.264 .

rs912428 T = 0.228 T = 0.170 0076 C=0.772 C=0.830 .

rs1888475 A = 0.188 A = 0.135 0 G=0.812 G=0.865 .

[0217] All of the single marker alleles set forth in Table A were considered validated, since the genotyping data agreed with the allelotyping data and each SNP significantly associated with osteoarthritis. Particularly significant associations with osteoarthritis are indicated by a calculated p-value of less than 0.05 for genotype results.
Example 3 Association of Pol,~phic Variants with Osteoarthritis in Replication Cohorts [0218] The single marker polymorphisms set forth in Table A were genotyped again in two replication cohorts consisting of individuals selected for OA.
Sample Selection and Poolin S~gies - Replication Sample 1 [0219] A second case control sample (replication sample #1) was created by using 100 Caucasian female cases from Chingford, UK, and 148 unrelated female cases from the St.
Thomas twin study.
Cases were defined as having I~ellgren-Lawrence (KL) scores of at least 2 in at least one knee x-ray. In addition, 199 male knee replacement cases from Nottingham were included. (For a cohort description, see the Nottingham description provided in Example 1). The control pool was made up of unrelated female individuals from the St. Thomas twin study (England) with normal knee x-rays and without other indications of OA, regardless of anatomical location, as well as lacking family history of OA. The St. Thomas twin study consists of Caucasian, female participants from the St.
Thomas' Hospital, London, adult-twin registry, which is a voluntary registry of >4,000 twin pairs ranging from 18 to 76 years of age. The replication sample 1 cohort was used to replicate the initial results. Table 6 below summarizes the selected phenotype data collected from the case and conh~ol individuals.

Phenotype Female cases (n=248):Male cases (n=199):Female controls median (range)! median (range)/ (n=313):
(n,%) (n,%) mean (range)/ (n,%) Age 59 (39- 73) 66 (45- 73) 55 (50- 72) Height (cm) 162 (141- 178) 175 (152- 198) 162 (141- 176) Weight (kg) 68 (51- 123) 86 (62- 127) 64 (40- 111) Body mass 26 (18- 44) 29 (21- 41 ) 24 (18- 46) index Phenotype Female cases (n=248):Male cases (n=199):Female controls (n=313):

median (range)/ median (range)/mean (range)/ (n,%) (n,%) (n,%) (kg/m') Kellgren- 0 (63, 26%), 1 (20, 8%), 2 Lawrence* (105, 43%), 3 (58,NA NA
left 23%), 4 knee (1, 0%) Kellgren- 0 (43, 7%), 1 (18, 7%), 2 Lawrence* (127, 52%), 3 (57,NA NA
right 23%), 4 knee (1, 0%) KL* >2 both No (145, 59%), NA NA
Yes (101, knees 41 %) KL* >2 eitherNo (0, 0%), Yes NA NA
(248, 100%) knee * 0: normal, 1: doubtful, 2: definite osteophyte (bony protuberance), 3: joint space narrowing (with or without osteophyte), 4: joint deformity Sample Selection and Pooling Strategies - Replication Sample 2 [0220] A third case control sample (replication sample #2) was created by using individuals with symptoms of OA from Newfoundland, Canada. These individuals were recruited and examined by rheumatologists. Affected joints were x-rayed and a final diagnosis of definite or probable OA was made according to American College of Rheumatology criteria by a single rheumatologist to avoid any inter-examiner diagnosis variability. Controls were recruited from volunteers without any symptoms from the musculoskeletal system based on a normal joint exam performed by a rheumatologist. Only cases with a diagnosis of definite OA were included in the study. Only individuals of Caucasian origin were included. The cases consisted of 228 individuals with definite knee OA, 106 individuals with definite hip OA, and 74 individuals with hip OA.

Phenotype Case Control Age at Visit 62.7 52.5 Sex (Female/Male) 227/119 174/101 Knee OA Xray: No 35% (120) 80% (16) Unknown 1 % (4) 0% (0) Yes 64% (221 ) 20% (4) Hip OA Xray: No 63% (215) 80% (16) Unknown ( ) 0 / 0 ( ) Yes 35% (121) 20% (4) Assay for Veri ins, Allelotypin~, and Genotyping SNPs [0221] Genotyping of the replication cohorts described in Tables 6 and 7 was performed using the same methods used for the original genotyping, as described herein. A
MassARRAYTM system (Sequenom, Inc.) was utilized to perform SNP genotyping in a high-throughput fashion. This genotyping platform was complemented by a homogeneous, single-tube assay method (hMETM or homogeneous MassEXTENDTM (Sequenom, Inc.)) in which two genotyping primers anneal to and amplify a genomic target surrounding a polymorphic site of interest. A third primer (the MassEXTENDTM primer), which is complementary to the amplified target up to but not including the polymorphism, was then enzymatically extended one or a few bases through the polymorphic site and then terminated.
[0222] For each polymorphism, SpectroDESIGNERTM software (Sequenom, Inc.) was used to generate a set of PCR primers and a MassEXTENDTM primer which where used to genotype the polymorphism. Other primer design software could be used or one of ordinary skill in the art could manually design primers based on his or her knowledge of the relevant factors and considerations in designing such primers. Table 3 shows PCR primers and Table 4 shows extension probes used for analyzing (e.g., genotyping) polymorphisms in the replication cohorts. The initial PCR amplification reaction was performed in a 5 p1 total volume containing 1X PCR buffer with 1.5 mM MgCl2 (Qiagen), 200 pM each of dATP, dGTP, dCTP, dTTP (Gibco-BRL), 2.5 ng of genomic DNA, 0.1 units of HotStar DNA polymerase (Qiagen), and 200 nM each of forward and reverse PCR primers specific for the polymorphic region of interest.
[0223] Samples were incubated at 95°C for 15 minutes, followed by 45 cycles of 95°C for 20 seconds, 56°C for 30 seconds, and 72°C for 1 minute, finishing with a 3 minute final extension at 72°C.
Following amplification, shrimp alkaline phosphatase (SAP) (0.3 units in a 2 p.1 volume) (Amersham Pharmacia) was added to each reaction (total reaction volume was 7 p,1) to remove any residual dNTPs that were not consumed in the PCR step. Samples were incubated for 20 minutes at 37°C, followed by minutes at 85°C to denature the SAP.
[0224] Once the SAP reaction was complete, a primer extension reaction was initiated by adding a polymorphism-specific MassEXTENDTM primer cocktail to each sample. Each MassEXTENDTM
cocktail included a specific combination of dideoxynucleotides (ddNTPs) and deoxynucleotides (dNTPs) used to distinguish polymorphic alleles from one another. Methods for verifying, allelotyping and genotyping SNPs are disclosed, for example, in U.S. Pat. No. 6,258,538, the content of which is hereby incorporated by reference. In Table 7, ddNTPs are shown and the fourth nucleotide not shown is the dNTP.
[0225] The MassEXTENDTM reaction was performed in a total volume of 9 p,1, with the addition of 1X ThermoSequenase buffer, 0.576 units of ThermoSequenase (Amersham Pharmacia), 600 nM
MassEXTENDTM primer, 2 mM of ddATP and/or ddCTP and/or ddGTP and/or ddTTP, and 2 mM of dATP or dCTP or dGTP or dTTP. The deoxy nucleotide (dNTP) used in the assay normally was complementary to the nucleotide at the polymorphic site in the amplicon.
Samples were incubated at 94°C for 2 minutes, followed by 55 cycles of 5 seconds at 94°C, 5 seconds at 52°C, and 5 seconds at 72°C.

[0226] Following incubation, samples were desalted by adding 16 p,1 of water (total reaction volume was 25 p.1), 3 mg of SpectroCLEANTM sample cleaning beads (Sequenom, Inc.) and allowed to incubate for 3 minutes with rotation. Samples were then robotically dispensed using a piezoelectric dispensing device (SpectroJETTM (Sequenom, Inc.)) onto either 96-spot or 384-spot silicon chips containing a matrix that crystallized each sample (SpectroCHl1'TM (Sequenom, Inc.)). Subsequently, MALDI-TOF mass spectrometry (Biflex and Autoflex MALDI-TOF mass spectrometers (Bruker Daltonics) can be used) and SpectroTYPER RTTM software (Sequenom, Inc.) were used to analyze and interpret the SNP genotype for each sample.
Genetic Analysis [0227] Genotyping results for replication cohorts #1 and #2 are provided in Tables 8 and 9, respectively.

Replication Meta-analysis rslD #1 Disc. + Rep (Mixed #1 MaleIFemale P-value cases and Female controls) AF OA Con AF OA
Cas Delta P-value rs552 0.87 0.85 0.02 0.344 0.0300 rs12904 0.57 0.57 0.00 0.936 0.2700 rs22821460.08 0.1 -0.020.342 0.0190 rs734784 0.52 0.54 -0.020.451 0.7200 rs10421640.79 0.82 -0.030.161 0.9100 rs749670 0.62 0.66 -0.040.173 0.0019 rs955592 0.93 0.94 -0.010.521 0.0600 rs11430160.93 0.93 0.00 0.869 NA

rs755248 0.9 0.89 0.01 0.544 0.1600 rs10550550.64 0.64 0.00 0.947 0.3300 rs835409 0.34 0.35 -0.010.715 0.1300 rs927663 0.64 0.65 -0.010.611 0.0690 rs831038 0.35 0.37 -0.020.399 NA

rs33079 0.14 0.14 0.00 0.995 0.3100 rs17108800.66 0.62 0.04 0.087 0.9000 rs799570 0.29 0.29 0.00 0.903 0.2500 rs12827300.88 0.87 0.01 0.751 0.4800 rs15686940.93 0.94 0.00 0.928 0.2600 rs905042 0.21 0.2 0.01 0.829 0.2200 rs19577230.13 0.16 -0.030.124 0.0009 rs794018 0.74 0.72 0.02 0.518 0.0710 rs707723 0.18 0.19 -0.010.658 0.0650 rs19149030.15 0.14 0.01 0.605 0.5500 rs20622320.91 0.91 0.00 0.788 0.2100 rs26609 0.16 0.19 -0.020.226 0.0032 rs13709870.63 0.63 -0.010.857 0.3900 rs10124140.12 0.13 -0.010.669 0.5600 rs435903 0.27 0.27 0.00 0.950 0.2800 rs 1248 0.36 0.36 0.00 0.917 0.2400 ~

Replication Meta-analysis rslD #1 Disc. + Rep (Mixed #1 MaleIFemale P-value cases and Female controls) AF OA
Con AF
OA Cas Delta P-value rs703508 0.11 0.12 -0.010.558 0.0660 rs226465 0.87 0.88 -0.010.436 0.0500 rs241448 0.74 0.75 -0.010.805 0.4100 rs763155 0.86 0.88 -0.020.273 0.8800 rs1040461 0.92 0.92 0.00 0.826 NA

rs1022646 0.85 0.87 -0.020.219 0.8200 rs1569112 0.16 0.18 -0.020.402 0.8800 rs805623 0.87 0.88 -0.010.460 0.0370 rs1019850 0.69 0.7 0.00 0.890 0.3700 AA 0.47 0.48 -0.010.681 0.1200 rs279941 0.87 0.89 -0.010.400 0.0340 rs1062230 0.26 0.26 0.00 0.896 0.4200 rs1859911 0.71 0.75 -0.040.128 0.9000 rs1477261 0.16 0.16 0.00 0.986 0.3000 rs 11911190.89 0.88 0.01 0.569 0.1200 rs1393890 0.29 0.31 -0.020.527 0.1400 rs1478714 0.69 0.67 0.03 0.300 0.0140 rs868213 0.92 0.93 -0.010.455 0.7000 rs690115 0.2 0.21 -0.010.729 0.4900 rs1465501 0.11 0.1 0.01 0.718 0.5600 rs899173 0.1 0.11 0.00 0.924 0.3300 rs10477 0.89 0.88 0.01 0.691 0.4700 rs926393 0.3 0.31 -0.010.830 0.4200 rs465271 0.86 0.85 0.01 0.516 0.0660 rs13847 0.86 0.85 0.01 0.547 0.5900 rs738658 0.14 0.15 -0.010.536 0.6700 rs756519 0.4 0.43 -0.040.140 0.0098 rs1042327 0.49 0.52 -0.030.234 0.0430 rs8770 0.51 0.48 0.03 0.303 0.0480 rs1563055 0.31 0.35 -0.040.083 0.0002 rs912428 0.86 0.8 0.06 0.004 0.00001 rs1888475 0.86 0.81 _ 0.032 0.0002 I
0.04 Replication Meta-analysis rslD #2 (Newfoundland) Disc. + Rep (MaleIFemale #2 cases Not Done and controls) AF OA Con AF OA
Cas Delta P-value rs552 0.85 0.86 -0.0140.496 rs12904 0.58 0.57 0.011 0.719 rs22821460.08 0.08 0.002 0.876 rs734784 0.53 0.54 -0.0030.907 rs10421640.83 0.80 0.026 0.248 rs749670 0.66 0.62 0.036 0.208 rs955592 0.95 0.92 0.033 0.027 rs 11430160.96 0.94 0.015 0.236 rs755248 0.89 0.90 -0.0090.608 Replication Meta-analysis rslD #2 (Newfoundland) Disc. + Rep (MaleIFemale #2 cases Not Done and controls) AF OA
Con AF
OA Cas Delta P-value rs 10550550.64 0.61 0.034 0.249 rs835409 0.36 0.31 0.047 0.101 rs927663 0.67 0.68 -0.013Ø631 rs831038 0.34 0.35 -0.0140.612 rs33079 0.17 0.19 -0.0190.417 rs1710880 0.64 0.62 0.029 0.309 rs799570 0.35 0.30 0.058 0.033 rs1282730 0.89 0.89 -0.0010.982 rs1568694 0.95 0.94 0.009 0.518 rs905042 0.19 0.20 -0.0020.933 rs1957723 0.18 0.20 -0.0170.454 rs794018 0.73 0.72 0.015 0.586 rs707723 0.20 0.21 -0.0070.759 rs1914903 0.14 0.16 -0.0220.285 rs2062232 0.92 0.91 0.008 0.632 rs26609 0.19 0.18 0.005 0.827 rs1370987 0.59 0.61 -0.0230.423 rs 10124140.15 0.14 0.008 0.679 rs435903 0.24 0.26 -0.0260.316 rs1248 0.33 0.38 -0.0510.078 rs703508 0.10 0.11 -0.0020.916 rs226465 0.89 0.89 -0.0070.699 rs241448 0.76 0.77 -0.0070.778 rs763155 0.89 0.84 0.049 0.016 rs 10404610.91 0.91 0.001 0.948 rs1022646 0.86 0.86 -0.0010.974 rs1569112 0.16 0.17 -0.0160.446 rs805623 0.89 0.87 0.022 0.256 rs1019850 0.71 0.69 0.026 0.341 AA 0.48 0.44 0.035 0.234 rs279941 0.91 0.87 0.037 0.047 rs1062230 0.23 0.22 0.011 0.653 rs1859911 0.72 0.71 0.015 0.560 rs1477261 0.17 0.14 0.031 0.143 rs1191119 0.86 0.88 -0.0170.377 rs1393890 0.30 0.28 0.017 0.516 rs1478714 0.68 0.70 -0.0250.358 rs868213 0.91 0.93 -0.0190.260 rs690115 0.19 0.18 0.005 0.811 rs1465501 0.10 0.12 -0.0200.282 rs899173 0.14 0.12 0.020 0.319 rs10477 0.86 0.88 -0.0160.442 rs926393 0.37 0.32 0.042 0.137 rs465271 0.87 0.85 0.023 0.263 rs13847 0.84 0.85 -0.0120.582 rs738658 0.18 0.15 0.021 0.340 rs756519 0.39 0.40 -0.0070.816 rs1042327 0.49 0.51 -0.0240.405 rs8770 0.53 I 0.49 0.039 0.195 Replication Meta-analysis rslD #2 (Newfoundland) Disc. + Rep (MaleIFemale #2 cases Not Done and controls) AF OA Con AF OA
Cas Delta P-value rs15630550.34 0.34 -0.0050.864 rs912428 0._82 0.76 0.058 0.016 - -.

~ ~ _ -0.0250.280 rs1888475x.80 0.82 I

[0228] To combine the evidence for association from multiple sample collections, a meta-analysis procedure was employed. The allele frequencies were compared between cases and controls within the discovery sample, as well as within the replication cohort #1 using the DerSimian-Laird approach (DerSimonian, R. and N. Laird. 1986. Meta-analysis in clinical trials. Control Clin Trials 7: 177-188.) [0229] The absence of a statistically significant association in one or more of the replication cohorts should not be interpreted as minimizing the value of the original fording. There are many reasons why a biologically derived association identified in a sample from one population would not replicate in a sample from another population. The most important reason is differences in population history. Due to bottlenecks and founder effects, there may be common disease predisposing alleles present in one population that are relatively rare in another, leading to a lack of association in the candidate region. Also, because common diseases such as arthritis-related disorders are the result of susceptibilities in many genes and many environmental risk factors, differences in population-specific genetic and environmental backgrounds could mask the effects of a biologically relevant allele. For these and other reasons, statistically strong results in the original, discovery sample that did not replicate in one or more of the replication samples may be further evaluated in additional replication cohorts and experimental systems.
Example 4 KIAA0296 Reeion Proximal SNPs [0230] SNP rs749670 is associated with osteoarthritis and is described in Table A. It lies within the KIAA0296 gene and codes for a G327E amino acid change. The thymine allele of SNP rs749670 is associated with osteoarthritis (see Table 5) and codes for glutamic acid.
KIAA0296 shares homology with C2H2-type Zn-finger protein and is likely a novel transcription factor.
One-hundred one additional allelic variants proximal to rs749670 were identified and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 10. The chromosome positions provided in column four of Table 10 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position ChromosomeAllele Chromosomein SEQ

rs# ID NO: Position Variants rs750017616 247 31077197 a/

rs656521216 1535 31078485 c/t dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants 1D NO:

rs805404616 2386 3107933_6 c/t rs805684216 6440 3108339 c/t rs73217316 9133 _ It rs73217216 9143 31086093 a/

rs718855716 9471 3108642 alt rs228800416 13150 _ c/

rs433731016 13717 31090667 c/t rs201655416 14466 31091416 al rs656521316 15769 31092719 a/c rs720476216 16870 31093820 a/

rs488952916 18545 31095495 clt rs656521416 18749 31095699 c/t rs749967416 19123 31096073 /t rs656521516 20736 31097686 al rs102362316 21038 31097988 c/t rs102362416 21046 31097996 c/t rs102362516 21050 31098000 c/t rs154929716 21056 31098006 alt rs308489416 21706 31098656 -/acc rs804822816 23170 31100120 a/

rs740543216 25028 31101978 a/t rs805424916 27871 31104821 a/

rs806104716 28070 31105020 c/t rs718722016 31717 31108667 a/

rs804697816 32019 31108969 a/

rs228800316 32318 31109268 a/

rs719642116 33080 31110030 a/

rs719643116 33101 31110051 a/

rs720315816 34236 31111186 a/

rs230322316 34285 31111235 c/t rs203291716 34818 31111768 c/

rs804413416 35168 31112118 c/

rs488953116 37981 31114931 c/t rs488953216 38113 31115063 c/

rs488953316 38117 31115067 c/t rs88192916 38481 31115431 /t rs804710416 38615 31115565 c/

rs804780316 38944 31115894 a/c rs464487416 39288 31116238 a/c rs235967316 41385 31118335 c/t rs443527116 42136 31119086 a/t rs719771716 42185 31119135 a/c rs235967416 42353 31119303 a/

rs656521716 42434 31119384 a/

rs230322216 44580 31121530 a/

rs488961516 44675 31121625 alt rs462419716 45739 31122689 /t rs375185316 46439 31123389 c/t rs74967116 47457 31124407 c/t rs74967016 47735 31124685 c/t rs375185516 50319 31127269 clt rs375185616 50708 31127658 a/

dbSNP ChromosomePosition ChromosomeAllele rs# in SEQ Position Variants ID NO:

rs719672616 51185 31128135 a/

rs88955016 53002 31129952 a/

rs75095216 53064 31130014 c/t rs207763316 53637 31130587 a/

rs719994916 55274 31132224 c/

rs203291616 55825 31132775 c/t rs446864116 55986 31132936 a/c rs488953516 56684 31133634 c/

rs431677516 57653 31134603 c/t rs431381916 57659 31134609 c/

rs656521816 57692 31134642 /t rs431822416 57775 31134725 c/t rs104603016 61313 31138263 clt rs7294 16 61431 31138381 a/

rs720074916 61699 31138649 al rs235961216 62906 31139856 a/

rs805089416 63619 31140569 c/

rs288473716 64664 31141614 a/c rs189551416 68452 31145402 /t rs806020916 69665 31146615 c/t rs806021716 69681 31146631 c/t rs719616116 70091 31147041 a/

rs806233616 74637 31151587 a/

rs804377816 74760 31151710 a/

rs203291516 76523 31153473 a/

rs488961616 78559 31155509 c/

rs104556416 79549 31156499 a/c rs230322116 79882 31156832 c/t rs154929616 81339 31158289 a/

rs88955516 81681 31158631 c/t rs581652116 81696 31158646 -/

rs74976716 83517 31160467 c/t rs288473816 85431 31162381 a/c rs205258116 86332 31163282 c/t rs488961716 87358 31164308 a/

rs488961916 87725 31164675 c/t rs197848716 89052 31166002 a/

rs197848616 90020 31166970 a/

rs197848516 90231 31167181 al rs488962016 90284 31167234 a/

rs488962116 90447 31167397 c/t rs321447716 90601 31167551 -!

rs452703416 90724 31167674 a/

rs106050616 92559 31169509 c/t rs720012516 95176 31172126 a/

rs656521916 95195 31172145 c/t rs88954816 96822 31173772 a/

Assay for Verifying and Allelotypin~NPs [0231] The methods used to verify and allelotype the 101 proximal SNPs of Table 10 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 11 and Table 12, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs7500176ACGTTGGATGACAGTGGCTCATGCCTGTAAACGTTGGATGTTTCACCATATTGGCCAGGC

rs6565212ACGTTGGATGTTAGGAAGGATGTGGAAGGGACGTTGGATGGACCTGACCTCAAAGAGAAG

rs8054046ACGTTGGATGCACTGAAGTTTAGAGCAGCCACGTTGGATGTGCACAGTGGGTAACTGTAG

rs8056842ACGTTGGATGATGAGGTTTCACCTTGTTGGACGTTGGATGATCATAGCACTTTGCGAGGC

rs732173ACGTTGGATGAGACCAGGCTCAGTCCAAACACGTTGGATGTGGCCAAACCTGGAAGACAC

rs732172ACGTTGGATGCTCAGTCCAAACTGCCAGACACGTTGGATGCATGGCCAAACCTGGAAGAC

rs7188557ACGTTGGATGAACATCTGTACAAGGCTGGGACGTTGGATGATTGGCTGTAGCATGACTGA

rs2288004ACGTTGGATGAAAGACACTGGAAGGCTGTGACGTTGGATGAGAGAAGGTGGAGCTCTTTC

rs4337310ACGTTGGATGAGGGAAGAGATGTACACAGGACGTTGGATGTTTGGAGCAGATCTGGTAGG

rs2016554ACGTTGGATGAAGCAATCCTCCCACCTCAGACGTTGGATGCAAGAGCAAAACTCCCTCTC

rs6565213ACGTTGGATGAGATGGAGTCTCACTCCATCACGTTGGATGTGAGGCAGGAGAATCGCTTG

rs7204762ACGTTGGATGAGTGGCTCACACCTGTAATCACGTTGGATGGCTGGTCTTGAACTTCTGAC

rs4889529ACGTTGGATGCAAGCAATCCTTGCCTCAAGACGTTGGATGGGTGGTTCACATCTGCAATC

rs6565214ACGTTGGATGTGATCTCGGCTCACTGCAAGACGTTGGATGAAAATTAGCCGGGCATGGTG

rs7499674ACGTTGGATGAACTAGGGAACTCTTCCCACACGTTGGATGTGGGCCCCACTAAGTCTAAA

rs6565215ACGTTGGATGAGACGGAAAGTTCCAGCTTGACGTTGGATGTGGGACCACTCTGTTCTATG

rs1023623ACGTTGGATGACAGAGCAAGACTCCATCTCACGTTGGATGTCCTCTTCAGAGCTGTTCAC

rs1023624ACGTTGGATGTGACAGAGCAAGACTCCATCACGTTGGATGGTCCTAACCAGTGAGCCTAT

rs1023625ACGTTGGATGTGGTGACAGAGCAAGACTCCACGTTGGATGTCAGGTCCTAACCAGTGAGC

rs1549297ACGTTGGATGTTGCATTGATCCGAGATCGCACGTTGGATGTCAGGTCCTAACCAGTGAGC

rs3084894ACGTTGGATGTCCCAGGTTCAAGCGATTCTACGTTGGATGCCATGAAACCCCATCTCTAC

rs8048228ACGTTGGATGAATTGCTTGAACCTGGGAGGACGTTGGATGTTCGACAGTCTCCCTCTATC

rs7405432ACGTTGGATGAGATCATGCCACTGCACTACACGTTGGATGCACTGCACTTGGCCTAATTG

rs8054249ACGTTGGATGATCTCCTGACCTCATGATCTACGTTGGATGTAATCAAACACCAGGCTGGG

rs8061047ACGTTGGATGATGATCACAGCTCACTGCAGACGTTGGATGCTCCCTGCCTCTACAAAAAG

rs7187220ACGTTGGATGAAGGAGACCTTCTCCACAATACGTTGGATGCCGGTCAGAGAAGCTCTTGC

rs8046978ACGTTGGATGTGCACAGGAGCTGGTGGTGACGTTGGATGATCACACCACCTGACTCCGG

rs2288003ACGTTGGATGACCGGCCGTTCAAGTGCCTGACGTTGGATGAGAGTGCACCAGCGCGTGC

rs7196421ACGTTGGATGTTCACGCCATTCTCCTGCCTACGTTGGATGAAATTAGCCAGGCGTGGTGG

rs7196431ACGTTGGATGAGATCTCGGCTCACTGCAAGACGTTGGATGATGTAGTCCCAGCTACTCGG

rs7203158ACGTTGGATGAAGCCTATGCGGAGCTCAAGACGTTGGATGATTGGCTGCAGCAACGCTGT

rs2303223ACGTTGGATGACCCTCACCGCTCATGGTTGACGTTGGATGTGCGGCCCTACAGCTGTGA

rs2032917ACGTTGGATGCCTGGGCGCGTTTGGAAATGACGTTGGATGAGCCCCCGGCTACAAGCGCT

rs8044134ACGTTGGATGACTAAGAAAGGAGGCTGAGGACGTTGGATGACAGTGTTTGGAAAAGCCCG

rs4889531ACGTTGGATGATTCCTCACCCAACTCTGTCACGTTGGATGGACCGTGTGTAATGTACTGC

rs4889532ACGTTGGATGGGGACAAGAATCCCTATCTCACGTTGGATGTAGAGCCAGACACATTGCTG

rs4889533ACGTTGGATGCTCTGTAAAGTAGGGACAAGACGTTGGATGTAGAGCCAGACACATTGCTG

rs881929ACGTTGGATGTTGACCCAGTGGTTCTGAGCACGTTGGATGCCAGCTACCTGGTGTCTAAC

rs8047104ACGTTGGATGGTGGGATGTTAGACAGAGACACGTTGGATGTGCCAGGTTGGTCTCAGCAT

rs8047803ACGTTGGATGAAAGTGCTGGGATTACAGGCACGTTGGATGAAATACAGATTCCTGAGGCC

rs4644874ACGTTGGATGAGTCTTGCTATGTTGCCTGGACGTTGGATGTAATCCCAGCACTTTGGGAG

rs2359673ACGTTGGATGGTGTGATGTCAGTTCACTGCACGTTGGATGATCCCAAATACTTGGGAGGC

rs4435271ACGTTGGATGACAGTGGTCTCAAGAACTCCACGTTGGATGTGGCTCATGCCTGTAATCAC

dbSNP Forward Reverse rs# PCR primer PCR primer rs7197717ACGTTGGATGTGTGATTACAGGCATGAGCCACGTTGGATGGCTTGCAAGGAGTATTGTCC

rs2359674ACGTTGGATGGCCTAGCAGTTCATTATGAGACGTTGGATGCCTTGTCTCCAAATACAGTC

rs6565217ACGTTGGATGAAGAACGCTAATCCTACTGGACGTTGGATGTGGAGACAAGGCCTTTATGG

rs2303222ACGTTGGATGTTGGGAAAAGTCCTCCAGAGACGTTGGATGGCGCAGAAAGGGAGAAAAAG

rs4889615ACGTTGGATGTAAGTTCTAGGTCTGCACGGACGTTGGATGATGCACCGGAACGATTCTAG

rs4624197ACGTTGGATGCGCTAAGAGAGTCTTTTGGGACGTTGGATGCAGAGCGAGACTCCATCTCA

rs3751853ACGTTGGATGTCCCCTAGGCTTAAGTCATCACGTTGGATGGGTCTGTGATCAGAAGTAGG

rs749671ACGTTGGATGTGACTACATTTGTACCGCCGACGTTGGATGTCAGTAGTGAACTTCACAGG

rs749670ACGTTGGATGTCTCATCTGTGTGCCCATTGACGTTGGATGATGAGGGTGAAAGGCAGGAG

rs3751855ACGTTGGATGAAGAAGAGGTGTGGGAGGAGACGTTGGATGTCAGAGCTGGCTTCAGTCTG

rs3751856ACGTTGGATGAGCTGTACTGGCCCGTCTCGACGTTGGATGCAGTGCGGGCGGACCTATC

rs7196726ACGTTGGATGGACCTAGTTAGGAACTGAGGACGTTGGATGTCAGGGCAGCAAGCTCAGAAG

rs889550ACGTTGGATGTCCACCCAGCACTGCTGGAACGTTGGATGCAGGTCCTGCTGAGGGAAC

rs750952ACGTTGGATGTTCCCTCAGCAGGACCTGGACGTTGGATGGGTGGCCACTAGATGGAATG

rs2077633ACGTTGGATGTTTCTCAGGAGTAGTTCGGGACGTTGGATGAAAGAAGCCAGATCTGGGTC

rs7199949ACGTTGGATGTCCCCATCAGGCAGGTGGTACGTTGGATGCAGCCTGTGACACTGGGAG

rs2032916ACGTTGGATGGTTCCCCTCATTACTGAAGGACGTTGGATGTGCCACTTGCCTGTAGTTAC

rs4468641ACGTTGGATGATGAGTCAGGAATACGGGAGACGTTGGATGAATGCCCCTACTTGTCACTC

rs4889535ACGTTGGATGCTATGGCAGACACCCTCTGAACGTTGGATGGAAGAGAAGGAGCAGAAGGG

rs4316775ACGTTGGATGAGTAGCTCACGCTTGTAATCACGTTGGATGCTATGTTGCACAGGCTAGTC

rs4313819ACGTTGGATGTGCACAGGCTAGTCTTGAACACGTTGGATGAGTAGCTCACGCTTGTAATC

rs6565218ACGTTGGATGTTAAAGTCACAGACTGAGGCACGTTGGATGTTGAACTCTTGGGCTCAAGC

rs4318224ACGTTGGATGTCAGTCTGTGACTTTAAGCGACGTTGGATGACCACCTTTCATGGTAGAAG

rs1046030ACGTTGGATGGTCTCCAAAGCTCTTTCCATTACGTTGGATGGATTGATCTAAGAAACTTTA

rs7294 ACGTTGGATGGCACTGGGTGTAAAAAAGAGACGTTGGATGTTCTAGATTACCCCCTCCTC

rs7200749ACGTTGGATGGAGCACGAAGAACAGGATCCACGTTGGATGTCTGTCCTGATGCTGCTGAG

rs2359612ACGTTGGATGAAATCGGCCAAGTCTGAACCACGTTGGATGTCCAGAGAAGGCATCACTGA

rs8050894ACGTTGGATGAATCTTGGTGATCCACACAGACGTTGGATGTAGTTACCTCCCCACATCCC

rs2884737ACGTTGGATGTCATTATGCTAACGCCTGGCACGTTGGATGTTGACGATGGTCTCAAGGAC

rs1895514ACGTTGGATGCAATCTCAGCTCACTGCAACACGTTGGATGTAATCCCAGCTACTTGGGAG

rs8060209ACGTTGGATGGGTCAGGAGTTTAAGACAAGACGTTGGATGCCATGCCCGGCTAATTTTTG

rs8060217ACGTTGGATGTGAGTAGCTGGGATTACAGGACGTTGGATGAGACAAGCTTGGCCAACATG

rs7196161ACGTTGGATGGTGTTTTTAGTAGAGACGGGACGTTGGATGATCCCAGCACTTTAGGAAGC

rs8062336ACGTTGGATGTGCTCCCCACATCTCAGACGACGTTGGATGAAGCGAGGAGCGCCTCTTC

rs8043778ACGTTGGATGTTCCTCACTTCTCAGACGGGACGTTGGATGATCGTCTGAGATGTGGGGAG

rs2032915ACGTTGGATGATTCCCACCCGTTCTTTCCCACGTTGGATGTTCCCGCTCCCTTTTACCAC

rs4889616ACGTTGGATGGAACCAAGAACTGGAAGGAGACGTTGGATGTGTAAAGCGCACAGATCACG

rs1045564ACGTTGGATGTGTCAGCATCCTCGACGCACACGTTGGATGACCCAGGCGACCCAAAATGG

rs2303221ACGTTGGATGAGAACCCCCAACACTCTCCCACGTTGGATGAGCGGAGAAGGTGCGCAAG

rs1549296ACGTTGGATGATGCTGCTGAACTTCCTAACACGTTGGATGAGCAGGGTTTCTCAACCATG

rs889555ACGTTGGATGAGACCAGTAGGTACAAGCACACGTTGGATGTCAAGAATGCCATGAGGTGG

rs5816521ACGTTGGATGATTGTGGCTCTATGCAGAGGACGTTGGATGTCAAGAATGCCATGAGGTGG

rs749767ACGTTGGATGCTGATAGAAAGGACCAAGGAACGTTGGATGCTGGAGTTCTGATTCAGGTC

rs2884738ACGTTGGATGAGAACTGCTTGAACCCAGGAACGTTGGATGATGGAGTCTTGTTGTGTCGG

rs2052581ACGTTGGATGTGGGACATGCGGATATGGAGACGTTGGATGGAGGGTTCTGTGAGAGTCAG

rs4889617ACGTTGGATGCAGAGCGAGACTCCATCTCAACGTTGGATGACACTCGCGCTGGCCTAATG

rs4889619ACGTTGGATGAAAATTAGATGGGCGTGGTGACGTTGGATGATCTCGGCTCACTGCAACCT

rs1978487ACGTTGGATGTCCCTTCTCTATGTTCCTGCACGTTGGATGATGGAGGAAGACAGAGAGAG

rs1978486ACGTTGGATGTACCTAGGGTCACAGATTTGACGTTGGATGGGGTATGTGGTAAAATGAGC

rs1978485ACGTTGGATGTCAAGCAATTTTCCTGCCTCACGTTGGATGCCATCTGTACCAAAAAGACG

rs4889620ACGTTGGATGTGGCAAAACCCCATCTGTACACGTTGGATGAGTAGTTGGGATTACAGGTG

rs4889621ACGTTGGATGTACTCAATCACTGCCACAACACGTTGGATGGCCAGTTATTTTCTCATTCG

dbSNP Forward Reverse rs# PCR primer PCR primer rs3214477ACGTTGGATGACTCGAGACTGGATCACTTCACGTTGGATGCCTTTTGTTCCAGCCTTACC

rs4527034ACGTTGGATGAAGTATGGGCCATAAGAGTGACGTTGGATGTATGTACACTACGTGGGCTG

rs1060506ACGTTGGATGATCAGGAGTGCAAACCAGAGACGTTGGATGGGATGAAGCTGCAATAGCTG

rs7200125ACGTTGGATGATTTTGCCATTGCACTCCAGACGTTGGATGTACAGGCATGAGCCATAGCC

rs6565219ACGTTGGATGCTTGGCCTCTCAAAGTGCTGACGTTGGATGAGGGCGAGGCTCCATTTCAA

rs889548ACGTTGGATGCTGGCCAAGTCCTAATACAGACGTTGGATGCCCAATTCCAGAGATGTCAG

'TABLE 12 dbSNP Extend Term rs# Primer Mix rs7500176 GATCACGAGGTCAGGAGTTC ACT

rs6565212 GCTGGAAAACTGTTGAGGGT ACT

rs8054046 TTTAGAGCAGCCGATACCCA ACG

rs8056842 GCTGGTCTCGAACTCCTGA ACG

rs732173 GCTCAGTCCAAACTGCCAG CGT

rs732172 ACTGCCAGACTCCCGCCA ACG

rs7188557 CCTGGCCCTGGTTGTGAGT CGT

rs2288004 CGGCAGATCCAGTGTGTC ACT

rs4337310 CACGGAATCTCCAGTGCAC ACT

rs2016554 GGCACGTACCACTGACATG ACG

rs6565213 GCAGTGGCGCAATCTTGAC ACT

rs7204762 CCCAGCACTTTGGGAGGC ACG

rs4889529 CTCAAGTGATCCTCCTGCCT ACG

rs6565214 GAGTAGCTGGGACTACAGG ACG

rs7499674 GTTCTTCTCAACATCTGCCCA ACT

rs6565215 TTTCCTTCAGACAGGGCTCT ACT

rs1023623 GACTCCATCTCAAAAAAAAAAAAAACT

rs1023624 GAGCAAGACTCCATCTCAAAAA ACT

rs1023625 CAGAGCAAGACTCCATCTCA ACT

rs1549297 GGTGACAGAGCAAGACTCC CGT

rs3084894 CGAGTAGGTGGGACTACAG ACT

rs8048228 TGAGCCGAGATGGCAACAC ACG

rs7405432 CTACAGGCTAGGAGACAGAG CGT

rs8054249 AAAGTGCTGGGATTACAGGC ACT

rs8061047 CCTCCTGAGGAGCTGGTCT ACT

rs7187220 GGCCCTTCCCCTGCACC ACG

rs8046978 AGAGTTCAGCCGCCCCGG ACG

rs2288003 GTGACAAGACGTTCGTGGC ACT

rs7196421 CTCAGCCTCCCGAGTAGC ACG

rs7196431 CGGGTTCACGCCATTCTCC ACG

rs7203158 CAACCATGAGCGGTGAGGG ACG

rs2303223 TTGAGCTCCGCATAGGCTTT ACT

rs2032917 TGGAAATGTCTTGGTACAGGACA ACT

rs8044134 CCTACACGTCCCCCCCC ACT

rs4889531 CAACTCTGTCAGGTAAGTACT ACT

rs4889532 CAAGAATCCCTATCTCAGAAAG ACT

rs4889533 GGACAAGAATCCCTATCTCAG I ACT

dbSNP Extend Term rs# Primer Mix rs881929 CTGCCTCTTGCCAGCTCTG ACT

rs8047104 CAGAGACCTAGCCTACCTG ACT

rs8047803 TTACAGGCGAGAGCCACCA CGT

rs4644874 GGGCTCAAGTGATCCTCCC CGT

rs2359673 ACTGCGACCTCTGCCTCC ACG

rs4435271 GCTTCAGATGCTCCTCCACT CGT

rs7197717 GCATGAGCCGTGACCAGC CGT

rs2359674 GAATGTTTGTGTTCCCTGTCC ACT

rs6565217 CCAGGGCCATACCCTTATGA ACG

rs2303222 AAAGTGTCACCAAAGTAC ACG

rs4889615 GCGGCGTCTTTGCACGCTA CGT

rs4624197 AGAGAGTCTTTTGGGGTTTTTT ACT

rs3751853 CCTACAGGTATAGCTAAGGAA ACT

rs749671 ATTTGTACCGCCGCTCCTC ACG

rs749670 GGTGGTGGGCATCCCTTTC ACG

rs3751855 AGAGCCCAGGCTGGAGAC ACG

rs3751856 CCGTCTCGTGGCTGCGC ACG

rs7196726 GTTAGGAACTGAGGAACCCAG ACG

rs889550 AGCACTGCTGGAAGCCGC ACT

rs750952 GCTGGCCTCTCCACCTCC ACG

rs2077633 CCATATCTTCTCCTCTCCCC ACG

rs7199949 CAGGCAGGTGGTGGTCAG ACT

rs2032916 CCAAAGTTCCAGAGAGGTTAA ACT

rs4468641 ATACGGGAGGCAGGCCCA ACT

rs4889535 CAGACACCCTCTGATTGCAG ACT

rs4316775 GAGGATCGCTTGAGCCCAA ACT

rs4313819 GCTAGTCTTGAACTCTTGGG ACT

rs6565218 CTCACGCTTGTAATCCCAGC CGT

rs4318224 TTCCCTTGCAACCTGAGTTTT ACG

rs1046030 GCCCAGGGAGGGAAGGTT ACG

rs7294 TTGGTCCATTGTCATGTG ACG

rs7200749 GAAGAACAGGATCCAGGCCA ACT

rs2359612 CCATGTGTCAGCCAGGACC ACT

rs8050894 CCAGCTAGCTGCTCATCAC ACT

rs2884737 TCGCCAACACCCCCCTTC CGT

rs1895514 CCCCTCTCGGGTTCAAGC CGT

rs8060209 TGGCCAACATGGCGAAACC ACG

rs8060217 CCATGCCCGGCTAATTTTTGT ACT

rs7196161 AACTCCTGACCTCATGATCC ACT

rs8062336 TCACTTCCTAGATGGGAAGG ACG

rs8043778 CGCTCCTCACCTCCCAGA ACG

rs2032915 TTCTTTCCCAACGTCCTGGA ACT

rs4889616 GAACTGGAAGGAGGACAAGA ACT

rs1045564 GTCCCTGAAGTCGGAGAAG CGT

rs2303221 CTCTCCCTCCCGCCTACAT ACG

rs1549296 TGCACGGGGCAGCCCCT ACT

rs889555 AGCACCCCGGTTCCTGTCC ACT

rs5816521 CCAGTA ACT
GGTACAAGCACCC

rs749767 _ ~ ACT
I GACCAAGGATTTGGGCAAAG

dbSNP Extend Term rs# Primer Mix rs2884738 CCAGGAGGTGGAGGTTGCA ACT

rs2052581 GGATATGGAGGGCCGATTGT ACT

rs4889617 GAGACTCCATCTCAAAAAAAAAA ACT

rs4889619 GCAGAGGAATCGCTTGAACC ACG

rs1978487 GTTCCTGCAACATTTTTTTCCTA ACG

rs1978486 GGGTCACAGATTTGAAAAGTG ACT

rs1978485 TTTTCCTGCCTCAGCCTCC ACG

rs4889620 ACCCCATCTGTACCAAAAAGA ACG

rs4889621 CTGTGAGGTGGATCAGGTTG ACT

rs3214477 GCAGAATCTGTGATGGAAAAAG ACT

rs4527034 CCAGGGCAGCCAACTCCC ACG

rs1060506 AAGTCTCCAGACACCCAGA ACG

rs7200125 AGGCTCCATTTCAAAAAAAAAAAAACT

rs6565219 AAAGTGCTGGGATTACAGGC ACT

rs889548 AGTCCTAATACAGTGGATGTC ACT
I

Genetic Analysis [0232] Allelotyping results from the discovery cohort are shown for cases and controls in Table 13. The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency.
The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (Al AF = 1-A2 AF).
For example, the SNP rs732173 has the following case and control allele frequencies: case A1 (G) _ 0.55; case A2 (T) = 0.45; control A1 (G) = 0.58; and control A2 (T) = 0.42, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.
'TABLE 13 dbSNP PositionChromosomeAl/A2 F A2 F A2 F p-rs# in position Allele Case Control Value SEQ iD AF AF
NO:

rs7500176247 31077197 A/G

rs65652121535 31078485 C/T

rs80540462386 31079336 C/T

rs80568426440 31083390 C/T

rs732173 9133 31086083 G/T 0.45 0.42 0.382 rs732172 9143 31086093 A/G

rs71885579471 31086421 A/T

rs228800413150 31090100 C/G 0.52 0.45 0.026 rs433731013717 31090667 C/T 0.18 unt ed rs201655414466 31091416 A/G

rs656521315769 31092719 A/C

rs720476216870 31093820 A/G

rs488952918545 31095495 C/T

rs656521418749 31095699 C/T

rs749967419123 31096073 GlT

rs656521520736 31097686 A/G

rs102362321038 31097988 C/T 0.02 unt ed rs102362421046 31097996 C/T 0.16 0.11 0.035 rs102362521050 31098000 C/T 0.32 NA

rs154929721056 31098006 A/T

dbSNP PositionCpromosomeAl/A2 F A2 F A2 F p-rs# in position Allele Case Control Value SEA iD AF AF
NO:

rs308489421706 31098656 -/ACC

rs804822823170 31100120 A/G 0.54 0.61 0.040 rs740543225028 31101978 A/T 0.35 0.43 0.025 rs805424927871 31104821 A/G

rs806104728070 31105020 C/T 0.21 0.21 0.903 rs718722031717 31108667 A/G

rs804697832019 31108969 A/G 0.34 0.28 0.083 rs228800332318 31109268 A/G

rs719642133080 31110030 A/G

rs719643133101 31110051 A/G

rs720315834236 31111186 A/G

rs230322334285 31111235 C/T 0.52 0.45 0.060 rs203291734818 31111768 C/G

rs804413435168 31112118 C/G 0.97 0.97 0.856 rs488953137981 31114931 ClT

rs488953238113 31115063 CIG

rs488953338117 31115067 C/T

rs881929 38481 31115431 G/T 0.38 0.34 0.228 rs804710438615 31115565 C/G 0.60 0.65 0.117 rs804780338944 31115894 A/C 0.35 0.33 0.437 rs464487439288 31116238 A/C

rs235967341385 31118335 C/T 0.18 0.20 0.563 rs443527142136 31119086 A/T

rs719771742185 31119135 A/C

rs235967442353 31119303 A/G 0.22 0.18 0.122 rs656521742434 31119384 A/G 0.35 0.33 0.608 rs230322244580 31121530 A/G 0.60 0.52 0.022 rs488961544675 31121625 A/T

rs462419745739 31122689 G/T

rs375185346439 31123389 C/T

rs749671 47457 31124407 C/T 0.32 0.37 0.095 rs'T4967047735 31124685 C/T

rs375185550319 31127269 C/T 0.53 0.57 0.287 rs375185650708 31127658 A/G

rs719672651185 31128135 A/G 0.41 0.37 0.258 rs889550 53002 31129952 A/G

rs750952 53064 31130014 C/T 0.43 0.41 0.535 rs207763353637 31130587 A/G

rs719994955274 31132224 C/G 0.46 0.53 0.051 rs203291655825 31132775 C/T

rs446864155986 31132936 A/C 0.26 0.25 0.902 rs488953556684 31133634 C/G

rs431677557653 31134603 C/T

rs431381957659 31134609 C/G

rs656521857692 31134642 G/T

rs431822457775 31134725 C/T

rs104603061313 31138263 C/T

rs7294 61431 31138381 A/G 0.38 0.37 0.669 rs720074961699 31138649 A/G

rs235961262906 31139856 A/G 0.56 0.48 0.017 rs805089463619 31140569 C/G 0.48 0.45 0.320 rs288473764664 31141614 AIC 0.68 0.60 0.016 rs189551468452 31145402 G/T

rs806020969665 31146615 C/T

rs806021769681 31146631 C/T

rs719616170091 31147041 A/G

rs806233674637 31151587 A/G

rs804377874760 31151710 A/G

rs203291576523 31153473 A/G 0.43 0.41 0.505 rs488961678559 31155509 C/G

rs104556479549 31156499 A/C

rs230322179882 31156832 C/T

rs154929681339 31158289 A/G

dbSNP PositionChromosomeAl/A2 F A2 F A2 F p-rs# in position Allele Case Control Value NO:

rs889555 81681 31158631 C/T 0.49 0.50 0.740 rs581652181696 31158646 -/G

rs749767 83517 31160467 C/T 0.28 0.36 0.020 rs288473885431 31162381 AlC

rs205258186332 31163282 C/T

rs488961787358 31164308 A/G

rs488961987725 31164675 ClT

rs197848789052 31166002 A/G 0.62 0.57 0.124 rs197848690020 31166970 A/G

rs197848590231 31167181 A/G 0.90 0.88 0.513 rs488962090284 31167234 A/G

rs488962190447 31167397 C/T

rs321447790601 31167551 -/G

rs452703490724 31167674 A/G 0.37 0.43 0.079 rs106050692559 31169509 C/T 0.29 0.28 0.720 rs720012595176 31172126 AlG

rs656521995195 31172145 C/T

rs889548 96822 31173772 A/G 0.54 0.51 0.320 rs6145813Not mappedNot mapped~TTTTT p,33 0.32 0.909 TTTTTT

[0233] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1A for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1 C can be determined by consulting Table 13. For example, the left-most X on the left graph is at position 31077197. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0234] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a l Okb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0235] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 5 Chromosome 4 Region Proximal SNPs [0236] SNP rs1957723 is associated with osteoarthritis and is described in Table A. SNP
rs 1957723 falls in an intergenic region on chromosome 4 that does not include a known gene, therefore, the region is referred to herein as the Ch~om 4 region. One hundred-thirty additional allelic variants proximal to rs1957723 were identified and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 14. The chromosome positions provided in column four of Table 14 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs38490234 211 36870611 /t rs14443114 7217 36877617 a/

rs20442954 7895 36878295 alC

rs21660934 13308 36883708 C/t rs23763344 14279 36884679 /t rs14443204 17026 36887426 c/t rs20442944 18271 36888671 a/

rs18998644 20417 36890817 C/t rs15620944 21843 36892243 a/

rs15620984 22069 36892469 a/

rs15620974 22145 36892545 al rs15620964 22519 36892919 a/

rs15620954 22539 36892939 a/

rs14443194 23236 36893636 alC

rs14443184 23256 36893656 a/c rs10259384 23402 36893802 c/t rs10259374 23499 36893899 a/c rs10259364 23620 36894020 C/t rs10203334 23871 36894271 a/t rs21206544 24136 36894536 c/

rs25885474 25427 36895827 a/

rs20442934 25866 36896266 /t rs27603244 26541 36896941 a/

rs25885464 26576 36896976 /t rs25885454 26689 36897089 a/

rs27603284 26720 36897120 a/c rs25885444 27113 36897513 c/t rs27603314 27164 36897564 c/t rs25885434 27186 36897586 a/

rs25885424 28341 36898741 alt rs25885414 29160 36899560 C/t rs25885404 29844 36900244 a/g ~

dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs27603364 30665 36901065 /t rs27603374 30830 36901230 a/

rs20287324 31061 36901461 a/c rs25885384 31523 36901923 c/t rs19926174 32326 36902726 c/t rs19984694 32346 36902746 al rs19984704 32358 36902758 c/t rs19754984 34909 36905309 c/t rs15620934 34975 36905375 a/

rs19754974 35066 36905466 c/t rs15620924 35096 36905496 /t rs22487884 35375 36905775 c/t rs18998624 36304 36906704 a/

rs25885324 36712 36907112 a/t rs18858784 36770 36907170 c/t rs9866484 37342 36907742 c/t rs9866474 37412 36907812 c/t rs10100104 37884 36908284 al rs10100094 38077 36908477 a/c rs27603254 38300 36908700 c/t rs25885314 38301 36908701 c/t rs18383884 41189 36911589 c/t rs19754954 44408 36914808 c/t rs21814914 44493 36914893 a/c rs19754964 44571 36914971 a/

rs21814924 44670 36915070 a/

rs22247194 45219 36915619 a/

rs22247204 45258 36915658 C/t rs19517704 47261 36917661 a/

rs22960404 48473 36918873 a/c rs19577234 48771 36919171 a/

rs19577254 55292 36925692 c/t rs28893464 56479 36926879 a/

rs18858794 56747 36927147 a/c rs19577264 60620 36931020 /t rs19577274 60688 36931088 a/c rs18858804 61058 36931458 a/c rs18858814 61129 36931529 clt rs9421084 61577 36931977 c/t rs19517714 61961 36932361 a/

rs23763234 63351 36933751 /t rs20133584 63926 36934326 a/

rs21814944 65798 36936198 a/

rs19577284 66043 36936443 a/c rs19577294 66044 36936444 a/

rs19577304 66246 36936646 c/t rs19577314 66318 36936718 c/t rs19984684 66547 36936947 /t rs19577324 71238 36941638 c/t rs19577334 71283 36941683 a/

rs23763224 71492 36941892 a/

_ ~ 4 72274 36942674 alg rs2889345 dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs18152674 73762 36944162 alt rs19577344 74209 36944609 /t rs19577354 75284 36945684 a/t rs19577364 77347 36947747 a/c rs19577374 77589 36947989 c/t rs19577384 78096 36948496 a/

rs19577394 78606 36949006 a/

rs19577404 78862 36949262 /t rs19577414 79135 36949535 a/

rs19577424 79146 36949546 a/

rs19577434 79456 36949856 c/t rs19577444 79609 36950009 a/

rs19577454 80086 36950486 a/

rs19577464 80119 36950519 a/

rs19577474 80766 36951166 c/t rs21466704 81110 36951510 a/

rs21466714 81269 36951669 a/t rs19577484 81668 36952068 c/t rs21623074 82433 36952833 clt rs19628394 82559 36952959 c/

rs23763154 83298 36953698 c/t rs14264104 83821 36954221 a/

rs18959214 84121 36954521 c/t rs18959224 84147 36954547 c/t rs10357794 84543 36954943 a/

rs10357804 84554 36954954 a/

rs10357814 84691 36955091 a/

rs10357824 84727 36955127 a/

rs14264114 85678 36956078 c/t rs18346024 86699 36957099 clt rs18346034 86700 36957100 a/

rs18346044 86792 36957192 a/

rs18346054 86832 36957232 a/

rs21623084 87045 36957445 a/

rs13653414 87140 36957540 a/

rs18204584 87365 36957765 a/c rs14693104 88342 36958742 c/t rs30578794 88498 36958898 -/tca rs14693114 88589 36958989 a/

rs7683264 95502 36965902 a/

rs18635234 96968 36967368 c/t rs14693124 97448 36967848 c/t rs14693134 97568 36967968 c/t rs19517734 98724 36969124 c/t rs21206554 Not ma Not ma t/
ed ed rs21814954 Not ma Not ma /a ed ed Assay for Verifyin~ and AllelotYpin~ SNPs [0237] The methods used to verify and allelotype the 130 proximal SNPs of Table 14 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 15 and Table 16, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs3849023ACGTTGGATGGGTAATTGCTAACCATGTTCACGTTGGATGGACCCAGTCAAGTCAATAAAC

rs1444311ACGTTGGATGGCCTATTGGTTTAACTAGGCACGTTGGATGTCTGGCTTCTTCAGGAGTTC

rs2044295ACGTTGGATGCCACACCACTACTATTCAAGACGTTGGATGGTGGTGTGTTAGAAGGTTAC

rs2166093ACGTTGGATGAAAATCCTGGAGATGGATGGACGTTGGATGTAGGTGTACAGTTCAGTGTC

rs2376334ACGTTGGATGTCTCAGAGAACCAGCTTTTGACGTTGGATGGGGAATATTAAACATTGGGG

rs1444320ACGTTGGATGTAATTCTCTCCTCCAAATGCACGTTGGATGCTAGAAACAAAAGACTACATG

rs2044294ACGTTGGATGAACCTAAATCTCCTCAAGCCACGTTGGATGTTCTGACCACTTCTCTATGG

rs1899864ACGTTGGATGTTTATAGGCGTGGGCAATCGACGTTGGATGTTGTCAGAAAGTGTCGTGCC

rs1562094ACGTTGGATGTGGATTCCTTTCTTGAAGACACGTTGGATGGCAACAAAGAAACTTAATGC

rs1562098ACGTTGGATGTCTGAGTCCGAGTGATCATCACGTTGGATGAAACAATTAGCAGGGCACAG

rs1562097ACGTTGGATGCACAGGATCTTACTCTGTTGACGTTGGATGCGGACTCAGAAATTCAAGTC

rs1562096ACGTTGGATGACCCAGGGCATGTTATATAGACGTTGGATGTTTCTCTCTGGTACCCTCTC

rs1562095ACGTTGGATGTGTTAGTAACCCAGGGCATGACGTTGGATGTGACAGATGCCACCAGTTAC

rs1444319ACGTTGGATGTTCAACTTTAGCCTCTGGGCACGTTGGATGCCCTGCAAAGTCAAAGGAAC

rs1444318ACGTTGGATGCTCTGGGCAATTATCAAGCCACGTTGGATGAGTTCGCTGATGTGTTTGGG

rs1025938ACGTTGGATGCAGGTAAGAAAAGCTTTTTGGACGTTGGATGCCCTGCTAATGACTGAATTTC

rs1025937ACGTTGGATGGAATAGGAAAGGTAGTATACCACGTTGGATGAAATTCAGTCATTAGCAGGG

rs1025936ACGTTGGATGTCTCCAGGTAGATGAGTCAGACGTTGGATGCCACACACCAAAGCAATCAC

rs1020333ACGTTGGATGGCATCTCTTCAATCTGGACGACGTTGGATGGTGGATCACAGAAGTCAGAG

rs2120654ACGTTGGATGACCAGAAAGACCAGGGCATGACGTTGGATGAACCTTTAGCTCTTCTCCCC

rs2588547ACGTTGGATGTCACAAATGTAATATAAATCACGTTGGATGGATAGCTACGTTTAAAAATG

rs2044293ACGTTGGATGTGTCAACAATACAAGACTAAACGTTGGATGTGCACTGGACTTTTTTTTT

rs2760324ACGTTGGATGACAAACCAGTGGTTGAGGAGACGTTGGATGCCTCACGAATCCAACAGAAC

rs2588546ACGTTGGATGCTTAGAGGATGGAGTCAGTCACGTTGGATGTACTACCAGAGATGCTGGTG

rs2588545ACGTTGGATGCAACACAGCTACAGTGCATCACGTTGGATGTGGGTAAAGGGAAAAGAAGG

rs2760328ACGTTGGATGGCCATAAAATTGGGTAAAGGGACGTTGGATGGCATCTATTTGACACCAACG

rs2588544ACGTTGGATGTAAGAATTAGCATGTGAAAGACGTTGGATGTTTGTGCACAAAGAATTTGG

rs2760331ACGTTGGATGAAACAGTATGCCTTTTGTGCACGTTGGATGCTTCTCGTAATTTTACATGAC

rs2588543ACGTTGGATGGTGCCAAATTCTTTGTGCACACGTTGGATGCTAAGATAGGTAGATACCAG

rs2588542ACGTTGGATGTGGCAGCAAAGCTTAAGCTCACGTTGGATGTCCACAGTCACCTCTCATTC

rs2588541ACGTTGGATGTGACAAGGTCTATGTCAGGGACGTTGGATGGGCATTGTCATGGTGATGAG

rs2588540ACGTTGGATG.TGCTGTATGATCCAGCAATCACGTTGGATGGGTGCAAATACTGTCTCTTC

rs2760336ACGTTGGATGAAGCTGAGGCAGGAGAATGGACGTTGGATGTGTTTTGAGACGGAGTCTCG

rs2760337ACGTTGGATGGGTGTTCGAACTGATACAAGACGTTGGATGACTACCATTCTACTCTCTGC

rs2028732ACGTTGGATGTTCCTGGACAGCTAAATAGGACGTTGGATGGCCATTGTCGTTTTCTTGTT

rs2588538ACGTTGGATGTATCTTCTGGGAAGCCTTTCACGTTGGATGGACTTGAAATCACTCCATGC

rs1992617ACGTTGGATGGGAGGACATTGCCTTCAAAGACGTTGGATGCTGACCTTCTGTCTAGTCAC

rs1998469ACGTTGGATGTATATGCCAAGGACCAACGGACGTTGGATGCTGACCTTCTGTCTAGTCAC

rs1998470ACGTTGGATGATTTCCCCCATTAAGCTTTGACGTTGGATGGAAAAGTATTATATGCCAAGG

rs1975498ACGTTGGATGAGCTCTCTTTTTGCCTGCTGACGTTGGATGAGGAGGCTTCACAATCATGG

rs1562093ACGTTGGATGTGATTGTGAAGCCTCCTCTGACGTTGGATGAAAGACATACCCAAGACTGG

rs1975497ACGTTGGATGTCAGCAGCATGAAAACTGACACGTTGGATGCATTTAGACTTTTTCTGGGG

Irs1562092ACGTTGGATGTTCCAGTGACTGGACCATAGACGTTGGATGTCAGCAGCATGAAAACTGAC

dbSNP Forward Reverse rs# PCR primer PCR primer rs2248788ACGTTGGATGGGGAAAAGAAAAAAGACTTCCACGTTGGATGGTAGTAGCTGCTTCTAAAAG

rs1899862ACGTTGGATGTAATCTCCCATAATAAGTGCACGTTGGATGGCTACAAAAGAAAATGAATAC

rs2588532ACGTTGGATGCAAACAATAGTGGCTGAGAGACGTTGGATGTTTGTAGCACAGGCGCATAG

rs1885878ACGTTGGATGTGACTCAGCGAGTTTGTAGCACGTTGGATGAGCCAGATTGGGTGCTTTTC

rs986648ACGTTGGATGTGAGAAAGCTTTCTGAGGACACGTTGGATGGGTTTTCTGTTGTGAATGGG

rs986647ACGTTGGATGACACACTCTTTCTCAAGCAGACGTTGGATGCTTATTTGTCCTCAGAAAGC

rs1010010ACGTTGGATGACTGTAGCTAAGTTGGCATACGTTGGATGTTCACCAACACCAATAAGGC

rs1010009ACGTTGGATGTCTCATCAGCTCTTTCCTGGACGTTGGATGAAAGGGATGAGGAAGTGAGG

rs2760325ACGTTGGATGATCCCCAGCATGTAGCATAGACGTTGGATGCTGCCCATAAGTCTCTTCTG

rs2588531ACGTTGGATGATCCCCAGCATGTAGCATAGACGTTGGATGCTGCCCATAAGTCTCTTCTG

rs1838388ACGTTGGATGGTACCTCATGGATATTTACACACGTTGGATGTTGGTGTTGTTATAAATGAC

rs1975495ACGTTGGATGCAGGTCAGGAGTTTAAGACCACGTTGGATGAGCTGGGATTACAGTCATGC

rs2181491ACGTTGGATGGTACCTAATATATGCTTCTGGACGTTGGATGTTATTCCCGTCTTACTTTCC

rs1975496ACGTTGGATGTATATTAGGTACAGTGTGGCACGTTGGATGCAACCAACTTCACTGAAAGC

rs2181492ACGTTGGATGCTTGCAGGAAGAGGAAGAAGACGTTGGATGACAATCACCTTTGGAGGCAG

rs2224719ACGTTGGATGTCAAGGGTGTAGATGTGTAGACGTTGGATGCCAGAGAGGAGTAATGGTAT

rs2224720ACGTTGGATGCCAATTACTCAAGGGTGTAGACGTTGGATGAATTCAGTACAGACAGAGGG

rs1951770ACGTTGGATGCCTGGGAACTTCAGCTTTTCACGTTGGATGTGGCACAGCAGGAATATCAG

rs2296040ACGTTGGATGGGGCATCATGAAATGCAGACACGTTGGATGGCATGTACAGGAAAGCAGTG

rs1957723ACGTTGGATGTACTCACTTGTGTACTGCTCACGTTGGATGGCTGCAGCGTCACATTAATC

rs1957725ACGTTGGATGTTATTGGAATTCTCCAGGTCACGTTGGATGAAGATGATTAGTCCAGCCTG

rs2889346ACGTTGGATGTGACTGACTTCCTAGGTCAGACGTTGGATGTGACAGTGTTTGAGTGGCAG

rs1885879ACGTTGGATGTTCACCCCTTCACATCTGATACGTTGGATGCTACAAGGAAGATAACAGAG

rs1957726ACGTTGGATGAAATTCAGCCACTCAACCAGACGTTGGATGAAGTGGTTGGGATTTGTGAG

rs1957727ACGTTGGATGGCCAACGTATCTTTAAAACCCACGTTGGATGGTTTTGTCTTGGTTCTCATC

rs1885880ACGTTGGATGTGGAATGCCCCAAGATTTCAACGTTGGATGCTGGAATCCCAAGGTTCCTG

rs1885881ACGTTGGATGTAGACGTGTTCTGCATCATGACGTTGGATGATGAAATCTTGGGGCATTCC

rs942108ACGTTGGATGGAGCTGTTAGGGTAGAAATGACGTTGGATGGTCCTTGGACTAATTTTGACC

rs1951771ACGTTGGATGGGCATTCCCTTTTGTCTAAGACGTTGGATGAGTAAACAAGGACTAGAGCC

rs2376323ACGTTGGATGTCCTTACTTGCTAGCACTGCACGTTGGATGGCATCCCTTGGTGACTGATA

rs2013358ACGTTGGATGGGAATTTTAGGAGTACTGTAGACGTTGGATGGCCAACCATAGAACCTAAATC

rs2181494ACGTTGGATGATTCAATTACCTCCCACTGGACGTTGGATGTATCCCCACCCAAATGTCAC

rs1957728ACGTTGGATGAAATAGATCCCAACCAAGGGACGTTGGATGGTAACATTTACCTAAGCGGG

rs1957729ACGTTGGATGAAATAGATCCCAACCAAGGGACGTTGGATGGTAACATTTACCTAAGCGGG

rs1957730ACGTTGGATGGGTCTAAACATGAGAGACTCACGTTGGATGTCTTTATGGATATAGGGTCC

rs1957731ACGTTGGATGTATTGGAACCTGGTACCTGGACGTTGGATGGACCTGAATCATGTCTCCAG

rs1998468ACGTTGGATGTATAAAGCCTCAAAAGTGGGACGTTGGATGACCTTATTCCAGAATGAAAC

rs1957732ACGTTGGATGAAGAGAGGAGTTTATTGGCCACGTTGGATGCGGCCTGATCTTTATTTTCG

rs1957733ACGTTGGATGCTATCAAGACTCTGATTGCCACGTTGGATGTGTTTGCAGGTAAACTTGGC

rs2376322ACGTTGGATGTCGTTCTCTCTCTGTGCATGACGTTGGATGTTAGTCAGATGCTTGGTGAG

rs2889345ACGTTGGATGTGGAATCCCAAACCTTTCAGACGTTGGATGTTCTTGCTAAATGTAGGCC

rs1815267ACGTTGGATGCAGGAAAGGGCTACTATCAGACGTTGGATGGTAGGCCAAACTAGCTTTGG

rs1957734ACGTTGGATGCTACCCCTGCCTTATAATTCACGTTGGATGCAAGTGGTAAAAGGATGTGG

rs1957735ACGTTGGATGAGCTTCCCATGGTTATAGAGACGTTGGATGCTGAAAACAATACCGGTCTC

rs1957736ACGTTGGATGCTGAAGCAAAGATTTCTCTCACGTTGGATGAGCATCTTTTGCTGTCACTG

rs1957737ACGTTGGATGACATGGAAGCTGAAGCCAAGACGTTGGATGCAGAGCTTTGACCTTACTCC

rs1957738ACGTTGGATGATGTCCCTTAAAAGGCTGCCACGTTGGATGCAGATGATCTTGCTTCCCAG

rs1957739ACGTTGGATGTCACTGCCTGAGTGCTTTAGACGTTGGATGCTGATGGCCTGAGAACTAAG

rs1957740ACGTTGGATGGCCCAGTCAAGTTGACATACACGTTGGATGCACCTGCTCCAGTTATATAC

rs1957741ACGTTGGATGAGGAGCATTATCCCTATTAGACGTTGGATGCCTCTTAGTAAAATATGGATG

rs1957742ACGTTGGATGGGATGATATCTACTTTGTACGACGTTGGATGGACTCCATCTGAGATGTTAG

rs1957743ACGTTGGATGCAACTGTCTTGTATTTGAAGACGTTGGATGGACAGACTTTCATTGTTTTC

dbSNP Forward Reverse rs# PCR primer PCR primer rs1957744ACGTTGGATGTCAGTGTACCCTGTAATGCCACGTTGGATGTGCCCAGCAGTGAGTAATTG

rs1957745ACGTTGGATGGTTTAGAAAGTGTTGGGTTCCACGTTGGATGAGCAAATGCAGCTTATTACC

rs1957746ACGTTGGATGTCTCATACAACATAGTTAGCACGTTGGATGGGTTTAGGTTTGGTTTGATG

rs1957747ACGTTGGATGGTCACTCAAGATAACAGTTCCACGTTGGATGTTACCTAACGTGAAGGTAGC

rs2146670ACGTTGGATGCCTAACACATCTTTATGAGCACGTTGGATGCTCATAAGATATGCTAAGCAC

rs2146671ACGTTGGATGATGAGGAGCAACTAGAAGGCACGTTGGATGAAAGGGCTGGAAGAAACAGG

rs1957748ACGTTGGATGTGAAGTTTGTAGTAGGGAGCACGTTGGATGTTCTGTCACACAAACACTCC

rs2162307ACGTTGGATGACATGCGGTGCCTGGCCCTTTACGTTGGATGCCTTTGTAGGGACATGGATG

rs1962839ACGTTGGATGGGCTGCATAGTATTCCATGGACGTTGGATGAGGGAATCCTTTCCCCATTG

rs2376315ACGTTGGATGTGGCCTTGGATTTCTTCCACACGTTGGATGAGAATTGGACAGAGTGGCAG

rs1426410ACGTTGGATGGAGAAAGTTGCATCTTGCCCACGTTGGATGGGGAAGTTTTACCTTGGCTC

rs1895921ACGTTGGATGGGTGATGGTGTTTGAGGTACACGTTGGATGATTAGGCTTCTCCCACCATC

rs1895922ACGTTGGATGCAATGCATTAGGCTTCTCCCACGTTGGATGGAGGTACATTTCTCAGGCAG

rs1035779ACGTTGGATGGAGAATCACTTGAACCCGGGACGTTGGATGTGGAGTGCAGTGGCATGATC

rs1035780ACGTTGGATGTTTGAGATGGAGTCTCGCTCACGTTGGATGAATCACTTGAACCCGGGAGG

rs1035781ACGTTGGATGGGAAGATGCTGACTCTGAACACGTTGGATGCCTTGACTGTTTAGGGATCC

rs1035782ACGTTGGATGGGATCCCTAAACAGTCAAGGACGTTGGATGAGTTGGCTAGACTTGCGTTC

rs1426411ACGTTGGATGCAAGAGTGCTACACAAGTCGACGTTGGATGTGTACCTTGGTCAGGTGATC

rs1834602ACGTTGGATGGATGGGCCCTATTTTTCTTGACGTTGGATGCTTTTCCAACCCAGTAATGTC

rs1834603ACGTTGGATGGATGGGCCCTATTTTTCTTGACGTTGGATGTCTTTTCCAACCCAGTAATG

rs1834604ACGTTGGATGGAAAGACATTACTGGGTTGGACGTTGGATGAGAATTCTTCCTGACTGTGG

rs1834605ACGTTGGATGGCCCACAGTCAGGAAGAATTACGTTGGATGTTGTGGAGACTGGCCAAAAG

rs2162308ACGTTGGATGTAAAGAAACAGAGGGACACCACGTTGGATGTATGATCAGAGTCATCAGGG

rs1365341ACGTTGGATGTCCCTCTGTTTCTTTAGGCAACGTTGGATGCATCTCCCCTGGTAGCATTT

rs1820458ACGTTGGATGCACCCTCAGACTTGGAAATGACGTTGGATGGTCAGGTGACTCTATTCAGC

rs1469310ACGTTGGATGTACTACAGCGTGTTTAGCAGACGTTGGATGTGTCAAAGGGAGAGTTAGAG

rs3057879ACGTTGGATGGGCACATTGGAAAATAAAGCCACGTTGGATGACGGCATGAACAATTCTCAG

rs1469311ACGTTGGATGCCTGAGAATTGTTCATGCCGACGTTGGATGTTTTCAGTGTTCTCTCCAGG

rs768326ACGTTGGATGAATTAGCCAGGCATGGTGTCACGTTGGATGACATCCTAGGCTCAAGTGAC

rs1863523ACGTTGGATGGGCAGACACATTCCTATTCGACGTTGGATGGGGAAAGGTGTGCTGAGTAA

rs1469312ACGTTGGATGCATTTCGTCAGCATTCTAGCACGTTGGATGGGACTCATGTCATCTCTTGG

rs1469313ACGTTGGATGAGTGAGGGAGAAAAGTGAACACGTTGGATGCCTAACTTCTCTCCAATCTC

rs1951773ACGTTGGATGAAGGTTCAAGTTACCGCATGACGTTGGATGCACTGTGGTCCATGAAAAA

rs2120655ACGTTGGATGACAGGGTTTCTGCATGTTGCACGTTGGATGACGCCTGTAATCCCAGCACT

rs2181495ACGTTGGATGGAATTGTGGGAGTTACAATTC~ACGTTGGATGGAATCAAGCTAATTAACATGTG~

dbSNP Extend Term rs# Primer Mix rs3849023 CTCATAACATAAGAAGTTGATGC CGT

rs1444311 CTAGGCATGCTAGCTTGGC ACT

rs2044295 CACTACTATTCAAGATTACCCTTTACT

rs2166093 GGTGGTGATGGCTGCACAA ACG

rs2376334 TCAGAGAACCAGCTTTTGATTTCAACT

rs1444320 GCCTAGACCCCGTGCAAC ACG

rs2044294 CTCCTCAAGCCAATAGGTCTTA ACG

rs1899864 CGCACCTGGCCGAAAATAAC ACT

rs1562094 AACCTGCAAAAGATTTACACTTGCACT

rs1562098 TCCTGCCTCAGCCTTCCTAGA ACT

~9 dbSNP Extend Term rs# Primer Mix rs1562097 ACTCTGTTGTTCAGGCTGGGGT ACT

rs1562096 TAAGCTAGCTAGTAACTGGTG ACT

rs1562095 ATGTTATATAGAACATCCCTTTTTACT

rs1444319 TCTGGGCAATTATCAAGCCTTT ACT

rs1444318 CTTTGCATTTTCCTGAGTTCCTTTACT

rs1025938 AAGAAAAGCTTTTTGGTTTGGG ACT

rs1025937 GGTAGTATACCTAAAAAAACAGC CGT

rs1025936 TCAAAGGACACCCAGCATTCA ACG

rs1020333 ACGTTTATCTGTAACCTTTCCA CGT

rs2120654 GAAAGACCAGGGCATGATTAGA ACT

rs2588547 ACAAATGTAATATAAATCAAGCTCACG

rs2044293 ACCAGCCTGGGTAACATAGCCA ACT

rs2760324 GGTTGAGGAGAAGCACCAGCA ACG

rs2588546 TACAATTTCTAGCCTTAATAAGATACT

rs2588545 TACAGTGCATCTATTTGACACCAAACG

rs2760328 AAATTGGGTAAAGGGAAAAGAAG ACT

rs2588544 ATTAGCATGTGAAAGACTTCTC ACT

rs2760331 AGTATGCCTTTTGTGCACAAAGA ACT

rs2588543 ATTCTTTGTGCACAAAAGGCATA ACG

rs2588542 GCTTAAGCTCTTACAGGCAG CGT

rs2588541 AGGTCTATGTCAGGGAAAACCTTAACG

rs2588540 GATCCAGCAATCCCACTGAT ACG

rs2760336 AGGCGGAGCTTGCAGTGAG ~ ACT

rs2760337 CACCAATACTGTATGATTCTTTT ACT

rs2028732 CAGCTAAATAGGGCTTGAGTCAAT~ CGT

rs2588538 AATTTGTACAAATTTATGGGGTATACT

rs1992617 ATTGCCTTCAAAGAACATCAAAGCACG

rs1998469 GACCAACGGGAGGACATTG ACG

rs1998470 CTTTGAAGGCAATGTCCTCC ACG

rs1975498 TTTTGCCTGCTGCTATCCAC ACT

rs1562093 CTCCTCTGCCATGTGGAAC ACG

rs1975497 AAAACTGACTAATACACACTGTT ACT

rs1562092 TTTGGTTAATGGACATTTAGACT ACT

rs2248788 TGTGGGATTTTATTATTTTCATCAACT

rs1899862 TAAGTGCATAACTTGTCTTTGAGGACT

rs2588532 ATAGTGGCTGAGAGCCAGAT CGT

rs1885878 GCGAGTTTGTAGCACAGGC ACT

rs986648 GTACATGTAATGCTAGTAAAGAAAACG

rs986647 CTCTTTCTCAAGCAGGAGTTA ACG

rs1010010 AGCTAAGTTGGCATGTGGGA ACT

rs1010009 CCTGGCTACCTTCCAAAAAG ACT

rs2760325 TCTCAGGAAGTATGAAATAAATAGACG

rs2588531 CTCAGGAAGTATGAAATAAATAGTACT

rs1838388 TCATGGATATTTACACCTACTAC ACT

rs1975495 AGGAGTTTAAGACCAGCCTG ACT

rs2181491 TGCTTCTGGATTTTTAATGATCACACT

rs1975496 ATGATCAAATCATTTTGAGGGC ACT

rs2181492 GTTGCATTGCTATGGTCTGC ACT

rs2224719 CATATATCCCTCTGTCTGTAC ~ ACG

dbSNP Extend Term rs# Primer Mix rs2224720 GGGTGTAGATGTGTAGATTTATA ACT

rs1951770 ACAAGCATTAGAGACTTGATTG ACG

rs2296040 CTTTGTTTCTAAAATCTGATAGTCACT

rs1957723 AGCATGGCATAGGCACTGG ACG

rs1957725 GCGAGGAAAGACCTGTTCTA ACG

rs2889346 GGTCAGCTCAGCTGGTTTTT ACG

rs1885879 CACATCTGATGCTCTCCTAAA ACT

rs1957726 GCCACTCAACCAGTAGGAAA ACT

rs1957727 GTATCTTTAAAACCCTCACAAAT CGT

rs1885880 TTACGTTAGTCTGCCTACTTCCA ACT

rs1885881 TGGGCTATCAATGATGGAAAC ACT

rs942108 AAATGAAATAGAATTGTGTACTTCACT

rs1951771 TCCCTTTTGTCTAAGAATATTAG ACG

rs2376323 CTAGCACTGCCAAGTGCAAC ACT

rs2013358 TTTTAGGAGTACTGTAGAACACA ACG

rs2181494 TGGGTCCCTCCCATAACAC ACT

rs1957728 AGAAGCATGTGCTTATAACAATAACGT

rs1957729 GAAGCATGTGCTTATAACAATAAAACT

rs1957730 ACATGAGAGACTCTGAAGACT ACT

rs1957731 GGGTGAGCTTTGGGATCAC ACT

rs1998468 GGGCATAATTAATCCATGTTAG ACT

rs1957732 GGCCAAGTTTACCTGCAAAC ACT

rs1957733 TCTAATGTTAAAGAGAGGAGTTTAACG

rs2376322 GCGCCAAGGAAAGGCCAC ACT

rs2889345 TCATTTCTCACCCTTGATATCCA ACT

rs1815267 AAAGGGCTACTATCAGTTTTGT CGT

rs1957734 CTGCCTTATAATTCTAAAAAGGT ACT

rs1957735 CTAAAACTAAGAAATGTTTCCAC CGT

rs1957736 TAATACTAAGGAGAGGGCTCCT ACT

rs1957737 AGCCAAGGGTGTGGATGAG ACT

rs1957738 CCTTAAAAGGCTGCCTACAAAATAACT

rs1957739 CTGAGTGCTTTAGCTGGATTA ACG

rs1957740 TTAAGCATCACACTGAGTTTGAG ACT

rs1957741 AGCTGAATTAAGCGCGACAGCTA ACG

rs1957742 TCTACTTTGTACGTAGCTGTCGC ACT

rs1957743 GAAAATATTACTAAAAAAGACCTCACG

rs1957744 TGTACCCTGTAATGCCTAAAGC ACG

rs1957745 TTTTCAAAGGTTTAGGTTTGGTTTACT

rs1957746 ACAACATAGTTAGCAAATGCAG ACG

rs1957747 GATAACAGTTCCAATTACAACAA ACG

rs2146670 ATCTTTATGAGCTTTTCCTTTCTTACG

rs2146671 TACAACCCTTTCAGGACTTCA CGT

rs1957748 TTGTAGTAGGGAGCCATGGT ACT

rs2162307 CCTGGCCCTTTGTCCCTG ACG

rs1962839 CCACATCTTTGACAAACCTGA ACT

rs2376315 CCCCCTTCCTTTTCCAGGC ACT

rs1426410 CATCTTGCCCTAAAATCACTC ACG

rs1895921 GTACATTTCTCAGGCAGCTC ACG

rs1895922 ATTAGGCTTCTCCCACCATC I ACT

dbSNP Extend Term rs# Primer Mix rs1035779 ACCCGGGAGGGTTGCAGT ACT

rs1035780 GGCTGGAGTGCAGTGGCA ACG

rs1035781 ACCTAGACTAAGAGAGTGATTGCAACT

rs1035782 CCTAAACAGTCAAGGCAAAGG ACT

rs1426411 TTTATGGTCTTCTTAGGATATCAACG

rs1834602 AGGAAGGTGCCCAGATCCT ACG

rs1834603 AGGAAGGTGCCCAGATCCTT ACT

rs1834604 AGTTTTCTAGTAACTTCTCTAAAAACT

rs1834605 ACAGTCAGGAAGAATTCTGTCT ACT

rs2162308 CACCTACAGAGTTTAAGTAAATTTACG

rs1365341 AAATCTCCTGGAGGGCTTCATAAACT

rs1820458 TGGAAATGGCAACTGAATCCT ACT

rs1469310 ACCCACACAATGCCAATAGCAC ACT

rs3057879 TGGAAAATAAAGCCTTTTGAGGTTACT

rs1469311 TGCCGTTAAAGAGGAAAAGCT ACT

rs768326 CAGCTACTCTGTAAAGCTGAA ACT

rs1863523 ATATTCTTGCTCATCTTTCTCTATACT

rs1469312 TAGTCCAGCAAACGCCAGC ACT

rs1469313 GTGAACAAATAATGCAAGTTCAGACT

rs1951773 CCCTTTGGGAGAGAAGGGC ACT

rs2120655 AGCAATCCTCCCACTTTGGC CGT

rs2181495 GGTGACATTTGGGTGGGGATACAACT

Genetic Analysis [0238] Allelotyping results from the discovery cohort are shown for cases and controls in Table 17.
The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (A1 AF
= 1-A2 AF). For example, the SNP rs1444311 has the following case and control allele frequencies: case A1 (A) = 0.74;
case A2 (G) = 0.26; control A1 (A) = 0.75; and control A2 (G) = 0.25, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 2 rs3849023211 36870611 G/T

rs14443117217 36877617 A/G 0.26 0.25 0.566 rs20442957895 36878295 A/C

rs216609313308 36883708 C/T

rs237633414279 36884679 G/T 0.15 0.16 0.734 rs144432017026 36887426 C/T

rs204429418271 36888671 A/G 0.16 0.14 0.412 rs189986420417 36890817 C/T

rs156209421843 36892243 A/G 0.22 0.23 0.586 rs156209822069 36892469 A/G

rs156209722145 36892545 A/G NA 0.97 NA

rs156209622519 36892919 A/G 0.20 0.21 0.773 rs156209522539 36892939 A/G 0.53 0.51 0.407 rs144431923236 36893636 A/C 0.74 0.79 0.023 ~

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 2 rs144431823256 36893656 A/C 0.12 0.13 0.559 rs102593823402 36893802 C/T 0.18 0.19 0.633 rs102593723499 36893899 A/C

rs102593623620 36894020 C/T 0.84 0.84 0.907 rs102033323871 36894271 A/T

rs212065424136 36894536 CIG 0.15 0.16 0.718 rs258854725427 36895827 A/G 0.39 0.40 0.603 rs204429325866 36896266 G/T

rs276032426541 36896941 A/G 0.59 0.61 0.395 rs258854626576 36896976 G/T 0.07 0.05 0.352 rs258854526689 36897089 A/G

rs276032826720 36897120 A/C 0.25 0.26 0.791 rs258854427113 36897513 C/T

rs276033127164 36897564 C/T 0.91 0.94 0.184 rs258854327186 36897586 A/G 0.59 0.59 0.828 rs258854228341 36898741 A/T

rs258854129160 36899560 ClT 0.61 0.59 0.313 rs258854029844 36900244 A/G 0.62 0.62 0.999 rs276033630665 36901065 G/T

rs276033730830 36901230 A/G 0.16 0.16 0.826 rs202873231061 36901461 A/C 0.60 0.58 0.432 rs258853831523 36901923 C/T 0.62 0.61 0.853 rs 199261732326 36902726 C/T 0.61 0.59 0.282 rs199846932346 36902746 A/G

rs199847032358 36902758 C/T 0.81 0.86 0.018 rs197549834909 36905309 C/T

rs156209334975 36905375 A/G 0.89 0.87 0.529 rs197549735066 36905466 C/T 0.13 0.13 0.691 rs156209235096 36905496 G/T

rs224878835375 36905775 C/T 0.29 0.31 0.368 rs189986236304 36906704 A/G 0.18 0.16 0.274 rs258853236712 36907112 A/T 0.30 0.32 0.443 rs188587836770 36907170 C/T 0.35 0.35 0.866 rs986648 37342 36907742 C/T 0.74 0.73 0.679 rs986647 37412 36907812 C/T 0.78 0.76 0.263 rs101001037884 36908284 A/G 0.25 0.26 0.649 rs101000938077 36908477 A/C 0.26 0.25 0.781 rs276032538300 36908700 C/T

rs258853138301 36908701 C/T

rs183838841189 36911589 C/T 0.75 0.74 0.650 rs197549544408 36914808 C/T

rs218149144493 36914893 A/C 0.14 _0.12 0.235 rs197549644571 36914971 A/G 0.26 0.26 0.944 rs218149244670 36915070 A/G 0.11 0.09 0.311 rs222471945219 36915619 A/G 0.78 0.78 0.866 rs222472045258 36915658 C/T 0.20 0.21 0.641 rs 195177047261 36917661 A/G 0.22 0.18 0.029 rs229604048473 36918873 A/C 0.41 0.43 0.459 rs995772348771 36919171 A/G 0.42 0.38 0.113 rs195772555292 36925692 CIT 0.75 0.78 0.196 rs288934656479 36926879 A/G 0.54 0.55 0.677 rs188587956747 36927147 A/C 0,44 0.48 0.123 rs195772660620 36931020 G/T 0.14 0.14 0.741 rs195772760688 36931088 A/C 0.73 0.76 0.271 rs188588061058 36931458 A/C 0.43 0.43 0.935 rs188588161129 36931529 C/T 0.12 0.11 0.681 rs942108 61577 36931977 C/T 0.49 0.52 0.317 rs195177161961 36932361 A/G 0.93 NA NA

rs237632363351 36933751 G/T

rs201335863926 36934326 A/G 0.13 0.13 0.821 rs218149465798 36936198 A/G 0.42 0.43 0.512 rs195772866043 36936443 A/C

rs 195772966044 36936444 A/G 0.79 0.77 0.405 rs195773066246 36936646 C/T 0.15 0.16 0.719 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
N~: 2 rs195773166318 36936718 C/T 0.14 0.16 0.413 rs199846866547 36936947 G/T 0.13 0.12 0.468 rs195773271238 36941638 C/T 0.10 0.10 0.841 rs195773371283 36941683 A/G 0.63 0.61 0.632 rs237632271492 36941892 A/G 0.26 0.28 0.509 rs288934572274 36942674 A/G 0.20 0.18 0.234 rs181526773762 36944162 A/T 0.46 0.45 0.674 rs195773474209 36944609 G/T 0.55 0.64 0.003 rs195773575284 36945684 A/T 0.63 0.61 0.430 rs195773677347 36947747 A/C 0.05 0.05 0.903 rs195773777589 36947989 C/T 0,71 0.75 0.164 rs195773878096 36948496 A/G

rs195773978606 36949006 A/G

rs195774078862 36949262 G/T

rs195774179135 36949535 A/G 0.76 0.80 0.077 rs195774279146 36949546 A/G 0.95 0.96 0.500 rs195774379456 36949856 C/T 0.21 0.16 0.039 rs195774479609 36950009 A/G 0.66 0.70 0.088 rs195774580086 36950486 A/G 0.88 0.90 0.354 rs195774680119 36950519 A/G 0.40 0.44 0.120 rs195774780766 36951166 C/T 0.72 0.76 0.093 rs214667081110 36951510 A/G 0.73 0.77 0.072 rs214667181269 36951669 A/T 0.17 0.15 0.250 rs195774881668 36952068 C/T 0.16 0.14 0.407 rs216230782433 36952833 C/T 0.73 0.76 0.170 rs196283982559 36952959 C/G

rs237631583298 36953698 C/T 0.62 0.66 0.179 rs142641083821 36954221 A/G 0.75 0.77 0.307 rs189592184121 36954521 C/T 0.75 0.78 0.175 rs189592284147 36954547 C/T 0.15 0.12 0.095 rs103577984543 36954943 A/G 0.66 0.64 0.649 rs103578084554 36954954 A/G

rs103578184691 36955091 A/G 0.73 0.77 0.100 rs103578284727 36955127 A/G

rs142641185678 36956078 C/T 0.76 0.80 0.084 rs183460286699 36957099 C/T 0.20 0.16 0.072 rs183460386700 36957100 A/G 0.94 0.92 0.326 rs183460486792 36957192 A/G 0.70 0.73 0.287 rs183460586832 36957232 A/G 0.72 0.76 0.057 rs216230887045 36957445 A/G

rs136534187140 36957540 A/G 0.18 0.15 0.086 rs182045887365 36957765 A/C 0.23 0.21 0.298 rs146931088342 36958742 C/T 0.20 0.18 0.265 rs305787988498 36958898 -ITCA 0.70 0.71 0.649 rs146931188589 36958989 A/G 0.70 0.74 0.065 rs768326 95502 36965902 A/G

rs186352396968 36967368 C/T 0.21 0.18 0.247 rs146931297448 36967848 C/T 0.78 0.76 0.312 rs146931397568 36967968 C/T 0.81 0.80 0.617 rs195177398724 36969124 C/T

rs2120655Not ma Not ma T/G
ed ed rs2181495Not ma Not ma G/A 0.78 0.76 0.617 ed ed [0239] The chrorn 4 proximal SNPs were also allelotyped in the replication cohorts using the methods described herein and the primers provided in Tables 15 and 16. The replication allelotyping results for replication cohort #1 and replication cohort #2 are provided in Tables 18 and 19, respectively.

Position dbSNP in ChromosomeAl/A2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ D
NO:

rs3849023211 36870611 G/T

rs14443117217 36877617 A/G 0.27 0.25 0.441 rs20442957895 36878295 A/C

rs216609313308 36883708 C/T

rs237633414279 36884679 G/T 0.14 0.14 0.970 rs144432017026 36887426 C/T

rs204429418271 36888671 A/G 0.16 0.14 0.423 rs189986420417 36890817 C/T

rs156209421843 36892243 A/G 0.22 0.21 0.725 rs156209822069 36892469 A/G

rs156209722145 36892545 A/G

rs156209622519 36892919 A/G 0.20 0.19 0.795 rs156209522539 36892939 A/G 0.55 0.53 0.453 rs144431923236 36893636 A/C 0.70 0.80 0.003 rs144431823256 36893656 A/C 0.12 0.13 0.645 rs102593823402 36893802 C/T 0.18 0.18 0.824 rs102593723499 36893899 A/C

rs102593623620 36894020 C/T 0.85 0.83 0.622 rs102033323871 36894271 A/T

rs212065424136 36894536 C/G 0.16 0.16 0.914 rs258854725427 36895827 A/G 0.40 0.40 0.980 rs204429325866 36896266 G/T

rs276032426541 36896941 A/G 0.57 0.61 0.287 rs258854626576 36896976 G/T 0.08 0.05 0.265 rs258854526689 36897089 A/G

rs276032826720 36897120 A/C 0.25 unt ed NA

rs258854427113 36897513 C/T

rs276033127164 36897564 C/T 0.88 0.92 0.193 rs258854327186 36897586 A/G 0.57 0.58 0.869 rs258854228341 36898741 A/T

rs258854129160 36899560 C/T 0.61 0.57 0.230 rs258854029844 36900244 A/G 0.64 0.64 0.926 rs276033630665 36901065 G/T

rs276033730830 36901230 A/G 0.16 0.16 0.956 rs202873231061 36901461 A/C 0.60 0.57 0.330 rs258853831523 36901923 C/T 0.62 0.61 0.747 rs199261732326 36902726 C/T 0.62 0.59 0.341 rs199846932346 36902746 A/G

rs199847032358 36902758 C/T 0.78 0.88 0.0001 rs197549834909 36905309 CIT

rs156209334975 36905375 A/G 0.89 0.90 0.905 rs197549735066 36905466 C/T 0.12 0.12 0.873 rs156209235096 36905496 G/T

rs224878835375 36905775 C/T 0.28 0.31 0.308 rs189986236304 36906704 A/G 0.19 0.14 0.088 rs258853236712 36907112 A/T 0.30 0.33 0.347 rs188587836770 36907170 C/T 0.36 0.34 0.362 rs98664837342 36907742 C/T 0.74 0.75 0.773 rs98664737412 36907812 C/T 0.78 0.77 0.693 rs101001037884 36908284 A/G 0.25 0.26 0.690 rs101000938077 36908477 A/C 0.27 0.26 0.870 rs276032538300 36908700 C/T

rs258853138301 36908701 C/T

rs183838841189 36911589 C/T 0.74 0.75 0.826 rs197549544408 36914808 C/T

rs218149144493 36914893 A/C 0.16 0.10 0.057 rs 197549644571 36914971 A/G 0.25 0.26 0.596 rs218149244670 36915070 A/G 0.11 0.08 0.167 rs222471945219 36915619 A/G 0.78 0.79 0.705 rs222472045258 36915658 C/T 0.19 0.21 0.478 rs195177047261 36917661 A/G 0.25 0.16 0.003 Position dbSNP in ChromosomeAl/A2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ D
NO:

rs229604048473 36918873 A/C 0.39 0.43 0 .241 rs195772348771 36919171 A/G 0.44 0.36 _ 0.027 rs195772555292 36925692 C/T 0.73 0.80 0.024 rs288934656479 36926879 A/G 0.53 0_.55 0.552 rs188587956747 36927147 A/C 0.43 0.50 0.057 rs195772660620 36931020 G/T 0.14 0.14 0.918 rs19577276_0688 36931088 A/C 0.71 0_.78 0.038 rs188588061058 36931458 A/C 0.44 0.42 0.627 rs188588161129 36931529 C/T 0.12 0.12 0.833 rs94210861577 36931977 C/T 0.42 0.49 0.096 rs195177161961 36932361 A/G 0.93 NA NA

rs237632363351 36933751 G/T

rs201335863926 36934326 A/G 0.13 0.12 0.795 rs218149465798 36936198 A/G 0.38 0.41 0.424 rs195772866043 36936443 A/C

rs195772966044 36936444 A/G 0.78 0.77 0.672 rs195773066246 36936646 C/T 0.15 0.15 0.885 rs 195773166318 36936718 CIT 0.15 0.16 0.719 rs199846866547 36936947 G/T 0.14 0.10 0.243 rs195773271238 36941638 C/T 0.10 0.09 0.817 rs195773371283 36941683 A/G 0.62 NA 0.628 rs237632271492 36941892 A/G 0.26 0.27 0.660 rs288934572274 36942674 A/G 0.22 0.16 0.020 rs181526773762 36944162 A/T 0.46 0.48 0.626 rs195773474209 36944609 G/T 0.44 0.61 0.0001 rs195773575284 36945684 A/T 0.63 0.63 0.792 rs195773677347 36947747 A/C 0.03 0.03 0.987 rs195773777589 36947989 C/T 0.69 0.77 0.024 rs195773878096 36948496 A/G

rs195773978606 36949006 A/G

rs195774078862 36949262 G/T

rs195774179135 36949535 A/G 0.75 0.83 0.008 rs195774279146 36949546 A/G 0.94 0.96 0.459 rs195774379456 36949856 C/T 0.24 0.14 0.009 rs195774479609 36950009 A/G 0.63 0.72 0.006 rs195774580086 36950486 A/G 0.86 0.90 0.229 rs195774680119 36950519 A/G 0.42 0.50 0.019 rs195774780766 36951166 C/T 0.71 0.79 0.009 rs214667081110 36951510 A/G 0.72 0.81 0.004 rs214667181269 36951669 A/T 0.17 0.13 0.106 rs195774881668 36952068 C/T 0.17 0.13 0.133 rs216230782433 36952833 C/T 0.72 0.78 0.020 rs196283982559 36952959 C/G

rs237631583298 36953698 C/T 0.61 0.67 0.074 rs142641083821 36954221 A/G 0.73 0.79 0.058 rs189592184121 36954521 C/T 0.72 0.80 0.013 rs189592284147 36954547 C/T 0.17 0.11 0.014 rs103577984543 36954943 A/G 0.66 0.64 0.613 rs103578084554 36954954 A/G

rs103578184691 36955091 A/G 0.71 0.78 0.059 rs103578284727 36955127 A/G

rs142641185678 36956078 C/T 0.75 0.82 0.008 rs183460286699 36957099 C/T 0.22 0.15 0.020 rs183460386700 36957100 A/G 0.94 0.92 0.483 rs183460486792 36957192 A/G 0.69 0.75 0.056 rs183460586832 36957232 A/G 0.71 0.79 0.007 rs216230887045 36957445 A/G

rs136534187140 36957540 A/G 0.19 0.13 0.017 rs182045887365 36957765 A/C 0.24 0.19 0.141 rs146931088342 36958742 C/T 0.22 0.17 0.061 rs305787988498 36958898 -/TCA 0.67 NA NA

rs146931188589 36958989 A/G 0.67 0.76 0.006 rs76832695502 36965902 A/G

Position dbSNP in ChromosomeAl/A2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ D
NO:

rs186352396968 36967368 C/T 0.22 0.17 0.103 rs146931297448 36967848 C/T 0.80 0.77 0.236 rs146931397568 36967968 C/T 0.83 0.80 0.422 rs195177398724 36969124 C/T

rs2120655Not ma Not ma T/G
ed ed rs2181495Not ma Not ma G/A 0.78 0.76 0.617 ed ed Position dbSNP in ChromosomeAllA2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ D
NO:

rs3849023211 36870611 G/T

rs14443117217 36877617 A/G 0.25 0.26 0.876 rs20442957895 36878295 A/C

rs216609313308 36883708 C/T

rs237633414279 36884679 G/T 0.16 0.18 0.532 rs144432017026 36887426 C/T

rs204429418271 36888671 A/G NA 0.15 NA

rs189986420417 36890817 C/T

rs156209421843 36892243 A/G NA 0.28 NA

rs156209822069 36892469 A/G

rs156209722145 36892545 A/G

rs156209622519 36892919 A/G 0.20 0.23 0.364 rs156209522539 36892939 A/G 0.50 0.48 0.588 rs144431923236 36893636 A/C 0.79 0.79 0.923 rs144431823256 36893656 A/C 0.12 0.13 0.711 rs102593823402 36893802 ClT 0.18 0.22 0.247 rs102593723499 36893899 A/C

rs102593623620 36894020 C/T 0.84 0.86 0.403 rs102033323871 36894271 A/T

rs212065424136 36894536 ClG 0.14 0.16 0.682 rs258854725427 36895827 A/G 0.37 NA

rs204429325866 36896266 G/T

rs276032426541 36896941 A/G 0.60 0.60 0.965 rs258854626576 36896976 G/T 0.05 0.06 0.797 rs258854526689 36897089 A/G

rs276032826720 36897120 A/C 0.25 0.26 0.816 rs258854427113 36897513 C/T

rs276033127164 36897564 C/T 0.95 0.96 0.597 rs258854327186 36897586 A/G 0.60 0.61 0.801 rs258854228341 36898741 A/T

rs258854129160 36899560 C/T 0.62 0.61 0.972 rs258854029844 36900244 A/G 0.60 0.59 0.810 rs276033630665 36901065 G/T

rs276033730830 36901230 A/G 0.16 0.17 0.659 rs202873231061 36901461 A/C 0.60 0.60 0.976 rs258853831523 36901923 ClT 0.61 0.61 0.912 rs199261732326 36902726 C/T 0.61 0.59 0.583 rs199846932346 36902746 A/G

rs199847032358 36902758 C/T 0.84 0.81 0.338 rs197549834909 36905309 C/T

rs156209334975 36905375 A/G 0.88 0.84 0.199 rs197549735066 36905466 C/T 0.13 0.15 0.613 rs156209235096 36905496 G/T

rs224878835375 36905775 C/T 0.30 0.31 0.884 rs189986236304 36906704 A/G 0.17 0.18 0.563 rs258853236712 36907112 A/T 0.29 0.29 0.952 rs188587836770 36907170 C/T 0.33 0.36 0.405 rs98664837342 36907742 C/T 0.75 0.72 0.283 rs98664737412 36907812 C/T 0.79 0.74 0.186 Position dbSNP in ChromosomeAllA2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ D
NO:

rs101001037884 36908284 A/G _0.25 0.26 0.843_ rs101000938077 36908477 A/C 0.25 0.24 0.764 rs276032538300 36908700 C/T

rs258853138301 36908701 C/T

rs183838841189 36911589 C/T 0.76 0.72 0.284 rs197549544408 36914808 ClT

rs218149144493 36914893 A/C 0.12 0.15 0.464 rs197549644571 36914971 A/G 0.27 0.25 0.577 rs218149244670 36915070 A/G 0.10 0.11 0.844 rs222471945219 36915619 A/G 0.78 0.75 0.426 rs222472045258 36915658 C/T 0.21 0.20 0.790 rs195177047261 36917661 A/G 0.19 0.20 0.796 rs229604048473 36918873 A/C 0.43 0.42 0.804 rs195772348771 36919171 A/G 0.41 0.42 0.653 rs195772555292 36925692 C/T 0.77 0.75 0.439 rs288934656479 36926879 A/G 0.56 0.56 0.948 rs188587956747 36927147 A/C 0.46 0.45 0.959 rs195772660620 36931020 G/T 0.14 0.15 0.673 rs195772760688 36931088 A/C 0.76 0.73 0.255 rs188588061058 36931458 A/C 0.43 0.45 0.614 rs188588161129 36931529 C/T 0.13 0.10 0.346 rs94210861577 36931977 C/T 0.58 0.56 0.730 rs195177161961 36932361 A/G

rs237632363351 36933751 GlT

rs201335863926 36934326 A/G 0.13 0.15 0.469 rs218149465798 36936198 A/G 0.46 0.47 0.820 rs195772866043 36936443 A/C

rs195772966044 36936444 A/G 0.80 0.78 0.440 rs195773066246 36936646 C/T 0.15 0.17 0.668 rs195773166318 36936718 C/T 0.14 0.16 0.387 rs199846866547 36936947 G/T 0.12 0.13 0.615 rs195773271238 36941638 C/T 0.09 0.11 0.469 rs195773371283 36941683 A/G 0.60 0.02 rs237632271492 36941892 A/G 0.27 0.29 0.582 rs288934572274 36942674 A/G 0.17 0.21 0.308 rs181526773762 36944162 A/T 0.46 0.41 0.151 rs195773474209 36944609 G/T 0.68 0.69 0.766 rs195773575284 36945684 A/T 0.62 0.58 0.311 rs195773677347 36947747 A/C 0.07 0.08 0.688 rs195773777589 36947989 C/T 0.75 0.71 0.305 rs195773878096 36948496 A/G

rs195773978606 36949006 A/G

rs195774078862 36949262 G/T

rs195774179135 36949535 A/G 0.78 0.76 0.446 rs195774279146 36949546 A/G 0.96 0.96 0.938 rs 195774379456 36949856 C/T 0.17 0.19 0.667 rs195774479609 36950009 A/G 0.69 0.66 0.423 rs195774580086 36950486 A/G 0.90 0.89 0.738 rs195774680119 36950519 A/G 0.37 0.35 0.708 rs195774780766 36951166 C/T 0.72 0.70 0.639 rs214667081110 36951510 A/G 0.75 0.72 0.306 rs214667181269 36951669 A/T 0.16 0.17 0.806 rs195774881668 36952068 C/T 0.14 0.17 0.453 rs216230782433 36952833 C/T 0.76 0.73 0.465 rs196283982559 36952959 CIG

rs237631583298 36953698 C/T 0.64 0.63 0.767 rs142641083821 36954221 A/G 0.77 0.74 0.465 rs189592184121 36954521 C/T 0.78 0.75 0.320 rs189592284147 36954547 C/T 0.12 0.13 0.586 rs103577984543 36954943 A/G NA 0.65 NA

rs103578084554 36954954 A/G

rs103578184691 36955091 A/G 0.75 0.76 0.830 rs103578284727 36955127 A/G

Position dbSNP in ChromosomeAllA2 A2 CaseA2 Control rs# position Allele AF AF -Value SEQ ~D
NO:

rs142641185678 36956078 C/T 0.78 0.76 0.488 rs183460286699 36957099 C/T 0.18 0.18 0.945 rs183460386700 36957100 A/G 0.95 NA

rs183460486792 36957192 A/G 0.72 0.69 0.427 rs183460586832 36957232 A/G 0.73 0.72 0.647 rs216230887045 36957445 A/G

rs136534187140 36957540 A/G 0.16 0.17 0.667 rs182045887365 36957765 A/C 0.23 0.24 0.670 rs146931088342 36958742 C/T 0.19 0.21 0.592 rs305787988498 36958898 -/TCA 0.74 0.71 0.478 rs146931188589 36958989 A/G 0.74 0.72 0.582 rs76832695502 36965902 A/G

rs186352396968 36967368 C/T 0.20 0.21 0.687 rs146931297448 36967848 C/T 0.76 0.75 0.807 rs146931397568 36967968 C/T 0.78 0.79 0.824 rs195177398724 36969124 C/T

rs2120655Not ma Not ma T/G
ed ed rs2181495Not mapped~ Not G/A
~ mapped [0240] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1B for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1B can be determined by consulting Table 17. For example, the left-most X on the left graph is at position 36870611. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0241] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a l Okb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0242] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 6 Chrom 6 Region Proximal SNPs [0243] It has been discovered that SNPs rs756519, rs1042327 and rs8770 on chromosome 6 (6q27) are associated with occurrence of osteoarthritis in subjects. This region contains genes that encode proteasome (prosome, macropain) subunit, beta type, 1 (PSMBI), TATA box binding protein (TBP), and programmed cell death 2 (PDCD2).
[0244] One hundred-nine additional allelic variants proximal to rs756519, rs1042327 and rs8770 were identified and subsequently allelot0yped in osteoarthritis case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 20. The chromosome positions provided in column four of Table 20 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs14745556 229 170689279 c/t rs14745546 6310 170695360 a/

rs10334 6 11840 170700890 /t rs10541 6 11870 170700920 a/t rs38232996 12064 170701114 a/

rs742348 6 13392 170702442 c/

rs14746446 16354 170705404 a/

rs14746436 16559 170705609 c/t rs20569706 16935 170705985 a/

rs22234746 17616 170706666 c/t rs22062846 17737 170706787 c/t rs756519 6 18321 170707371 c/t rs756518 6 18453 170707503 a/

rs756517 6 18811 170707861 c/t rs14746426 20020 170709070 c/t rs20380936 21662 170710712 c/

rs20380926 23197 170712247 cl rs22234736 23446 170712496 /t rs760909 6 24339 170713389 /t rs20763196 25504 170714554 a/

rs37785896 27174 170716224 a/

rs38002366 28008 170717058 alt rs22062866 29294 170718344 c/t rs12717 6 29759 170718809 c/

rs21793736 30832 170719882 a/

rs38002356 44512 170733562 a/c rs38232986 44850 170733900 c/

rs20763186 45884 170734934 a/

rs22355066 46345 170735395 clt rs20729166 48589 170737639 a/

rs37347ti36 53371 170742421 a/

dbSNP ChromosomePosition ChromosomeAllele rs# in SEQ Position Variants ID NO:

rs31775716 53911 170742961 /t rs8770 6 53990 170743040 al rs31732196 55152 170744202 c!

rs9607446 55667 170744717 c/t rs20669546 58952 170748002 a/c rs20729176 59315 170748365 /t rs31732206 60029 170749079 a/

rs7342496 61477 170750527 a/c rs20923106 62988 170752038 c/t rs20923096 63090 170752140 c/

rs10165366 64021 170753071 alc rs22355066 65685 170754735 c/t rs20769986 70220 170759270 a/

rs20769976 70323 170759373 a/c rs23454786 70959 170760009 a/c rs20218996 73436 170762486 c/

rs20218986 82945 170771995 a/

rs23456826 82958 170772008 /t rs23456836 82961 170772011 c/

rs28811956 82964 170772014 c/t rs23456846 82965 170772015 It rs30462616 83006 170772056 -/cttt rs40834136 83025 170772075 c/t rs40834126 83034 170772084 a/

rs23456856 83074 170772124 /t rs20218976 83132 170772182 /t rs40362116 83155 170772205 c/t rs40362126 83172 170772222 alt rs40362136 83174 170772224 /t rs23456866 83206 170772256 c/t rs40362146 83216 170772266 /t rs40362156 83234 170772284 /t rs23456876 83252 170772302 a/

rs23456886 83260 170772310 a/c rs28811966 83263 170772313 a/c rs30462886 83296 170772346 -/at rs40362166 83319 170772369 a/

rs40362056 83322 170772372 c/

rs20923076 83324 170772374 alc rs40362066 83357 170772407 c/

rs23456896 83375 170772425 c/t rs23456906 83381 170772431 c/t rs23456916 83389 170772439 a/t rs23456926 83443 170772493 a/

rs30463066 83499 170772549 -/ t rs40362076 83545 170772595 clt rs23456936 83566 170772616 clt rs23456946 83591 170772641 c/t rs23456956 83619 170772669 /t rs23456966 83698 170772748 a/

rs40362096 83780 170772830 /t rs2345697~ 83784 170772834 g/t dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs28811976 83826 170772876 /t rs23456986 83832 170772882 c/t rs23456996 83852 170772902 c/t rs27446406 86297 170775347 c/t rs27446396 86315 170775365 /t rs27446386 86420 170775470 c!

rs27446376 86460 170775510 c/

rs27446366 86714 170775764 c/t rs27446356 86718 170775768 clt rs27446346 86736 170775786 c/

rs27446336 86753 170775803 c/t rs27446326 86766 170775816 It rs27446306 88162 170777212 c/

rs27446296 88218 170777268 a/

rs27446286 88246 170777296 al rs27446276 88255 170777305 c/t rs29776166 88309 170777359 /t rs29776176 88310 170777360 a/t rs27446266 88471 170777521 a/

rs27446256 88619 170777669 c/t rs31158476 88904 170777954 c/t rs27446236 89044 170778094 c/

rs40361936 90531 170779581 -/aaaaa rs40361946 90534 170779584 a/

rs40361966 90613 170779663 c/

rs10423276 46252 170735302 c/t Assay for Verifying and Allelotypin~ SNPs [0245] The methods used to verify and allelotype the 109 proximal SNPs of Table 20 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 21 and Table 22, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs1474555ACGTTGGATGACATCAACTGAAGCCGACAGACGTTGGATGAATGGTGGAATGTGATGAGA

rs1474554ACGTTGGATGATACACCTAGGACACCTCCAACGTTGGATGCAGAAGGAGATAAACCCAGC

rs10334ACGTTGGATGAACAGTTTCCTCCCTGATGCACGTTGGATGCGGCTGGTGAAAGATGTCTT

rs10541ACGTTGGATGACTATGCAGATCCGGAGTGCACGTTGGATGGTCCTTGGACAGAGCCATG

rs3823299ACGTTGGATGCTCATGTGTACGAGGATTTGACGTTGGATGGTCTGGAAGGGTCTTTATTC

rs742348ACGTTGGATGTGTGGATTTTCCAGTGCTCGACGTTGGATGCTGTACTTGAACTCCCAAGC

rs1474644ACGTTGGATGGCAAGACAAGCATAATTGGGACGTTGGATGTAAAGGGCATTTTGGCTTCC

rs1474643ACGTTGGATGTCTCCCAAATTAAAAGTGGCACGTTGGATGGATACCAAAGTCCTACTTAC

rs2056970ACGTTGGATGTGGGACTACAGGAAGAGAAGACGTTGGATGCAAAACACAGACCTTCAGCC

rs2223474ACGTTGGATGCCAGGGTAAAGAAAAGATCCACGTTGGATGAGAGGCTTACCTCCTAAAAG

rs2206284ACGTTGGATGTCACATACTAGGTGGATCCCACGTTGGATGAAAGAGGAGAACACAGGATG

rs756519ACGTTGGATGTCTAGAGACACCTGAGGTTGACGTTGGATGTGTTTCACTTCAGAGCCCTG

rs756518ACGTTGGATGCCCAGATTAGACTCTCTAACACGTTGGATGAAATAGCTGAGCTGCCATTG

dbSNP Forward Reverse rs# PCR primer PCR primer rs756517ACGTTGGATGCTCGGTTGTTGACTCCTATCACGTTGGATGGCGGATGTTAAGAGTCAGAG

rs1474642ACGTTGGATGGGAGGTCATACATTAGCTTCACGTTGGATGTACCATCTGACACAATTCTC

rs2038093ACGTTGGATGGAGACAGAGTTTCACTCTTGACGTTGGATGTAATCACTTGAACCCAGGAG

rs2038092ACGTTGGATGTTACCTGAGGTCAGGAGTTTACGTTGGATGCCACACCCAGCTGATTTTTG

rs2223473ACGTTGGATGCCTTTATGTTATTGCTTTCCACGTTGGATGCAGGGAAATTTAAGAATAGC

rs760909ACGTTGGATGGGAAGAGGCAAGCTTAGTTCACGTTGGATGGCAGCATTAACGAATGCCTG

rs2076319ACGTTGGATGGACATTTCACAATGCCTTTGACGTTGGATGCCAACAGCAACTTAAAAACTC

rs3778589ACGTTGGATGGCAAGAGAGAGAAAAGTTCCACGTTGGATGGTGTTTCTGTCCCATTTCAC

rs3800236ACGTTGGATGAGAGAATGAGGCCTCATTTTACGTTGGATGCTCAGTCATTGTTCTTTTTC

rs2206286ACGTTGGATGTTCAGACGCTAACCCTCTACACGTTGGATGAACATAGCCTCTGCTCTGTG

rs12717ACGTTGGATGAAAATCGCAGCTGCAAAGGGACGTTGGATGAGACAGCAAGTGTCGGATCC

rs2179373ACGTTGGATGGAAGTGACCTATGCTCACACACGTTGGATGAATGTCACTTCCGCCAGTTC

rs3800235ACGTTGGATGCTATGTGTTGATACCTCCAAGACGTTGGATGGCTTCATAAATGAACTGAAC

rs3823298ACGTTGGATGGGTGGTTTCTTGTCTTGATGACGTTGGATGTTTTTGTCCCAGAGCATCTG

rs2076318ACGTTGGATGTCCGCCAAATTATTGTAGCCACGTTGGATGCTCAGTAGAAATGCATGGGC

rs2235506ACGTTGGATGTAACCATGTCAACTGTTCTCACGTTGGATGCCCACCAACAATTTAGTAGG

rs2072916ACGTTGGATGACGCTGGAGTCACTAAGATGACGTTGGATGCAGATTAAGGCACAGGCATG

rs3734763ACGTTGGATGGCCTTTTGCCTTTCAGTGTCACGTTGGATGTAAAGAGGCTGGACCTTCAG

rs3177571ACGTTGGATGGTCTGTTGTCAATATAGGTGACGTTGGATGACAAAAGTGTCCAGTGACAG

rs8770 ACGTTGGATGAATTCCCTGTCACTGGACACACGTTGGATGCCAAAAATAGAGGTGCAGAG

rs3173219ACGTTGGATGACATAACCACACTGGAGGTGACGTTGGATGCCTAGTTTTCAGACACGGTC

rs960744ACGTTGGATGAAAGGCATGTCACAGTTCCCACGTTGGATGGCCCTCTGAGTCAGATAAAC

rs2066954ACGTTGGATGGAGGTTCTGGGTATAACTTTCACGTTGGATGCTACAAACCAGTAAGCTGATG

rs2072917ACGTTGGATGTGCTAGGCACTCACACTATCACGTTGGATGAGGCTTGGTAAGTTCCTCTG

rs3173220ACGTTGGATGTATCTGGGTTGACAAAGGCGACGTTGGATGACATAAGCAGGCTTGTGCAC

rs734249ACGTTGGATGAGGTGGACACCAGCAGGGAAACGTTGGATGTCACCTCTGCACATGTCTTG

rs2092310ACGTTGGATGTTAGTCAGGTAAAGCGGGACACGTTGGATGTCAGTGGAAGGCTGATCAAG

rs2092309ACGTTGGATGATCTAATTGCTTCCCCTCCCACGTTGGATGCAGCCTTCCACTGAATACAC

rs1016536ACGTTGGATGCCCCAAAAATTGGAGACAGGACGTTGGATGGGCTGTCATAATCGTGTGTC

rs2235506ACGTTGGATGAAGTGATTCTCCTGCCTCAGACGTTGGATGTGGTGAAACCCTGTCTCTAC

rs2076998ACGTTGGATGGCTCTGTGATTTCGATGATGACGTTGGATGAGCTACTTCTTGCAGGAGTC

rs2076997ACGTTGGATGCAGAGCTTCCAAGTGTTTTCACGTTGGATGAAAGGAGTGCTTAAAGGAGC

rs2345478ACGTTGGATGCCTTCAACAAGTGCTGACACACGTTGGATGATCCAGGCATTATTGCCAGC

rs2021899ACGTTGGATGGTTTTGTGGTGGATGATGGGACGTTGGATGAGAGTGCCCATAATGGACAG

rs2021898ACGTTGGATGCGCAAGAAACTCCTTGGATGACGTTGGATGCCAATTAAAGCCAAGGTCAC

rs2345682ACGTTGGATGATTCGCAAGAAACTCCTTGGACGTTGGATGGGAAGAAATCTTACCAGAAC

rs2345683ACGTTGGATGATTCGCAAGAAACTCCTTGGACGTTGGATGGGAAGAAATCTTACCAGAAC

rs2881195ACGTTGGATGATTCGCAAGAAACTCCTTGGACGTTGGATGGGAAGAAATCTTACCAGAAC

rs2345684ACGTTGGATGATTCGCAAGAAACTCCTTGGACGTTGGATGGGAAGAAATCTTACCAGAAC

rs3046261ACGTTGGATGCTCCACTCAGACATCAAAAGACGTTGGATGGTGACCTTGGCTTTAATTGG

rs4083413ACGTTGGATGGTGACCTTGGCTTTAATTGGACGTTGGATGCTCCACTCAGACATCAAAAG

rs4083412ACGTTGGATGGTGACCTTGGCTTTAATTGGACGTTGGATGCTCCACTCAGACATCAAAAG

rs2345685ACGTTGGATGGTTCTGGTAAGATTTCTTCCACGTTGGATGAGTCTTACAATAGATGACTG

rs2021897ACGTTGGATGGCAATTATTTACAGAAGCCCACGTTGGATGTCCCACACAGTCATCTATTG

rs4036211ACGTTGGATGCCCATTACAAGTTGGGCAGTTACGTTGGATGCTTTCTGATTCCTTTTTTTTCC

rs4036212ACGTTGGATGCTTTCTGATTCCTTTTTTTTCCACGTTGGATGCCCATTACAAGTTGGGCAGTT

rs4036213ACGTTGGATGCCCATTACAAGTTGGGCAGTTACGTTGGATGCTTTCTGATTCCTTTTTTTTCC

rs2345686ACGTTGGATGCCCATTACAAGTTGGGCAGTTACGTTGGATGCTTTCTGATTCCTTTTTTTTCC

rs4036214ACGTTGGATGCCCATTACAAGTTGGGCAGTTACGTTGGATGCTTTCTGATTCCTTTTTTTTCC

rs4036215ACGTTGGATGCTTTCTGATTCCTTTTTTTTCCACGTTGGATGCCCATTACAAGTTGGGCAGTT

rs2345687ACGTTGGATGGGATTGTAAGGTGAGACTTGACGTTGGATGTTCCTCCCCATTACAAGTTG

rs2345688ACGTTGGATGAGGGTCCCATCTAAGAATTC~ ACGTTGGATGGGATTGTAAGGTGAGACTTG

dbSNP Forward Reverse rs# PCR primer PCR primer rs2881196ACGTTGGATGAGGGTCCCATCTAAGAATTCACGTTGGATGGGATTGTAAGGTGAGACTTG

rs3046288ACGTTGGATGCCAACTTGTAATGGGGAGGAACGTTGGATGCAGTTTTTACAGAGGGTCCC

rs4036216ACGTTGGATGCTTGTAATGGGGAGGAAAAAAACGTTGGATGTTCTCATTTTAATCTGTCAG

rs4036205ACGTTGGATGCTTGTAATGGGGAGGAAAAAAACGTTGGATGTTCTCATTTTAATCTGTCAG

rs2092307ACGTTGGATGCTTGTAATGGGGAGGAAAAAAACGTTGGATGTTCTCATTTTAATCTGTCAG

rs4036206ACGTTGGATGGACCCTCTGTAAAAACTGACACGTTGGATGCCACTGCACCTCAAATCTTC

rs2345689ACGTTGGATGTTCCCTGAGTATCTCCCATGACGTTGGATGGGGACCCTCTGTAAAAACTG

rs2345690ACGTTGGATGTTCCCTGAGTATCTCCCATGACGTTGGATGGGGACCCTCTGTAAAAACTG

rs2345691ACGTTGGATGGCCACCTGTTGGAGATTTACACGTTGGATGGGGACCCTCTGTAAAAACTG

rs2345692ACGTTGGATGTACATGGGAGATACTCAGGGACGTTGGATGCCACTGCACCTCAAATCTTC

rs3046306ACGTTGGATGGTATAACAAACCTTACCCTTGACGTTGGATGTAAAGAAAGAAGATTTGAGG

rs4036207ACGTTGGATGTATCAATGGAGAATGCGTGGACGTTGGATGGGGAGTTAACCAGCAAAAGC

rs2345693ACGTTGGATGTCGACAACAAGAAGAGAAGGACGTTGGATGCACATTAGACAAGGGTAAGG

rs2345694ACGTTGGATGCTACCTCTCTCGACAACAAGACGTTGGATGCTTAAGTCCACGCATTCTCC

rs2345695ACGTTGGATGCGCATTCTCCATTGATAAGACACGTTGGATGCCATTTAAAAGCTACCTCTC

rs2345696ACGTTGGATGCCTTACACAAGTGTAACTTCACGTTGGATGCCCCAAAATATAATGGTAGG

rs4036209ACGTTGGATGGGAACACAGTGTATAAGACCACGTTGGATGGTTTTCACAACTTCGTTAGC

rs2345697ACGTTGGATGGTTTTCACAACTTCGTTAGCACGTTGGATGGCCACCCCAAAATATAATGG

rs2881197ACGTTGGATGGCTGGAGGAAAAACAAGAACACGTTGGATGCCTACCATTATATTTTGGGG

rs2345698ACGTTGGATGCTGGAGGAAAAACAAGAACTCACGTTGGATGCATTATATTTTGGGGTGGCAT

rs2345699ACGTTGGATGGCTGGAGGAAAAACAAGAACACGTTGGATGGGGTGGCATATTTTGGTCTT

rs2744640ACGTTGGATGGCAACAGCACTTAGTATGCCACGTTGGATGTGTGAAGCTGCAAATCTGGC

rs2744639ACGTTGGATGGCAACAGCACTTAGTATGCCACGTTGGATGTGTGAAGCTGCAAATCTGGC

rs2744638ACGTTGGATGAACCGTGGCAATACCACGTCACGTTGGATGTGGGTTTGGGCTGGATTTGG

rs2744637ACGTTGGATGTGAGTTGACAGCCTCTGCTGGACGTTGGATGCACGTCAGTAAGGCAGAGAC

rs2744636ACGTTGGATGTCGGAGATGACATTGTCACCACGTTGGATGTTCCAGGGGTTACGTGTGTG

rs2744635ACGTTGGATGTGAGTCTGACTGTGTCACGGACGTTGGATGTCGGAGATGACATTGTCACC

rs2744634ACGTTGGATGCGTGTTCCAGGGATTATATGACGTTGGATGGCACATAACGCTTGGAACTC

rs2744633ACGTTGGATGTATGAGTGTGACGGGTGTAGACGTTGGATGGCACATAACGCTTGGAACTC

rs2744632ACGTTGGATGTAGCTGCCTTCCACATCCAAACGTTGGATGTGTGACGGGTGTAGCGTTAG

rs2744630ACGTTGGATGGGGTTCAAATGCCTCTGATAGACGTTGGATGGGTCTAGGACAAGACCCATT

rs2744629ACGTTGGATGAACTTTCCCTTAGCCAGTGGACGTTGGATGATCAGAGGCATTTGAACCCC

rs2744628ACGTTGGATGTTGACCTCAAATCATGTCACACGTTGGATGTATCAGAGGCATTTGAACCC

rs2744627ACGTTGGATGGGGTGGTTTATGTTCCACTGACGTTGGATGCCAGAACTAATGCTAGCTTC

rs2977616ACGTTGGATGTTCCACTGGCTAAGAGAAAGACGTTGGATGCCAGAACTAATGCTAGCTTC

rs2977617ACGTTGGATGCCAGAACTAATGCTAGCTTCACGTTGGATGTTCCACTGGCTAAGAGAAAG

rs2744626ACGTTGGATGACAGTGAAATTGTATTTCCGACGTTGGATGGCACAAACTTAAGAATCTCC

rs2744625ACGTTGGATGAGCAAAATCCACCTATGTCCACGTTGGATGCTGAATTTTGTCTCCAGTAC

rs3115847ACGTTGGATGTCGAGGCAGAGGCGTAGTAACGTTGGATGATAGGAATGACATGAACCCG

rs2744623ACGTTGGATGACGCGAGTCCGTAGGTGCTGACGTTGGATGAAGAGGCTGCTACCCAGAG

rs4036193ACGTTGGATGAGAGCAAGACTCCGTCTCAAACGTTGGATGACATGTCGCTTGATGTGTGC

rs4036194ACGTTGGATGACATGTCGCTTGATGTGTGCACGTTGGATGAGAGCAAGACTCCGTCTCAA

rs4036196ACGTTGGATGCCCCAGCGTTCATATTTGTCACGTTGGATGTCTGGCCAAATGGTCATACC

rs1042327ACGTTGGATGAACTTCACATCACAGCTCCCACGTTGGATGCAGAAGTTGGGTTTTCCAGC

dbSNP Extend 'Perm rs# Primer Mix rs1474555 TGAAGCCGACAGTGACACC ACT

rs1474554 CCAATTTTGCACACCTCCAGCA ( ACG

dbSNP Extend Term rs# Primer Mix rs10334 CAGATCCGGAGTGCGTCC CGT

rs10541 TCTCTCTCAGCCGCAGAA CGT

rs3823299 GAGGATTTGTGATGAAAATACTA ACG

rs742348 AATCCCCGTGTTGTTCAAGG ACT

rs1474644 AAGGATGTTCATCATAGTGTTTA ACG

rs1474643 ACATGTTTATACATACACTCATG ACG

rs2056970 TTGGCAGCTTTTTAGGCCTC ACT

rs2223474 AAGTCTCAAAAAGGTCCC ACT

rs2206284 TAGGTGGATCCCTTTTCCC ACG

rs756519 CAGAGCCCTGTTCTTTGATTT ACG

rs756518 CAAAGGATGCTGTCTGGCC ACG

rs756517 GTTCCATGAGCGTTTTCTTTG ACG

rs1474642 CTTCAGTTTCTTCATCACTTTC ACT

rs2038093 TTTCACTCTTGTTGCCCAGG ACT

rs2038092 CCAACATGGTGAAACCCCATCT ACT

rs2223473 TAGAATTAAAATTAGACTTTGGGGACT

rs760909 GCAAGCTTAGTTCTAGGTCAG CGT

rs2076319 TCACAATGCCTTTGTAATGATTT ACT

rs3778589 GTTTTAGGAAGACTGCTCTGACAAACG

rs3800236 CTGAGAGCCAGCTGCAGTAA CGT

rs2206286 CCTCGCCGGCTGGCATAA ACT

rs12717 CCATCCCCAAGTCTCTGCCAG ACT

rs2179373 TGACCTATGCTCACACTTCTCA ACG

rs3800235 GTGTTGATACCTCCAAGTACATTTCGT

rs3823298 CTTGATGAAATAGTCATCCAACTAACT

rs2076318 TGAATTATCACCATCATCA ACT

rs2235506 TGTTGCCAATAACAATCA ACG

rs2072916 TGTGACAAGGGATTCCAC ACG

rs3734763 CATCTGTAAGCAGGGCCGC ACG

rs3177571 AAGACTGTGTAGCCTTCCTCTG ACT

rs8770 GTAGACACTGTGTAAGCAATC ACG

rs3173219 CACTGGAGGTGGAGAGCA ACT

rs960744 CCCCATCAGACCTGGCTGT ACT

rs2066954 TTACAATTTGAGCCTTGAGC CGT

rs2072917 CTATCCCGACCCGAGAAAC CGT

rs3173220 GCGATGAAACTGAACTGA ACT

rs734249 CACCAGCAGGGAAGGTTTG CGT

rs2092310 TTGAGGTGAGGGCTTCCAG ACT

rs2092309 TCCCCTCCCCTATTGTTTAC ACT

rs1016536 AAATTGGAGACAGGTCTCAGT ACT

rs2235506 CTGGGAGTACAGGTGCGC ACT

rs2076998 GTTTTTGTATAGTCTGCAGATGC ACT

rs2076997 ATCCATTTTAATGGGTTGCTAGCTACT

rs2345478 ACAACTGTACTTATTGGGCATA ACT

rs2021899 CTTTCTTGGAAACTCTTCCCA ACT

rs2021898 TTGGATGGGGTTAATGGCAG ACG

rs2345682 GTTAATGGCAGCTGTATTTTTCTGACT

rs2345683 GGCAGCTGTATTTTTCTGTGA ACT

rs2881195 CAGCTGTATTTTTCTGTGACCT ACG

dbSNP Extend Term rs# Primer Mix rs2345684 GCAGCTGTATTTTTCTGTGACCTTACT

rs3046261 GAAAACATTTGAGATACTGAAGATACT

rs4083413 TTCCTTTATCTTCAGTATCTCAA ACT

rs4083412 TCTTCAGTATCTCAAATGTTTTCAACG

rs2345685 CAACTTTTGATGTCTGAGTGGA ACT

rs2021897 ATTATTTACAGAAGCCCTATTCA ACT

rs4036211 TTTCCAAACAAAAGCTACCATGCAACT

rs4036212 AAATAATTGCATGGTAGCTTTTG CGT

rs4036213 ACAACTACTTTGATGTTATTTCC CGT

rs2345686 ACAATCCAAAAATCACATTCCTA ACT

rs4036214 GTCTCACCTTACAATCCAAAAAT CGT

rs4036215 AATGTGATTTTTGGATTGTAAGG ACT

rs2345687 AAGGTGAGACTTGTTTAGCTTT ACT

rs2345688 TCCTCCCCATTACAAGTTGGGCA ACT

rs2881196 TTTTCCTCCCCATTACAAGTTGG ACT

rs3046288 TAATGGGGAGGAAAAAAATTTTCTACT

rs4036216 ATGTTTTTGGAATTCTTAGATGG ACT

rs4036205 GTTTTTGGAATTCTTAGATGGGACACT

rs2092307 TGGAATTCTTAGATGGGACCC ACT

rs4036206 ACTGACAGATTAAAATGAGAAAAAACT

rs2345689 TCCCATGTATCCATAAGGTATAC ACT

rs2345690 GTATCTCCCATGTATCCATAAG ACT

rs2345691 CCCTGAGTATCTCCCATGTA CGT

rs2345692 TCTCCAACAGGTGGCTTTCA ACT

rs3046306 TTGCTGGTTAACTCCCCACT CGT

rs4036207 GCGTGGACTTAAGTCTGTATAAC ACT

rs2345693 AGAGTCTTATCAATGGAGAATGC ACT

rs2345694 GAAGAGAAGGATAACTAAATCACTACT

rs2345695 ATTTAGTTATCCTTCTCTTCTTG ACT

rs2345696 ACACAAGTGTAACTTCTACTCT ACT

rs4036209 GGAAACCAGAATATGCCACC CGT

rs2345697 AGCCAAAGGGACATATTTTGTGGTACT

rs2881197 GGAACACAGTGTATAAGACCAAA CGT

rs2345698 CGGTGGAACACAGTGTATAAG ACT

rs2345699 AAAACAAGAACTCTTTTCATTGCCACT

rs2744640 TTTATCTCCAGTTCCCCAGC ACG

rs2744639 AGCACTTAGTATGCCTTCTCCTT ACT

rs2744638 TGGCAATACCACGTCAGTAAG ACT

rs2744637 GCTGGGCTGGGTTTGGGCTG ACT

rs2744636 ACCCGTCACACTCATATAATCCC ACG

rs2744635 ACACATGCGTGTTCCAGGG ACT

rs2744634 GGGATTATATGAGTGTGACGG ACT

rs2744633 GGGTGTAGCGTTAGGTGAC ACT

rs2744632 GCGCACATAACGCTTGGAAC ACT

rs2744630 CGTGTTAAAACTCATGGCCAAAC ACT

rs2744629 ATAAACCACCCTGGAGTTCAT ACT

rs2744628 TTGAAGAAAACTTTCCCTTAGCCAACT

rs2744627 GTTTATGTTCCACTGGCTAAG ACT

~rs2977616 TTGAGGTCAAACATTAATATCAAGI ACT

dbSNP Extend Term rs# Primer Mix rs2977617 CTAGCTTCTCAATCTTTTGAGTT CGT

rs2744626 GTGAAATTGTATTTCCGGATTTC ACT

rs2744625 TCCTGAACACTTATCCACTTTAC ACT

rs3115847 CCAGGGCTGGAGGGGCC ACT

rs2744623 GGTGCTGGCGGGAGCGAGAGT ACT

rs4036193 GACTCCGTCTCAAAAAAAAAAAAAACT

rs4036194 CTTGATGTGTGCTTCAGGGTA ACG

rs4036196 CAGTGCAAGTAAAGAGCCTTA ACT

rs1042327 CATCACAGCTCCCCACCAT ACT

Genetic Anal, [0246] Allelotyping results from the discovery cohort are shown for cases and controls in Table 23.
The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (A1 AF
= 1-A2 AF). For example, the SNP rs1474555 has the following case and control allele frequencies: case Al (C) = 0.64;
case A2 (T) = 0.36; control A1 (C) = 0.70; and control A2 (T) = 0.30, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 3 rs1474555 229 170689279 C/T 0.36 0.30 0.024 rs1474554 6310 170695360 A/G 0.48 0.43 0.058 rs10334 11840 170700890 G/T

rs10541 11870 170700920 A/T

rs3823299 12064 170701114 A/G 0.45 0.41 0.125 rs742348 13392 170702442 C/G 0.46 0.44 0.275 rs1474644 16354 170705404 A/G 0.75 0.77 0.270 rs1474643 16559 170705609 C/T 0.45 0.40 0.042 rs2056970 16935 170705985 A/G 0.36 0.33 0.242 rs2223474 17616 170706666 C/T 0.42 0.46 0.140 rs2206284 17737 170706787 C/T 0.37 0.35 0.493 rs756519 18321 170707371 C/T

rs756518 18453 170707503 A/G 0.49 0.53 0.133 rs756517 18811 170707861 C/T

rs1474642 20020 170709070 ClT 0.12 0.12 0.904 rs2038093 21662 170710712 C/G

rs2038092 23197 170712247 C/G

rs2223473 23446 170712496 G/T 0.42 0.45 0.296 rs760909 24339 170713389 G/T 0.49 0.52 0.255 rs2076319 25504 170714554 A/G 0.43 0.46 0.219 rs3778589 27174 170716224 A/G 0.49 0.54 0.081 rs3800236 28008 170717058 A/T 0.47 0.50 0.319 rs2206286 29294 170718344 C/T 0.81 0.82 0.831 rs12717 29759 170718809 C/G 0.52 0.57 0.081 rs2179373 30832 170719882 A/G 0.58 0.62 0.089 rs3800235 44512 170733562 A/C 0.60 0.64 0.077 rs3823298 44850 170733900 C/G 0.44 0.38 0.022 rs2076318 45884 170734934 A/G 0.41 0.45 0.109 rs2235506 46345 170735395 C/T 0.68 0.66 0.320 rs2072916 48589 170737639 A/G 0.48 0.51 0.192 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele . Control Value SEQ ID Case AF
NO: 3 AF

rs373476353371 170742421A/G 0.50 0.54 0.142 rs317757153911 170742961G/T

rs8770 53990 170743040A/G

rs317321955152 170744202C/G 0.49 0.53 0.056 rs960744 55667 170744717C/T 0.39 0.35 0.179 rs206695458952 170748002A/C 0.37 0.32 0.057 rs207291759315 170748365G/T 0.46 0.42 0.153 rs317322060029 170749079A/G

rs734249 61477 170750527A/C 0.48 0.40 0.022 rs209231062988 170752038C/T

rs209230963090 170752140C/G 0.43 0.47 0.165 rs101653664021 170753071A/C 0.10 0.10 0.985 rs223550665685 170754735C/T

rs207699870220 170759270A/G

rs207699770323 170759373AlC 0.90 0.90 0.814 rs234547870959 170760009A/C 0.09 0.09 0.947 rs202189973436 170762486C/G 0.46 0.43 0.218 rs202189882945 170771995A/G

rs234568282958 170772008G/T

rs234568382961 170772011C/G 0.28 0.34 0.019 rs288119582964 170772014C/T

rs234568482965 170772015G/T

rs304626183006 170772056-/CTTT

rs408341383025 170772075C/T

rs408341283034 170772084A/G

rs234568583074 170772124G/T 0.71 0.71 0.835 rs202189783132 170772182G/T

rs403621183155 170772205C/T

rs403621283172 170772222A/T

rs403621383174 170772224G/T

rs234568683206 170772256C/T

rs403621483216 170772266G/T

rs403621583234 170772284G/T

rs234568783252 170772302A/G 0.55 0.50 0.085 rs234568883260 170772310AlC 0.53 0.52 0.958 rs288119683263 170772313A/C

rs304628883296 170772346-/AT

rs403621683319 170772369A/G

rs403620583322 170772372C/G

rs209230783324 170772374A/C

rs403620683357 170772407C/G

rs234568983375 170772425C/T

rs234569083381 170772431C/T

rs234569183389 170772439A/T

rs234569283443 170772493A/G

rs304630683499 170772549-/GGTG 0.42 0.43 0.761 rs403620783545 170772595C/T

rs234569383566 170772616C/T

rs234569483591 170772641C/T

rs234569583619 170772669G/T

rs234569683698 170772748A/G

rs403620983780 170772830G/T 0.79 0.73 0.156 rs234569783784 170772834G/T

rs288119783826 170772876G/T

rs234569883832 170772882C/T

rs234569983852 170772902C/T

rs274464086297 170775347C/T 0.53 0.53 0.973 rs274463986315 170775365G/T 0.40 0.40 0.789 rs274463886420 170775470C/G 0.39 0.39 0.941 rs274463786460 170775510C/G 0.40 0.42 0.497 rs274463686714 170775764C/T 0.76 0.73 0.271 rs274463586718 170775768C/T 0.03 0.02 0.425 rs274463486736 170775786C/G 0.96 0.94 0.436 rs274463386753 170775803C/T 0.14 0.16 0.409 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 3 rs274463286766 170775816G/T 0.80 0.83 0.217 rs274463088162 170777212CIG

rs274462988218 170777268A/G 0.80 0.80 0.978 rs274462888246 170777296AlG 0.71 0.67 0.206 rs274462788255 170777305C/T 0.32 0.30 0.335 rs297761688309 170777359G/T

rs297761788310 170777360A/T

rs274462688471 170777521A/G

rs274462588619 170777669C/T

rs311584788904 170777954C/T

rs274462389044 170778094ClG

rs403619390531 170779581-/AAAAA

rs403619490534 170779584AlG

rs403619690613 170779663C/G

rs 104232746252 170735302ClT 0.45 0.39 0.028 [0247] The Chrom 6 proximal SNPs were also allelotyped in the replication cohorts using the methods described herein and the primers provided in Tables 11 and 12. The replication allelotyping results for replication cohort # 1 and replication cohort #2 are provided in Tables 24 and 25, respectively.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 3 rs1474555 229 170689279C/T 0.37 0.27 0.004 rs1474554 6310 170695360A/G 0.50 0.42 0.020 rs10334 11840 170700890G/T

rs10541 11870 170700920A/T

rs3823299 12064 170701114A/G 0.45 0.40 0.080 rs742348 13392 170702442C/G 0.47 0.41 0.075 rs1474644 16354 170705404A/G 0.75 0.79 0.231 rs1474643 16559 170705609C/T 0.46 0.39 0.028 rs2056970 16935 170705985A/G 0.38 0.33 0.129 rs2223474 17616 170706666C/T 0.41 0.48 0.052 rs2206284 17737 170706787C/T 0.37 0.34 0.342 rs756519 18321 170707371C/T

rs756518 18453 170707503A/G 0.48 0.56 0.013 rs756517 18811 170707861C/T

rs1474642 20020 170709070C/T 0.10 0.13 0.27_7_ rs2038093 21662 170710712C/G

rs2038092 23197 170712247C/G

rs2223473 23446 170712496G/T 0.42 0.48 0.070 rs760909 24339 170713389G/T 0.47 0.54 0.077 rs2076319 25504 170714554A/G 0.41 0.49 0.017 rs3778589 27174 170716224A/G 0.50 0.57 0.035 rs3800236 28008 170717058A/T 0.47 0.52 0.126 rs2206286 29294 170718344ClT 0.80 0.80 0.952 rs12717 29759 170718809C/G 0.53 0.59 0.059 rs2179373 30832 170719882AlG 0.57 0.64 0.025 rs3800235 44512 170733562A/C 0.59 0.65 0.065 rs3823298 44850 170733900C/G 0.46 0.36 0.003 rs2076318 45884 170734934A/G 0.40 0.47 0.017 rs2235506 46345 170735395C/T 0.68 0.65 0.434 rs2072916 48589 170737639A/G 0.47 0.54 0.026 rs3734763 53371 170742421A/G 0.49 0.56 0.052 rs3177571 53911 170742961G/T

rs8770 53990 170743040A/G

rs3173219 55152 170744202C/G 0.49 0.55 0.069 rs960744 55667 170744717C/T 0.39 0.34 0.131 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 3 rs2066954 58952 170748002 A/C 0.36 0.31 0.096 rs2072917 59315 170748365 G/T 0.46 0.41 0.070 rs3173220 60029 170749079 A/G

rs734249 61477 170750527 A/C 0.37 NA 0.484 rs2092310 62988 170752038 C/T

rs2092309 63090 170752140 C/G 0.43 0.49 0.102 rs1016536 64021 170753071 A/C 0.08 0.11 0.277 rs2235506 65685 170754735 C/T

rs2076998 70220 170759270 A/G

rs2076997 70323 170759373 A/C 0.89 0.91 0.655 rs2345478 70959 170760009 A/C 0.08 0.09 0.660 rs2021899 73436 170762486 C/G 0.48 0.42 0.081 rs2021898 82945 170771995 A/G

rs2345682 82958 170772008 G/T

rs2345683 82961 170772011 C/G 0.32 0.39 0.046 rs2881195 82964 170772014 C/T

rs2345684 82965 170772015 G/T

rs3046261 83006 170772056 -/CTTT

rs4083413 83025 170772075 C/T

rs4083412 83034 170772084 A/G

rs2345685 83074 170772124 G/T 0.69 0.70 0.772 rs2021897 83132 170772182 G/T

rs4036211 83155 170772205 C/T

rs4036212 83172 170772222 A/T

rs4036213 83174 170772224 G/T

rs2345686 83206 170772256 C/T

rs4036214 83216 170772266 G/T

rs4036215 83234 170772284 G/T

rs2345687 83252 170772302 A/G 0.62 NA NA

rs2345688 83260 170772310 A/C 0.46 0.49 0.383 rs2881196 83263 170772313 A/C

rs3046288 83296 170772346 -/AT

rs4036216 83319 170772369 AIG

rs4036205 83322 170772372 C/G

rs2092307 83324 170772374 A/C

rs4036206 83357 170772407 C/G

rs2345689 83375 170772425 ClT

rs2345690 83381 170772431 C/T

rs2345691 83389 170772439 A/T

rs2345692 83443 170772493 A/G

rs3046306 83499 170772549 -/GGTG0.39 0.40 0.729 rs4036207 83545 170772595 C/T

rs2345693 83566 170772616 C/T

rs2345694 83591 170772641 C/T

rs2345695 83619 170772669 G/T

rs2345696 83698 170772748 A/G

rs4036209 83780 170772830 G/T 0.79 0.73 0.156 rs2345697 83784 170772834 G/T

rs2881197 83826 170772876 G/T

rs2345698 83832 170772882 C/T

rs2345699 83852 170772902 C/T

rs2744640 86297 170775347 C/T 0.49 0.51 0.583 rs2744639 86315 170775365 G/T 0.45 0.43 0.745 rs2744638 86420 170775470 C/G 0.38 0.38 0.852 rs2744637 86460 170775510 C/G 0.35 0.40 0.216 rs2744636 86714 170775764 C/T 0.71 0.73 0.482 rs2744635 86718 170775768 CIT 0.05 0.03 0.195 rs2744634 86736 170775786 C/G 0.93 0.92 0.601 rs2744633 86753 170775803 C/T 0.19 0.20 0.681 rs2744632 86766 170775816 G/T 0.85 0.90 0.070 rs2744630 88162 170777212 C/G

rs2744629 88218 170777268 A/G 0.78 0.79 0.891 rs2744628 88246 170777296 A/G 0.68 0.67 0.766 rs2744627 88255 170777305 C/T 0.32 0.30 0.636 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 3 rs2977616 88309 170777359G/T

rs2977617 88310 170777360A/T

rs2744626 88471 170777521A/G

rs2744625 88619 170777669C/T

rs3115847 88904 170777954C/T

rs2744623 89044 170778094C/G

rs4036193 90531 170779581-/AAAAA

rs4036194 90534 170779584A/G

rs4036196 90613 170779663C/G

rs1042327 46252 170735302C/T 0.46 0.37 0.004 dbSNP Position ChromosomAl/A2 F A2 F A2 F p-rs# in a PositionAllele Case Control Value SEQ ID AF AF
NO: 3 rs1474555 229 170689279C/T 0.35 0.36 0.770 rs1474554 6310 170695360A/G 0.45 0.44 0.873 rs10334 11840 170700890G/T

rs10541 11870 170700920A/T

rs3823299 12064 170701114A/G unt 0.43 NA
ed rs742348 13392 170702442C/G 0.45 0.47 0.600 rs1474644 16354 170705404A/G 0.74 0.75 0.775 rs 147464316559 170705609C/T 0.43 0.41 0.614 rs2056970 16935 170705985A/G 0.33 0.33 0.978 rs2223474 17616 170706666C/T 0.44 0.43 0.944 rs2206284 17737 170706787C/T 0.36 0.37 0.901 rs756519 18321 170707371C/T

rs756518 18453 170707503A/G 0.50 0.47 0.453 rs756517 18811 170707861C/T

rs1474642 20020 170709070C/T 0.15 0.11 0.147 rs2038093 21662 170710712C/G

rs2038092 23197 170712247ClG

rs2223473 23446 170712496G/T 0.43 0.40 0.408 rs760909 24339 170713389G/T 0.51 0.48 0.506 rs2076319 25504 170714554A/G 0.44 0.40 0.264 rs3778589 27174 170716224A/G 0.49 0.48 0.910 rs3800236 28008 170717058A/T 0.48 0.46 0.670 rs2206286 29294 170718344C/T 0.83 0.84 0.685 rs12717 29759 170718809C/G 0.51 0.53 0.726 rs2179373 30832 170719882A/G 0.59 0.58 0.880 rs3800235 44512 170733562A/C 0.60 0.62 0.632 rs3823298 44850 170733900C/G 0.41 0.41 0.945 rs2076318 45884 170734934A/G 0.43 0.42 0.636 rs2235506 46345 170735395C/T 0.69 0.67 0.594 rs2072916 48589 170737639A/G 0.49 0.46 0.399 rs3734763 53371 170742421A/G 0.51 0.51 0.888 rs3177571 53911 170742961G/T

rs8770 53990 170743040A/G

rs3173219 55152 170744202C/G 0.48 0.51 0.493 rs960744 55667 170744717C/T 0.38 0.37 0.738 rs2066954 58952 170748002A/C 0.37 0.34 0.378 rs2072917 59315 170748365G/T 0.45 0.45 0.982 rs3173220 60029 170749079A/G

rs734249 61477 170750527A/C 0.46 0.02 rs2092310 62988 170752038C/T

rs2092309 63090 170752140C/G 0.43 0.44 0.891 rs1016536 64021 170753071A/C 0.13 0.09 0.173 rs2235506 65685 170754735C/T

rs2076998 70220 170759270A/G

rs2076997 70323 170759373A/C 0.92 0.89 0.256 rs2345478 70959 170760009A/C 0.11 0.10 0.545 rs2021899 73436 170762486C/G 0.44 0.45 0.797 dbSNP Position Chromosom~ Al/A2F A2 F A2 F p-rs# in a PositionAllele Case Control Value SEQ ID AF AF
NO: 3 rs202189882945 170771995A/G

rs234568282958 170772008G/T

rs234568382961 170772011C/G 0.23 0.26 0.407 rs288119582964 170772014C/T

rs234568482965 170772015G/T

rs304626183006 170772056-/CTTT

rs408341383025 170772075C/T

rs408341283034 170772084A/G

rs234568583074 170772124G/T 0.74 0.71 0.533 rs202189783132 170772182GlT

rs403621183155 170772205C/T

rs403621283172 170772222A/T

rs403621383174 170772224G/T

rs234568683206 170772256C/T

rs403621483216 170772266G/T

rs403621583234 170772284G/T

rs234568783252 170772302A/G 0.47 0.50 0.457 rs234568883260 170772310A/C 0.61 0.58 0.434 rs288119683263 170772313A/C

rs304628883296 170772346-/AT

rs403621683319 170772369A/G

rs403620583322 170772372C/G

rs209230783324 170772374A/C

rs403620683357 170772407C/G

rs234568983375 170772425C/T

rs234569083381 170772431C/T

rs234569183389 170772439A/T

rs234569283443 170772493A/G

rs304630683499 170772549-/GGTG

rs403620783545 170772595C/T

rs234569383566 170772616C/T

rs234569483591 170772641C/T

rs234569583619 170772669G/T

rs234569683698 170772748A/G

rs403620983780 170772830G/T

rs234569783784 170772834G/T

rs288119783826 170772876G/T

rs234569883832 170772882C/T

rs234569983852 170772902C/T

rs274464086297 170775347C/T 0.57 0.55 0.595 rs274463986315 170775365G/T 0.35 0.34 0.752 rs274463886420 170775470C/G 0.41 0.40 0.793 rs274463786460 170775510C/G 0.47 0.46 0.836 rs274463686714 170775764C/T 0.83 NA

rs274463586718 170775768C/T

rs274463486736 170775786C/G unt 0.97 NA
ed rs274463386753 170775803C/T 0.09 0.10 0.691 rs274463286766 170775816G/T 0.74 0.72 0.529 rs274463088162 170777212C/G

rs274462988218 170777268A/G 0.81 0.81 0.959 rs274462888246 170777296A/G 0.74 NA

rs274462788255 170777305C/T 0.33 0.29 0.341 rs297761688309 170777359G/T

rs297761788310 170777360AIT

rs274462688471 170777521A/G

rs274462588619 170777669C/T

rs311584788904 170777954C/T

rs274462389044 170778094C/G

rs403619390531 170779581-lAAAAA

rs403619490534 170779584A/G

rs403619690613 170779663C/G

rs104232746252 170735302C/T 0.42 0.43 0.880 [0248] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1 C for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1 C can be determined by consulting Table 23. For example, the left-most X on the left graph is at position 170689279. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0249] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a l Okb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0250] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 7 ELP3 Region Proximal SNPs [0251] It has been discovered that SNP rs1563055 in elongation protein 3 homolog (ELP3) is associated with occurrence of osteoarthritis in subjects.
[0252] Thirty-three additional allelic variants proximal to rs1563055 were identified and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2.
The polymorphic variants are set forth in Table 26. The chromosome positions provided in column four of Table 26 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position Chromosome Allele in SEQ

rs# ChromosomeID NO: Position Variants rs10006588 211 27927511 c/t dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs19848808 473 27927773 c/t rs999112 8 1536 27928836 c/t rs735880 8 5639 279'32939 c/t rs20450298 17186 27944486 a/

rs20450288 17335 27944635 c/t rs19473848 25029 27952329 c/

rs19473858 25111 27952411 c/t rs19017448 28811 27956111 a/

rs19017458 28863 27956163 a/t rs971882 8 30809 27958109 alc rs13773388 40985 27968285 a/c rs23054528 45147 27972447 c/t rs23054518 45282 27972582 a/

rs21234728 46168 27973468 /t rs21677688 46328 27973628 al rs15630558 49077 27976377 a/

rs22903718 51925 27979225 c/t rs22903708 52141 27979441 a/

rs22903698 52168 27979468 c/t rs28749048 60852 27988152 c/t rs32139978 62468 27989768 a/

rs32139988 65572 27992872 /t rs15309298 79089 28006389 a/c rs10002758 79541 28006841 c/t rs10002748 79790 28007090 c/t rs37578968 90843 28018143 a/

rs37578958 90978 28018278 c/t rs37578948 91052 28018352 c/

rs37578938 91131 28018431 a/

rs37578928 91132 28018432 c/t rs37578918 94439 28021739 a/

rs37578908 94621 28021921 a/t Assay for Verifying and Allelotypin~ SNPs [0253] The methods used to verify and allelotype the 33 proximal SNPs of Table 26 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 27 and Table 28, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs1000658ACGTTGGATGTTCTCAAAAAAGAAACACATACGTTGGATGGGGTTATCAGTTTGAGATTC

rs1984880ACGTTGGATGCCATTTGCCAATTCCTGTGGACGTTGGATGATGGGCTGAAATGTATCCCC

rs999112ACGTTGGATGCTAAGCACATGCCTTTCTTGACGTTGGATGCTATTTTCTACTGGGAGATG

rs735880ACGTTGGATGTGCCTTCATTCTCCAACCACACGTTGGATGAACAGAGTGAGACCCATCTG

rs2045029ACGTTGGATGAGTCATTGCTAGCTTTCTGGACGTTGGATGGGGACTTTAGGGAAGTTATAG

rs2045028ACGTTGGATGAGCTTGTAGTGAGCCGAGATACGTTGGATGTGAGACAGAGTCTTGCTCTG

rs1947384ACGTTGGATGATTCTCCACCGAGAAACCAGACGTTGGATGTTGTGGCAGCAAGAAGGAAC
~

dbSNP Forward Reverse rs# PCR primer PCR primer rs1947385ACGTTGGATGAAATTTCAACAGTCAACAATACGTTGGATGGTCAGTTTTGAAAACTGATC

rs1901744ACGTTGGATGCCTTGATTGAAGAGTAAAGCACGTTGGATGATCAAATATTCCTCATCCCC

rs1901745ACGTTGGATGCTTCTGCCTTTACCTGTGTCACGTTGGATGAAATGAAGCAGCACTCACAG

rs971882ACGTTGGATGAAGCCCTAATCATTGGTACGACGTTGGATGGATGGGTGCTAAAAAGACAC

rs1377338ACGTTGGATGCCCACATATCTACACATCAAGACGTTGGATGAGGGAGATAGGTGGTTAAAG

rs2305452ACGTTGGATGCCGTGTTGCAACTAACAGGGACGTTGGATGAGACGTTCCCATCCTCCATC

rs2305451ACGTTGGATGGCAGAGCCACCAGAGATAAAACGTTGGATGTTTTACGACAGGCGGGATTG

rs2123472ACGTTGGATGCACTTAGAATTGTTGCTTGGACGTTGGATGGCTGTATCTGTGACCTCAAA

rs2167768ACGTTGGATGGAATCAACATGACTTGGTGACACGTTGGATGATCTCACTCTAACTTGCTCC

rs1563055ACGTTGGATGAGTTCTTTCTCCTCACATTGACGTTGGATGCCCTTTAGAAGCACATACTC

rs2290371ACGTTGGATGATCCTCTTGGTAGCTTGTCCACGTTGGATGCTGTCTTGGTTTTCACCCTG

rs2290370ACGTTGGATGCAACCTCTACCTCACTACACACGTTGGATGATGAGGTATCGACACACTGG

rs2290369ACGTTGGATGACACACTGGGTATCTGTTCTACGTTGGATGTCAGAATCCCCAACCTCTAC

rs2874904ACGTTGGATGAAATTCCAGGCTGGGTACAGACGTTGGATGTGCTGACCTTAAGTGATCCG

rs3213997ACGTTGGATGGGTTGGCTAGAAGAGAAAAAACGTTGGATGTACAGTCCTTTTGAAACTAC

rs3213998ACGTTGGATGACAGTTTGTTGACATAGTAGACGTTGGATGAGGCTGAAAAGACATTCATG

rs1530929ACGTTGGATGGGCTTTCACTATATTTCCTCACGTTGGATGGAATACAGTAAGCCTATGGG

rs1000275ACGTTGGATGAACCCCAGAAAGCAAAAAGCACGTTGGATGCACGCTTGCTAACTTAATGG

rs1000274ACGTTGGATGGCCTAAGACAGGATCCAAACACGTTGGATGTTACTGCGTGCCTTAGTACC

rs3757896ACGTTGGATGCCTTCAAGCAAGTCAGTTACACGTTGGATGCAGAAACTGTGTGACTGATC

rs3757895ACGTTGGATGAAAATCATTGGCCAAACTGCACGTTGGATGCTCCTTAGTATTCTTAGGTG

rs3757894ACGTTGGATGAGAAGGGTTGAACAACAAGGACGTTGGATGCACCTAAGAATACTAAGGAG

rs3757893ACGTTGGATGCCCTTGTTGTTCAACCCTTCACGTTGGATGCTGCATGTGGATACCTACAC

rs3757892ACGTTGGATGTCCTGCATGTGGATACCTACACGTTGGATGCCCTTGTTGTTCAACCCTTC

rs3757891ACGTTGGATGATGGGCCAATTCTCCATAGGACGTTGGATGAGGCCTGTTAAGGAAACCTG

rs3757890ACGTTGGATGCAGGTGGATGTAGGCTTAAGACGTTGGATGGCACCACTGCCTCTTGTTTT

dbSNP Extend Term rs# Primer Mix rs1000658 AATTGACAATGTTGGGACTGTT ACG

rs1984880 TGTGGTGTAAATAGGAGTTAGTGGACT

rs999112 GCACATGCCTTTCTTGGAACTG ACG

rs735880 AACCTTTACTTGTACTACATGC ACG

rs2045029 GCTAGCTTTCTGGTAATGAAAAT ACT

rs2045028 GATCGCACCACTGCACTCCAG ACG

rs1947384 ATAGCGGCAGTCCAAAAAGC ACT

rs1947385 TTCAACAGTCAACAATGAAACC ACT

rs1901744 ATAGTCAAGTATGCAAATGAAGC ACT

rs1901745 CCTTTACCTGTGTCTTCCCT CGT

rs971882 CCTAATCATTGGTACGGTCTCA ACT

rs1377338 AGTATTAGCTCAAATATCACATTGACT

rs2305452 CAGGGTAGCAGGCGGCC ACG

rs2305451 CCACAAACTCAGACCACGG ACT

rs2123472 CAGTTAATGTCAAGAAGCATAG ACT

rs2167768 ACATGACTTGGTGACAGAAGAA ACT

rs1563055 TTCTCCTCACATTGTTTCTACT ACG

rs2290371 GGTAGCTTGTCCTTAAATAACCGTACT

rs2290370 GGAGCAGGGACTTCTGCCA ACT

dbSNP Extend Term rs# Primer Mix rs2290369 AGTCCCTGCTCCATGTGAC ACT

rs2874904 GGCTAACGCCTGTAATCCCA ACT

rs3213997 AGAAAAATATTGTTATGCCCACA ACG

rs3213998 TAGTATTCTCAAATAGAGAGATTCACT

rs1530929 TTTCCTCTTTCCAGAATTGTATTTACT

rs1000275 ATGAGAATATCCTAGAATGAGGCAACG

rs1000274 GAATCATCAGGTCCTGTGCC ACG

rs3757896 TAATTCTCCTTAAGTAGTTAATTCACT

rs3757895 TTGGCCAAACTGCAGGATCT ACT

rs3757894 AAGGGCCACACAAGCAATTTCAA ACT

rs3757893 CCAAAGGACATTAGGTGGTG ACG

rs3757892 TGTGGATACCTACACTGCTC ACG

rs3757891 AGGATAAGTGTAACGGGGTC ACT

rs3757890 AGTGACACTCTTACTTCACAC I
CGT

Genetic Anal, sis [0254] Allelotyping results from the discovery cohort are shown for cases and controls in Table 29.
The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (A1 AF
= 1-A2 AF). For example, the SNP rs1000658 has the following case and control allele frequencies: case A1 (C) = 0.36;
case A2 (T) = 0.64; control A1 (C) = 0.37; and control A2 (T) = 0.63, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 4 rs1000658211 27927511 C/T 0.79 0.80 0.591 rs1984880473 27927773 C/T 0.47 0.48 0.735 rs999112 1536 27928836 C/T 0.72 0.72 0.775 rs735880 5639 27932939 C/T 0.20 0.19 0.561 rs204502917186 27944486 A/G 0.54 0.56 0.361 rs204502817335 27944635 C/T

rs194738425029 27952329 C/G 0.63 0.60 0.122 rs194738525111 27952411 C/T

rs190174428811 27956111 A/G 0.18 0.18 0.796 rs190174528863 27956163 A/T 0.14 0.18 0.117 rs971882 30809 27958109 A/C

rs137733840985 27968285 A/C 0.28 0.24 0.085 rs230545245147 27972447 C/T 0.31 0.27 0.078 rs230545145282 27972582 A/G 0.48 0.52 0.130 rs212347246168 27973468 G/T 0.42 0.45 0.239 rs216776846328 27973628 A/G 0.38 0.35 0.350 rs156305549077 27976377 A/G

rs229037151925 27979225 C/T 0.28 0.24 0.039 rs229037052141 27979441 A/G 0.85 0.84 0.551 rs229036952168 27979468 C/T 0.43 0.47 0.138 rs287490460852 27988152 C/T 0.26 0.23 0.132 rs321399762468 27989768 A/G 0.44 0.47 0.201 rs321399865572 27992872 G/T 0.83 0.80 0.223 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase C_on_trolValue SEQ ID AF AF
NO: 4 rs153092979089 28006389 A/C 0.47 0.49 0.556 rs100027579541 28006841 C/T 0.86 0.87 0.771 rs100027479790 28007090 C/T 0.54 0.56 0.510 rs375789690843 28018143 AlG

rs375789590978 28018278 C/T 0.46 0.47 0.874 rs375789491052 28018352 C/G 0.08 0.09 0.709 rs375789391131 28018431 A/G 0.16 0.15 0.590 rs375789291132 28018432 C/T 0.09 0.08 0.595 rs375789194439 28021739 A/G

rs375789094621 28021921 A/T 0.98 0.96 0.167 [0255] The ELP3 proximal SNPs were also allelotyped in the replication cohorts using the methods described herein and the primers provided in Tables 27 and 28. The replication allelotyping results for replication cohort #1 and replication cohort #2 are provided in Tables 30 and 31, respectively.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 4 rs1000658211 27927511 C/T 0.78 0.79 0.863 rs1984880473 27927773 C/T 0.46 0.48 0.594 rs999112 1536 27928836 C/T 0.71 0.70 0.759 rs735880 5639 27932939 C/T 0.20 0.17 0.255 rs204502917186 27944486 A/G 0.55 0.57 0.526 rs204502817335 27944635 C/T

rs194738425029 27952329 C/G 0.65 0.61 0.198 rs194738525111 27952411 C/T

rs190174428811 27956111 A/G 0.19 0.18 0.674 rs190174528863 27956163 A/T 0.15 0.18 0.448 rs971882 30809 27958109 A/C

rs137733840985 27968285 A/C 0.29 0.22 0.039 rs230545245147 27972447 C/T 0.31 0.26 0.067 rs230545145282 27972582 A/G 0.49 0.56 0.063 rs212347246168 27973468 G/T 0.42 0.49 0.039 rs216776846328 27973628 A/G 0.36 0.34 0.396 rs156305549077 27976377 AlG

rs229037151925 27979225 C/T 0.28 0.23 0.054 rs229037052141 27979441 A/G 0.85 0.83 0.488 rs229036952168 27979468 C/T 0.41 0.49 0.036 rs287490460852 27988152 C/T 0.29 0.22 0.062 rs321399762468 27989768 A/G 0.44 0.50 0.064 rs321399865572 27992872 G/T 0.84 0.82 0.336 rs153092979089 28006389 A/C 0.48 0.52 0.311 rs100027579541 28006841 C/T 0.86 0.87 0.566 rs100027479790 28007090 C/T 0.54 0.59 0.159 rs375789690843 28018143 A/G

rs375789590978 28018278 C/T 0.45 0.49 0.308 rs375789491052 28018352 C/G 0.09 0.09 0.914 rs375789391131 28018431 A/G 0.15 0.14 0.803 rs375789291132 28018432 C/T 0.09 0.08 0.798 rs375789194439 28021739 A/G

rs375789094621 28021921 A/T 0.98 0.95 0.159 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-in rs# SEQ ID Position AlleleCase Control Value NO: 4 AF AF

rs1000658211 27927511 C/T 0.80 0.82 0.443 rs1984880473 27927773 C/T 0.48 0.47 0.898 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 4 rs9991121536 27928836 C/T 0.72 0.76 0.319 rs7358805639 27932939 C/T 0.20 0.22 0.598 rs204502917186 27944486 AIG 0.52 0.54 0.581 rs204502817335 27944635 C/T

rs194738425029 27952329 C/G 0.62 0.59 0.348 rs194738525111 27952411 C/T

rs190174428811 27956111 A/G 0.18 0.18 0.928 rs190174528863 27956163 A/T 0.13 0.17 0.113 rs97188230809 27958109 A/C

rs137733840985 27968285 A/C 0.27 0.27 0.961 rs230545245147 27972447 C/T 0.32 0.30 0.673 rs230545145282 27972582 AlG 0.47 0.47 0.911 rs212347246168 27973468 G/T 0.41 0.38 0.348 rs216776846328 27973628 A/G 0.39 0.37 0.664 rs956305549077 27976377 A/G

rs229037151925 27979225 C/T 0.28 0.25 0.403 rs229037052141 27979441 A/G 0.85 0.84 0.939 rs229036952168 27979468 C/T 0.46 0.44 0.712 rs287490460852 27988152 C/T 0.24 0.24 0.888 rs321399762468 27989768 A/G 0.45 0.43 0.752 rs321399865572 27992872 G/T 0.81 0.78 0.373 rs153092979089 28006389 A/C 0.46 0.43 0.445 rs100027579541 28006841 C/T 0.87 0.86 0.767 rs100027479790 28007090 C/T 0.54 0.51 0.394 rs375789690843 28018143 A/G

rs375789590978 28018278 C/T 0.47 0.42 0.202 rs375789491052 28018352 C/G 0.07 0.09 0.478 rs375789391131 28018431 A/G 0.17 0.16 0.653 rs375789291132 28018432 C/T 0.09 0.07 0.567 rs375789194439 28021739 A/G

rs375789094621 28021921 A/T 0.97 0.97 0.728 [0256] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p values were plotted in Figure 1D for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1D can be determined by consulting Table 29. For example, the left-most X on the left graph is at position 27927511. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0257] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 201cb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
BrookslCole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a lOkb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0258] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 8 LRCHI Reason Proximal SNPs [0259] It has been discovered that SNP rs912428 in leucine-rich repeats and calponin homology (CIT) domain containing 1 (LRCHI) is associated with occurrence of osteoarthritis in subjects.
[0260] Forty-three additional allelic variants proximal to rs912428 were identified and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2.
The polymorphic variants are set forth in Table 32. The chromosome positions provided in column four of Table 32 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs101262813 243 44917643 c/t rs157097613 10208 44927608 c/t rs912436 13 15049 44932449 c/t rs912435 13 15111 44932511 a/

rs912433 13 15272 44932672 c/t rs912432 13 15287 44932687 a/

rs912431 13 15326 44932726 a/

rs912430 13 15327 44932727 c/t rs140822513 17038 44934438 c/t rs998657 13 19391 44936791 a/

rs132400613 21702 44939102 c/t rs192441713 22431 44939831 c/

rs203872813 22881 44940281 a/

rs912429 13 27744 44945144 a/t rs374226913 32564 44949964 a/

rs374227013 32698 44950098 a/c rs380319213 33104 44950504 /t rs380319113 33181 44950581 c/t rs754106 13 33256 44950656 c/t rs200505313 33543 44950943 c/t rs153579313 35567 44952967 c/t rs188622013 40085 44957485 c/t rs188621913 40482 44957882 alt rs153579213 45641 44963041 a/t rs153579113 46059 44963459 a/

rs912428 13 48504 44965904 c/t rs188621813 48919 44966319 a/c dbSNP ChromosomePosition ChromosomeAllele rs# in SEQ Position Variants ID NO:

rs157062213 49693 44967093 c/t rs912427 13 49874 44967274 a/

rs912426 13 50020 44967420 al rs306869313 50616 44968016 -/ttt rs157062113 50719 44968119 a/

rs188696513 55511 44972911 c/t rs100884913 65533 44982933 a/

rs912434 13 70529 44987929 a/c rs388909513 75591 44992991 c/t rs716223 13 77266 44994666 /t rs289720713 80368 44997768 /t rs157062013 82475 44999875 a/

rs146760513 92462 45009862 /t rs146760413 92480 45009880 c/t rs140822413 95819 45013219 c/t rs140822313 96275 45013675 c/t Assax for Veri in and Allelotyping SNPs [0261] The methods used to verify and allelotype the 43 proximal SNPs of Table 32 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 33 and Table 34, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs1012628ACGTTGGATGGATTTTCTGTGTCCCCCAAGACGTTGGATGTTGCAACAGAGAGAGCTCTG

rs1570976ACGTTGGATGTGATGTGTCTGCTGTGTTGGACGTTGGATGTTCACATGGCGAGGTCTTAG

rs912436ACGTTGGATGCCATATAAGGTGGTTATGGGACGTTGGATGCAAACAGGTTTTTCTGAGGC

rs912435ACGTTGGATGCAAGCCAATATCCAAGACAGACGTTGGATGAAAAACCTGTTTGTGAGGCC

rs912433ACGTTGGATGTGCCTTCCATCCTTAACACGACGTTGGATGGGCTTGAGCTTAGATATGGC

rs912432ACGTTGGATGAAATAGTTGGGTTTTGTGCCACGTTGGATGATTTGGTGTTAATTGCAGTG

rs912431ACGTTGGATGTGGAAGGCACAAAACCCAACACGTTGGATGCAGAAGCTAGGCTTCCTATG

rs912430ACGTTGGATGTGGAAGGCACAAAACCCAACACGTTGGATGCAGAAGCTAGGCTTCCTATG

rs1408225ACGTTGGATGGGGCACCATGACAATATTCCACGTTGGATGACACCTTGATCTTGGACTTC

rs998657ACGTTGGATGACTGGGCCAGGGAGGAATAGACGTTGGATGGTTGGGGAGATAATACAGAAG

rs1324006ACGTTGGATGGCTGAAAACCCAAATGTGTGACGTTGGATGCCAGCTATCAGCTCCATTTC

rs1924417ACGTTGGATGACAAAAGCAAGCCTTCACAGACGTTGGATGGTACTGTAAAAGGTACTGTG

rs2038728ACGTTGGATGAAGGCTTTTGGACACAAGTCACGTTGGATGGCACCTCTTATGATGTTCCC

rs912429ACGTTGGATGTTCAATTCCCCAAAGCCCTCACGTTGGATGGGCAAGTTCCATAACCTCTC

rs3742269ACGTTGGATGGAGAAAAGAGAACGAGAAGGACGTTGGATGTAAATGACAGCAGTCTGGAG

rs3742270ACGTTGGATGCTAAAACCAAAGCTGACGGGACGTTGGATGTTCTGCTCCTGTGGCATAGC

rs3803192ACGTTGGATGTCCTTTTGCTTCTGCGATGCACGTTGGATGTGCTTCCCCATCAGTTCTTG

rs3803191ACGTTGGATGCTGTCTGTACATTACCAGGCACGTTGGATGAATAGCAGCTGGAGGATCTC

rs754106ACGTTGGATGTTCTTACCATCCAGCAAGGCACGTTGGATGGCCTGGTAATGTACAGACAG

rs2005053ACGTTGGATGCTGTTGCTAGCTTGGATTTGACGTTGGATGTTCCCTGTCCTTTCTGGCAT

rs1535793ACGTTGGATGAACAAAGAGGAACAGAGCCCACGTTGGATGGCATAAGCCCCTTTTCCTAG

rs1886220ACGTTGGATGTCACCGTGTTAGCGAGAATGACGTTGGATGTAATCCCAGCACTTTGGGAG

rs1886219ACGTTGGATGTGTAACTGGATTTGCTGGAGACGTTGGATGTACATCAATAGCCGAGGAAG

dbSNP Forward Reverse rs# PCR primer PCR primer rs1535792ACGTTGGATGCTGTATATCAGTGACTGTCCACGTTGGATGCAGAGAAGAAACATCTCAGC

rs1535791ACGTTGGATGGAGGGTTTATCCTTACAATTGACGTTGGATGTTTTAGGGTCCCTTGATAAG

rs912428ACGTTGGATGACTACATCCATTCCAGGGAGACGTTGGATGTCAGATCAGAGTGAGTTTAG

rs1886218ACGTTGGATGTCCCGAAAACAAGTCAAGACACGTTGGATGAGTCCAGGCAAAACAGTAAG

rs1570622ACGTTGGATGATAGCTGCCACACTCTTTAGACGTTGGATGGCGCAGTTTAGAAAAACCTG

rs912427ACGTTGGATGTAGGGTTCTCGATGGGTATGACGTTGGATGTTTGCCCTGGTCACTTTAGG

rs912426ACGTTGGATGTTAGAGGATGCATAGGCCAGACGTTGGATGAAGTCACTTACTGCATGGTC

rs3068693ACGTTGGATGAAATTGGCCACATGGAATCCACGTTGGATGCTACCTTTAACATCCCTGTC

rs1570621ACGTTGGATGAATTAAGAATGGCAGCTATGACGTTGGATGGTTTAAAACTAAAAACAC

rs1886965ACGTTGGATGCTGCTAAGGATATGTGTTTCCACGTTGGATGACACCAGTGCTCAGTATTTG

rs1008849ACGTTGGATGGCAGTTGTGAATTGTGCAGCACGTTGGATGTGGTGCAGAACATGTCAGAC

rs912434ACGTTGGATGTTCTGACATGTACAGACGTGACGTTGGATGTCCTGGGAAATCTTTCCATC

rs3889095ACGTTGGATGAAGGTAATGATATGTCCCCCACGTTGGATGCGCATTTTACAGAGACATTG

rs716223ACGTTGGATGACACTGTCTCTAGAAGCAGGACGTTGGATGGAAGCAGGAAAAGAGTGAGG

rs2897207ACGTTGGATGTCAGCCTCCAGAACTATGAGACGTTGGATGAACAGAGAGAGACCCTGTCT

rs1570620ACGTTGGATGCTGTTCCTGCCTTGATATGGACGTTGGATGGAAGGAAGTCTATTCAGCCC

rs1467605ACGTTGGATGATGTTACAGGGTGGTAAGCGACGTTGGATGTAAAGTTGCCACGCTTCTCC

rs1467604ACGTTGGATGATATACGGCATGTTACAGGGACGTTGGATGTTAAAGTTGCCACGCTTCTC

rs1408224ACGTTGGATGACTTCCCACTCCTCTAGACAACGTTGGATGTATTGGCTGGGTAGCACTCC

rs1408223ACGTTGGATGTCATTACCAGTTCCACAGAGACGTTGGATGTTGAGACATCATGAGGAGTG

dbSNP Extend Term rs# Primer Mix rs1012628 CTGTGTCCCCCAAGTCTTTG ACG

rs1570976 TTGGCATTTCTTTGAGAA ACT

rs912436 AGGTGGTTATGGGTTTGTCACTCAACT

rs912435 TCCAAAAAGCCCAAGAAATTCT ACT

rs912433 CCTTAACACGTTTATAATAGATTAACG

rs912432 GTGCCTTCCATCCTTAACAC ACT

rs912431 GGCACAAAACCCAACTATTTTTC ACG

rs912430 GCACAAAACCCAACTATTTTTCC ACT

rs1408225 CCTCAGACTGGGTGGCTTA ACT

rs998657 CACCCACCTGAGGGAGGC ACT

rs1324006 GATACCTTGAAGAATTTTTAAAACACG

rs1924417 TTTAGGCACATTTGTACTTATAAAACT

rs2038728 TGGACACAAGTCCATGCAACA ACG

rs912429 CTGTGACAGGTGCTATTATCA CGT

rs3742269 TTTTGGACCGATTTCCGGTG ACT

rs3742270 GCTGACGGGGATTCCCTTTA ACT

rs3803192 GATGCACTAAAAGCAGCAATGT ACT

rs3803191 TCCAGCCTTCATATTTTCCTC ACG

rs754106 ATCCAGCAAGGCACTTAGAAT ACT

rs2005053 TGTGGCCTTCAGATGCTTACAT ACG

rs1535793 GAGGAACAGAGCCCAAAGGACA ACT

rs1886220 CTGACCTCGTGATCCGCC ACG

rs1886219 ACTGGATTTGCTGGAGTTAAGAA CGT

rs1535792 TATCAGTGACTGTCCTTTTCTTTTCGT

rs1535791 TTATCCTTACAATTGAAGAAAGGAI ACT

dbSNP Extend Term rs# Primer Mix rs912428 CCATTCCAGGGAGACTCCCA ACT

rs1886218 GAAAACAAGTCAAGACATTTATTGACT

rs1570622 CTGCCACACTCTTTAGATGAAGTTACG

rs912427 GGGAGATGACAGAACAAAACT ACT

rs912426 AGGTGCCAAGTGTTAGAAGAAACACG

rs3068693 GCCTCACATTGTTTTTTTTTTTTTACT

rs1570621 TCGGTCATAACTTTAATGAAGG ACG

rs1886965 TGATTTTATGACTCACATTATTTCACT

rs1008849 GTGAATTGTGCAGCTATAAACATGACG

rs912434 AGACGTGCCCAGCTATGATA ACT

rs3889095 TCCCCCATAACATTTCAGCAT ACT

rs716223 GTGGTTTGTATTTCCAGTGTCA ACT

rs2897207 AACTATGAGAAATAAATGTGTGGGACT

rs1570620 TTGATATGGTTCTTGGTTGTTGGACG

rs1467605 GTAAGCGCTAGAAAGAAAAATAAACT

rs1467604 ACGGCATGTTACAGGGTGGTAAGACG

rs1408224 GGGCACACATTCAGAACTGCCC ACG

rs1408223 ACAGAGGAAGACCAAATGACA I ACG

Genetic Anal, [0262] Allelotyping results from the discovery cohort are shown for cases and controls in Table 35.
The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the Al allele can be easily calculated by subtracting the A2 allele frequency from 1 (Al AF
= 1-A2 AF). For example, the SNP rs1570976 has the following case and control allele frequencies: case A1 (C) = 0.49;
case A2 (T) = 0.51; control A1 (C) = 0.53; and control A2 (T) = 0.47, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 rs# in Position Allele Case C AF Value SEQ ID AF ~l NO: 5 rs1012628243 44917643 C/T 0.70 0.70 0.768 rs157097610208 44927608 C/T 0.51 0.47 0.125 rs912436 15049 44932449 C/T 0.98 unt ed rs912435 15111 44932511 A/G 0.64 0.36 0.0001 .

rs912433 15272 44932672 C/T 0.22 0.23 0.581 rs912432 15287 44932687 AIG 0.46 0.44 0.282 rs912431 15326 44932726 A/G 0.46 0.46 0.969 rs912430 15327 44932727 C/T 0.20 0.19 0.584 rs140822517038 44934438 C/T

rs998657 19391 44936791 A/G 0.47 0.44 0.254 rs132400621702 44939102 C/T 0.55 0.53 0.419 rs192441722431 44939831 C/G 0.53 0.49 0.108 rs203872822881 44940281 A/G 0.34 0.38 0.082 rs912429 27744 44945144 A/T

rs374226932564 44949964 A/G 0.83 0.83 0.967 rs374227032698 44950098 A/C 0.53 0.50 0.170 rs380319233104 44950504 G/T

rs380319133181 44950581 C/T

dbSNP Position ChromosomeAl/A2 F A2 Co t of F p-rs# in Position Allele Case AF Value SEQ ID AF
NO: 5 rs754106 33256 44950656 C/T 0.40 0.41 0.714 rs200505333543 44950943 C/T 0.40 0.40 0.877 rs153579335567 44952967 C/T 0.26 0.26 0.910 rs188622040085 44957485 C/T

rs188621940482 44957882 A/T 0.21 0.22 0.867 rs153579245641 44963041 A/T 0.73 0.71 0.550 rs153579146059 44963459 A/G 0.08 0.15 0.009 rs912428 48504 44965904 C/T

rs188621848919 44966319 A/C

rs157062249693 44967093 C/T 0.73 0.75 0.451 rs912427 49874 44967274 A/G 0.68 0.70 0.352 rs912426 50020 44967420 A/G 0.76 0.77 0.680 rs306869350616 44968016 -/TTT 0.22 0.21 0.597 rs157062150719 44968119 A/G 0.19 0.18 0.569 rs188696555511 44972911 C/T

rs100884965533 44982933 AIG 0.48 0.43 0.160 rs912434 70529 44987929 A/C 0.23 0.23 0.988 rs388909575591 44992991 C/T 0.90 0.90 0.880 rs716223 77266 44994666 G/T 0.91 0.90 0.981 rs289720780368 44997768 G/T 0.46 0.46 0.921 rs157062082475 44999875 A/G 0.67 0.68 0.738 rs146760592462 45009862 G/T 0.29 0.22 0.044 rs146760492480 45009880 C/T 0.68 0.67 0.537 rs140822495819 45013219 ClT 0.66 0.65 0.683 rs140822396275 45013675 C/T 0.29 0.28 0.587 [0263] The LRCHI proximal SNPs were also allelotyped in the replication cohorts using the methods described herein and the primers provided in Tables 33 and 34. The replication allelotyping results for replication cohort #1 and replication cohort #2 are provided in Tables 36 and 37, respectively.

dbSNP Position ChromosomeAl/A2 F A2 Co t F p rs# in Position Allele Case of Value SEQ ID AF AF
NO: 5 rs1012628243 44917643 C/T 0.69 0.72 0.337 rs157097610208 44927608 C/T 0.48 0.46 0.490 rs912436 15049 44932449 C/T

rs912435 15111 44932511 A/G 0.16 unt 0.637 ed rs912433 15272 44932672 C/T 0.28 0.28 0.984 rs912432 15287 44932687 AIG 0.46 0.42 0.260 rs912431 15326 44932726 A/G 0.46 0.48 0.602 rs912430 15327 44932727 C/T 0.18 0.20 0.476 rs140822517038 44934438 C/T

rs998657 19391 44936791 A/G 0.46 0.43 0.380 rs132400621702 44939102 C/T 0.54 0.53 0.811 rs192441722431 44939831 C/G 0.51 0.49 0.440 rs203872822881 44940281 A/G 0.35 0.39 0.181 rs912429 27744 44945144 A/T

rs374226932564 44949964 A/G 0.84 0.85 0.911 rs374227032698 44950098 A/C 0.56 0.50 0.090 rs380319233104 44950504 G/T

rs380319133181 44950581 C/T

rs754106 33256 44950656 C/T 0.40 0.40 0.827 rs200505333543 44950943 C/T 0.40 0.37 0.328 rs153579335567 44952967 C/T 0.27 0.24 0.259 rs188622040085 44957485 C/T

rs188621940482 44957882 A/T 0.22 0.19 0.302 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case C AF Value SEQ ID AF of NO: 5 rs 153579245641 44963041 A/T 0.73 0.76 0.435 rs 153579146059 44963459 A/G 0.08 0.08 0.958 rs912428 48504 44965904 Cn- See replication genotyping results in Tables 8 &
9.

rs188621848919 44966319 A/C

rs157062249693 44967093 C/T 0.71 0.79 0.007 rs912427 49874 44967274 A/G 0.65 0.73 0.007 rs912426 50020 44967420 A/G 0.74 0.80 0.047 rs306869350616 44968016 -/TTT 0.25 0.21 0.236 rs157062150719 44968119 A/G 0.22 0.15 0.028 rs188696555511 44972911 C/T

rs100884965533 44982933 A/G 0.47 unt NA
ed rs912434 70529 44987929 AIC 0.24 0.19 0.083 rs388909575591 44992991 C/T 0.91 0.91 0.867 rs716223 77266 44994666 G/T 0.91 0.93 0.598 rs289720780368 44997768 G/T 0.48 0.45 0.321 rs157062082475 44999875 A/G 0.66 0.72 0.034 rs146760592462 45009862 G/T 0.29 0.22 0.044 rs146760492480 45009880 C/T 0.66 0.70 0.307 rs140822495819 45013219 C/T 0.64 0.67 0.312 rs140822396275 45013675 C/T 0.31 0.23 0.028 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 5 rs1012628243 44917643 C/T 0.71 0.68 0.438 rs157097610208 44927608 C/T 0.55 0.50 0.159 rs912436 15049 44932449 C/T

rs912435 15111 44932511 A/G 0.66 unt ed rs912433 15272 44932672 C/T 0.14 0.17 0.479 rs912432 15287 44932687 A/G 0.47 0.46 0.806 rs912431 15326 44932726 A/G 0.46 0.44 0.513 rs912430.15327 44932727 C/T 0.23 0.17 0.084 rs140822517038 44934438 C/T

rs998657 19391 44936791 A/G 0.48 0.45 0.518 rs132400621702 44939102 C/T 0.55 0.52 0.324 rs192441722431 44939831 C/G 0.54 0.49 0.123 rs203872822881 44940281 A/G 0.34 0.37 0.295 rs912429 27744 44945144 A/T

rs374226932564 44949964 A/G 0.82 0.82 0.861 rs374227032698 44950098 A/C 0.50 0.49 0.873 rs380319233104 44950504 G/T

rs380319133181 44950581 C/T

rs754106 33256 44950656 C/T 0.41 0.44 0.346 rs200505333543 44950943 C/T 0.40 0.44 0.302 rs 153579335567 44952967 C/T 0.25 0.31 0.096 rs188622040085 44957485 C/T

rs188621940482 44957882 A/T 0.20 0.27 0.053 rs153579245641 44963041 A/T 0.73 0.63 0.007 rs153579146059 44963459 A/G NA 0.27 NA

rs912428 48504 44965904 Cn- See replication genotyping results in Tables 8 &
9.

rs188621848919 44966319 A/C

rs 157062249693 44967093 C/T 0.75 0.67 0.040 rs912427 49874 44967274 A/G 0.71 0.64 0.059 rs912426 50020 44967420 A/G 0.78 0.72 0.065 rs306869350616 44968016 -/TTT 0.19 0.21 0.520 rs157062150719 44968119 A/G 0.15 0.21 0.077 rs188696555511 44972911 C/T

rs100884965533 44982933 A/G 0.49 0.43 0.138 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 5 rs912434 70529 44987929 A/C 0.21 0.28 0.027 rs388909575591 44992991 C/T 0.89 0.88 0.583 rs716223 77266 44994666 G/T 0.90 0.87 0.368 rs289720780368 44997768 G/T 0.44 0.48 0.276 rs157062082475 44999875 A/G 0.70 0.62 0.026 rs146760592462 45009862 G/T

rs146760492480 45009880 C/T 0.71 0.62 0.018 rs140822495819 45013219 C/T 0.68 0.61 0.060 rs140822396275 45013675 C/T 0.27 0.34 0.023 [0264] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1E for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1E can be determined by consulting Table 35. For example, the left-most X on the left graph is at position 44917643. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0265] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a lOkb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0266] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 9 SNWI Region Proximal SNPs [0267] SNP rs 1477261 is associated with osteoarthritis and is described in Table A. It lies within an intron of the SKI-interacting protein gene (SNWI ). This gene, a member of the SNW gene family, encodes a coactivator that enhances transcription from some Pol II promoters.
This coactivator can bind to the ligand-binding domain of the vitamin D receptor and to retinoid receptors to enhance vitamin D-, retinoic acid-, estrogen-, and glucocorticoid-mediated gene expression. It also can interact with poly(A)-binding protein 2 to directly control the expression of muscle-specific genes at the transcriptional level. One hundred sixty-three additional allelic variants proximal to rs1477261 were identii ed and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 38. The chromosome position provided in column four of Table 38 is based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO: 6 rs714392614 218 76161268 a/t rs154907114 1440 76162490 c/t rs801285814 1442 76162492 c/t rs715561114 2611 76163661 c/t rs176941 14 4317 76165367 a/c rs 17694214 4724 76165774 alg rs176943 14 4788 76165838 g/t rs176944 14 5202 76166252 g/t rs436522114 5780 76166830 c/t rs316895214 5974 76167024 c/t rs176945 14 6644 76167694 c/g rs176946 14 7430 76168480 a/g rs176947 14 7938 76168988 .~ c/t rs176948 14 8095 76169145 c/t rs176949 14 8183 76169233 a/c rs176950 14 8312 76169362 c/t rs176951 14 8352 76169402 a/c rs715690514 9348 76170398 c/t rs321719714 9378 76170428 -/tctc rs227044314 9617 76170667 a/g rs176952 14 9727 76170777 c/t rs176953 14 9834 76170884 c/t rs176954 14 9899 76170949 g/t rs176955 14 10211 76171261 c/t rs321441614 10377 76171427 -/t rs176956 14 10695 76171745 c/t rs254456614 10729 76171779 c/g rs254456714 10730 76171780 c/t rs176957 14 11433 76172483 a/g rs176958 14 11951 76173001 c/g rs176959 14 12697 76173747 c/t rs180222714 12982 76174032 a/c rs176961 14 14419 76175469 c/t rs176962 14 14501 76175551 c/t rs740128514 14983 76176033 a/c rs176963 14 15280 76176330 c/t rs176964 14 15475 76176525 a/g rs490363114 15888 76176938 a/g dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs490363214 15976 76177026 a/t rs176965 14 16307 76177357 a/c rs490363314 16442 76177492 a/c rs176966 14 17255 76178305 clt rs176968 14 18948 76179998 g/t rs176969 14 19435 76180485 a/t rs176970 14 19753 76180803 clt rs714919814 20021 76181071 c/t rs714791814 20022 76181072 a/c rs714868514 20503 76181553 a/g rs118423214 20590 76181640 g/t rs118423314 21804 76182854 g/t rs118423414 21919 76182969 c/t rs740199814 21990 76183040 a/t rs176974 14 22412 76183462 a/g rs657439014 22536 76183586 c/t rs176975 14 23432 76184482 a/g rs176976 14 23468 76184518 g/t rs176977 14 23772 76184822 c/t rs801372714 24325 76185375 c/t rs176978 14 24773 76185823 c/t rs211182914 26274 76187324 clt rs176980 14 27440 76188490 c/g rs580984814 28561 76189611 -/acag rs580984914 30071 76191121 -la rs438307014 31764 76192814 a/t rs749365214 33008 76194058 c/t rs211213314 35310 76196360 a/t rs196383314 35460 76196510 a/c rs657439114 37112 76198162 a/g rs715506214 37285 76198335 a/g rs489967414 37747 76198797 c/t rs802251614 38057 76199107 c/t rs714083814 38859 76199909 a/c rs714112714 38860 76199910 a/g rs657439214 39525 76200575 a/g rs800369114 40216 76201266 a/g rs800397914 40281 76201331 c/t rs801054114 41453 76202503 c/g rs801641614 42091 76203141 a/t rs801617514 42513 76203563 a/g rs715457114 42935 76203985 c/t rs715882614 42985 76204035 a/g rs715931014 43003 76204053 a/g rs740190014 43281 76204331 a/g rs716035514 43716 76204766 c/t rs203278114 43866 76204916 a/g rs657439414 44234 76205284 g/t rs800759814 44596 76205646 a/g rs226776714 44871 76205921 c/t rs657439514 45005 76206055 a/g rs715006614 45282 76206332 a/c dbSNP . Position Chromosome Allele rs# Chromosomein SEQ Position Variants I~ NO:

rs749233414 47178 76208228 a/c rs435936114 47816 76208866 g/t rs460508914 47887 76208937 a/g rs714644614 48134 76209184 c/t rs434614414 48135 76209185 alg rs714807814 48276 76209326 g/t rs714828614 48400 76209450 c/t rs378398014 48798 76209848 a/g rs154911914 48803 76209853 a/t rs198492514 49146 76210196 c/t rs147726114 49969 76211019 alt rs801644714 51059 76212109 a/g rs749404414 51064 76212114 c/t rs202328814 53285 76214335 alt rs715168514 54560 76215610 c/t rs211213514 54748 76215798 a/g rs216108814 54785 76215835 c/g rs490363814 55102 76216152 c/g rs147726214 55644 76216694 alg rs147726314 55705 76216755 g/t rs147726414 55841 76216891 a/g rs227791714 56623 76217673 c/g rs227791814 56825 76217875 ~~ ~a/c rs227791914 56827 76217877 a/g rs197841614 56892 76217942 c/t rs375972814 59150 76220200 a/t rs657439914 59958 76221008 ea/t rs715533614 60231 76221281 c/t rs715618614 60524 76221574 a/g rs714239014 61871 76222921 c/t rs714587514 62226 76223276 c/t rs801463514 63230 76224280 g/t rs801593814 63468 76224518 g/t rs801531314 63787 76224837 c/t rs800631514 65732 76226782 a/c rs657440014 65989 76227039 a/g rs714081614 68832 76229882 g/t rs456607814 69904 76230954 c/t rs714105014 70365 76231415 a/g rs304935614 70886 76231936 -/tatc rs490363914 73088 76234138 a/t rs490364114 73103 76234153 c/t rs236483814 75934 76236984 c/t rs236483914 75966 76237016 c/t rs463206614 76273 76237323 c/t rs211213614 77943 76238993 c/t rs464165514 78466 76239516 c/t rs463526914 78861 76239911 c/t rs457076414 78872 76239922 a/g rs759808 14 79836 76240886 g/t rs715053114 80908 76241958 c/t rs715496814 81509 76242559 c/g dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs714665714 83576 76244626 c/t rs714585914 83662 76244712 c/g rs490364314 83782 76244832 c/t rs71768214 84282 76245332 g/t rs71768314 84444 76245494 a/g rs147725914 85129 76246179 clg rs801906414 85151 76246201 a/g rs801897114 85296 76246346 a/c rs147726014 85809 76246859 c/g rs580985114 86387 76247437 -/t rs198514914 86494 76247544 a/g rs100898814 89786 76250836 a/g rs100898914 89894 76250944 a/t rs801822214 90122 76251172 glt rs100604014 92067 76253117 a/g rs100603914 92187 76253237 c/t rs100603814 92312 76253362 a/g rs800978414 92824 76253874 g/t rs490364414 93733 76254783 c/t rs714949614 96553 76257603 c/g rs657440214 96941 76257991 a/c Assay for Verifying and Allelotypin~ SNPs [0268] The methods used to verify and allelotype the 101 proximal SNPs of Table 38 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 39 and Table 40, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs7143926ACGTTGGATGGAGTCACCCAAAATTAAGGCACGTTGGATGGAAAGCCAAAATTAGCCTGC

rs1549071ACGTTGGATGGTGAGACGCTGTCTCAGTAAACGTTGGATGCTCCACACTTGGAGAAGTTG

rs8012858ACGTTGGATGGTGAGACGCTGTCTCAGTAAACGTTGGATGCTCCACACTTGGAGAAGTTG

rs7155611ACGTTGGATGATGGAATACAGGCACCGTTCACGTTGGATGCCCCTTCTTAATCTCCATGG

rs176941ACGTTGGATGTTAGTATGGGAAAAGGGCTCACGTTGGATGCAACAATCCTATGAGTTGGG

rs176942ACGTTGGATGAGTGGCTCAGATGTGAGTAGACGTTGGATGTGGTCTTCACCAACCACATG

rs176943ACGTTGGATGACCAAGCCCAGTAAAGTCTCACGTTGGATGGCATCCGCAAGATGCTAATG

rs176944CGTTGGATGGGCCTCAATATTGGCTAAATGACGTTGGATGCTTAACCATTAGAGCCCTTC

rs4365221ACGTTGGATGAAATAAGGCAGGAAGGGTAGACGTTGGATGTCCCAACTTACTGGTCTTTC

rs3168952ACGTTGGATGATGTACCAGACTTGGTGGTGACGTTGGATGTTTGCTGAGGATGGAGACTG

rs176945ACGTTGGATGCCTACTATACACTCACAAAAACGTTGGATGTTTTTTAAAACACTTTAAGC

rs176946ACGTTGGATGGCTTTATCATAGGTATTTGTGACGTTGGATGGAGAGATGTGTTGTTTTTGAG

rs176947ACGTTGGATGTGAGTAGCTGGGACTACAGGACGTTGGATGGGCCAACATAGCGAAACTCC

rs176948ACGTTGGATGCAGAGCCAAAGGTCAACAAGACGTTGGATGTACAGGTGTGAGCCTTCATG

rs176949ACGTTGGATGTAGGAACTCCCTGCAGTTCCACGTTGGATGCCTTGCTGGCTTTAAAGAAG

rs176950ACGTTGGATGAATCACAGGAGTGACATCCCACGTTGGATGTGGAGGAGAAACCTGACTTG

rs176951ACGTTGGATGCCCTATATAATCTCCTCCCCACGTTGGATGCAGGAGTGACATCCCATTAC

dbSNP Forward Reverse rs# PCR primer PCR primer rs7156905ACGTTGGATGTGAGAGAGAGAACCTGTCTCACGTTGGATGAAAGGCGGCTTTGATGTTGG

rs3217197ACGTTGGATGTTGATTGTGCCACTGCACTCACGTTGGATGACTCTAGTTGGAAATCCTGG

rs2270443ACGTTGGATGATAACTCAGTCCAGGTGTGGACGTTGGATGCACTCAAGCAGTCTACTCAC

rs176952ACGTTGGATGGATCTCAGCTCACTGCAATCACGTTGGATGTATCTGGGTGACTGAGGAAG

ys176953ACGTTGGATGTTGAGGTCAGGAGTTTGGGAACGTTGGATGGCCACCACACCCAGCTAATT

rs176954ACGTTGGATGAAAACATAGGCCAGGTGCAGACGTTGGATGAAACTCCTGACCTCAAGCCA

rs176955ACGTTGGATGCTAGAGTGCTTGGATGTACCACGTTGGATGGTCATCTACAGGGACTAGAC

rs3214416ACGTTGGATGACGACTATCATCACGTGTTCACGTTGGATGACCAGAAGTCTGTAACTAGG

rs176956ACGTTGGATGTACAGGCATAAGCCACCATGACGTTGGATGAGGAAGGGTGTAAAGCAAGG

rs2544566ACGTTGGATGCAAGCAATCTTCCCATCTGGACGTTGGATGTGATCCGATTTTTGGCTGGG

rs2544567ACGTTGGATGCAAGCAATCTTCCCATCTGGACGTTGGATGTGATCCGATTTTTGGCTGGG

rs176957ACGTTGGATGTTTCACCGTGTTAGCCAGGAACGTTGGATGTAATCCCAGCACTTTGGGAG

rs176958ACGTTGGATGAAAACTGGGCACTCTACCACACGTTGGATGAAAATCGCGCCATTGCACTC

rs176959ACGTTGGATGCAGGCAGTTTTTATTTGTCCCACGTTGGATGGGTTAGGGAGTCATAATACC

rs1802227ACGTTGGATGAACAAATAGTTGCACCAAGACGTTGGATGTTTTAATTTGGAGTGGGCA

rs176961ACGTTGGATGAACCCAGTTTAAGACCGGCCACGTTGGATGTACAGGTGTGTGCCACCATG

rs176962ACGTTGGATGATATTTCTGGCTGGGCACTGACGTTGGATGACTGGGTTCAAGCAATCTGC

rs7401285ACGTTGGATGACAGAGTGGGACTCCATATCACGTTGGATGGATTCAAACTGGGTGTCTTG

rs176963ACGTTGGATGTAAGCCTGGGAAAACACACGACGTTGGATGCCCACTCTACTTTCCAGTAG

rs176964ACGTTGGATGAGAGTCAGTGTCCTACAAAAACGTTGGATGTAATCCCGTTTTACAGCTTC

rs4903631ACGTTGGATGGTAAATGCCAGCATGATGACACGTTGGATGTCTCAGCCCACTATAAGAAG

rs4903632ACGTTGGATGTGTGAATACCTATCCTCAGGACGTTGGATGGTCATCATGCTGGCATTTAC

rs176965ACGTTGGATGAATGCTTTATAAGGGCTGCCACGTTGGATGTCTCAGAAACAAAGGATGTG

rs4903633ACGTTGGATGCAACCCCCAAACCATCATATACGTTGGATGCTAACAGATTCGTTGACATGG

rs176966ACGTTGGATGCTCTCGAGTAGCTGGGACTAACGTTGGATGTGGCCAACATGGTGAAACCC

rs176968ACGTTGGATGGCGAAACTCCGTCTCAAAACACGTTGGATGTAGTGATCTTCCCACCTAGG

rs176969ACGTTGGATGCTGTCTGTCCGATTTACTGCACGTTGGATGTCTAGAATCAAGCATGCGGC

rs176970ACGTTGGATGCTAATGTTCCTAGTACAGTGGACGTTGGATGCTTCTCTTCTAGCTATTTTGC

rs7149198ACGTTGGATGCAATGGGATATTACTCAGCCACGTTGGATGTTTCTGTGCCGGGCTTATTC

rs7147918ACGTTGGATGCAATGGGATATTACTCAGCCACGTTGGATGTTTCTGTGCCGGGCTTATTC

rs7148685ACGTTGGATGTGTCTTCTTTTGAGACCGTCACGTTGGATGCTCAATCGCAAAGAAACGAG

rs1184232ACGTTGGATGAAGAGGCCACCTACAGAATGACGTTGGATGCTCGTTTCTTTGCGATTGAG

rs1184233ACGTTGGATGAAGTGTTGGGATTACAGGTGACGTTGGATGAGTGAAAGATCGCCACAAAG

rs1184234ACGTTGGATGGCTATGTGCAGTGACTCATGACGTTGGATGTCTCAGACCTCAGGTGATCT

rs7401998ACGTTGGATGTGAGTAGCTAGGACAACAGGACGTTGGATGAACGTGGTGAAACCCCATCT

rs176974ACGTTGGATGTTACAGCGAGCTGAGATCATACGTTGGATGAGGATCATACTGTCTCTGAC

rs6574390ACGTTGGATGTGATGAAACCCCGTCTGTACACGTTGGATGTCCTGAGTAGCTGGGATTAC

rs176975ACGTTGGATGTGTAGAATCTAGGTGGTAGGACGTTGGATGCCAGCCTTTCCTGACATTTT

rs176976ACGTTGGATGGGTAGGAGATACAGGTGTTCACGTTGGATGCCCAGCCTTTCCTGACATTT

rs176977ACGTTGGATGTTGCATCATTACACTTCAGCACGTTGGATGGGGAAACATTATGCATAATTCC

rs8013727ACGTTGGATGTGCCTGGTTGTATACCTAACACGTTGGATGCTTGAGAACGATTCTGTTGTC

rs176978ACGTTGGATGGGGACCATGTTTTTGTTACCACGTTGGATGAATACTGTGGAATGGGCATG

rs2111829ACGTTGGATGCATGTGGAAAAAGGTATGACACGTTGGATGCCTACTTTATATGCAGTAGG

rs176980ACGTTGGATGATGGCCAATGCTATGAACGCACGTTGGATGAAGGGCAGTTGCAGGAAAAG

rs5809848ACGTTGGATGTCTATTTTTCCAGAGCTTGGGACGTTGGATGCCATTTCACTGATGCTTTGG

rs5809849ACGTTGGATGGTGAATACCGTGTCAGTTCCACGTTGGATGTGCAGTGAGCTGAGATCATG

rs4383070ACGTTGGATGAGCGATTCTCTTGTCTCAGCACGTTGGATGAACTTAGCTGGGCATTGTGG

rs7493652ACGTTGGATGGGTCATATACCACAAGTAACACGTTGGATGCTGGCCCTATGCTATTTTCA

rs2112133ACGTTGGATGGCCACCACAACTGGCTAATTACGTTGGATGTGTGGTCAGGAGATCGAAAC

rs1963833ACGTTGGATGTAAGCCAAGATTGCGTCACTACGTTGGATGAGCATTAAAGGTAGAATGCC

rs6574391ACGTTGGATGTAACCGTTGCTATGGAGAAGACGTTGGATGACCTATACAACCCTAAGCTG

rs7155062ACGTTGGATGGCTCCTTATTTGGGCATTCCACGTTGGATGCACTCAGCCTTGTGAGATAC

dbSNP Forward Reverse rs# PCR primer PCR primer rs4899674ACGTTGGATGAATGTGCTGAGGAAACTGAGACGTTGGATGGCTTCTGATACTTTCAAGAG

rs8022516ACGTTGGATGGTTGAAGGCATTCTTTTGGGACGTTGGATGCTAGCCTGGGCAATATAATG

rs7140838ACGTTGGATGCCTCGTTTCTGAAGAATACCACGTTGGATGGAGACTGAACAGGTTATTGG

rs7141127ACGTTGGATGCCTCGTTTCTGAAGAATACCACGTTGGATGGAGACTGAACAGGTTATTGG

rs6574392ACGTTGGATGAGAAAATAGCATAGGCTGGGACGTTGGATGAAATGATCCATCCTCCTCAG

rs8003691ACGTTGGATGACTGAAGTCAAGTGAAGGCCACGTTGGATGTTAGGCCCCTATACATGGAG

rs8003979ACGTTGGATGCACAAAACCACTTCTGAAGCACGTTGGATGGGGCCTAATTTTCCTTTTGC

rs8010541ACGTTGGATGCACTTTTCTTGGCTAGCTTCACGTTGGATGCAGAATGGCTAAAACTGAAC

rs8016416ACGTTGGATGTGCCCATAACTTCCTTTGACACGTTGGATGGCCACGGAATCCTATATAGA

rs8016175ACGTTGGATGTTGAGCACTGAGTGAGTGAGACGTTGGATGTCCTAACCGTGAGTGATCTG

rs7154571ACGTTGGATGATGTGAGGAGCACCTCTGCCACGTTGGATGCTCTTCCCTTCTCAGACGG

rs7158826ACGTTGGATGCACCTCCCTCCTGGACGGGACGTTGGATGGCCACCCCGTCTGAGAAGG

rs7159310ACGTTGGATGACCCCGTCTGAGAAGGGAAGACGTTGGATGCACCTCCCTCCTGGACGGG

rs7401900ACGTTGGATGCCCAACAGCTCATTGAGAACACGTTGGATGTCTTTTCCCCACATTTCCCC

rs7160355ACGTTGGATGTCACTTGTTTATCTGCTGACACGTTGGATGTTATTGATCATTCTTGGGTG

rs2032781ACGTTGGATGTATATCACTGTAGTAACAGCACGTTGGATGACCATAAGTATATATCACAAG

rs6574394ACGTTGGATGACCACACCCAGCCTATTTGTACGTTGGATGTTATGCTGAAAGCCTGGGAG

rs8007598ACGTTGGATGCTGGCAAAAGTCTCTTAACACACGTTGGATGTTGGTTAAAGTCACAGAATG

rs2267767ACGTTGGATGGTTTCACCATGTTAGCCAGGACGTTGGATGTAATCCCAGCACTTTGGGAG

rs6574395ACGTTGGATGAACCTTGAACTCTTGGGCTCACGTTGGATGAAAAAATTCACCGGGCATGG

rs7150066ACGTTGGATGAAGCAATCCTCCTGCTTCTGACGTTGGATGAGATCAGGTGTAGATCCAGG

rs7492334ACGTTGGATGGCCTTTGCATTGGCTATTTGACGTTGGATGTAGAAAGCAGTCATGGGAAG

rs4359361ACGTTGGATGGTAGTATTTGCTTAGTACACACGTTGGATGTTCTAAGCCTGAATGTTTCC

rs4605089ACGTTGGATGAATACCTATGAGATCTCAGGACGTTGGATGCCTTGTAACTCTTTAACATC

rs7146446ACGTTGGATGATTCACTTTTACAAGACCTCACGTTGGATGGCATATTGTACTTAGGAACTC

rs4346144ACGTTGGATGATTCACTTTTACAAGACCTCACGTTGGATGGCATATTGTACTTAGGAACTC

rs7148078ACGTTGGATGTGTGTCAGATTGATGGCTTGACGTTGGATGCCAAGAGAATAAAGCTGAGAG

rs7148286ACGTTGGATGGTGGTCATTAAGCTTGCCAGACGTTGGATGTGCTATGGATGCTGCTTGAG

rs3783980ACGTTGGATGTTTTTTGCCCCAGGTAAGACACGTTGGATGTGGTGCTTTTGTTCTCTCTG

rs1549119ACGTTGGATGTTTCATCTTCCTCTGCCTCCACGTTGGATGGTGAAGGCCAGTCATATTGC

rs1984925ACGTTGGATGAAGTAGCCAGGATTACAGGCACGTTGGATGCCAGCCTAGCAAACATGGTG

rs1477261ACGTTGGATGCAGGGTTATGTGGTATTATCACGTTGGATGGGGAAAGTAAAAGATAAGAG

rs8016447ACGTTGGATGAATTACAGACGTGTGCCACCACGTTGGATGTGACACAGAGAGACTCTGTC

rs7494044ACGTTGGATGAATTACAGACGTGTGCCACCACGTTGGATGTGACACAGAGAGACTCTGTC

rs2023288ACGTTGGATGGAGAAAAATTGTGATTGATTGACGTTGGATGGCCATCAAATCAATCTAATC

rs7151685ACGTTGGATGACAGTGCTGGCATTACTGGCACGTTGGATGTAAAGATCGTCTGCCACTGC

rs2112135ACGTTGGATGAGTGCAGTGGCCCAATCACAACGTTGGATGGTCTAGAGTCCCAGCTACTC

rs2161088ACGTTGGATGTATAGGGTCTCACTCTTGCCACGTTGGATGAGGAGGATCACCTGAGCCTT

rs4903638ACGTTGGATGATAGGGTGTTACTGCGTTGGACGTTGGATGAGGCCTAGGTGAGAAGATTG

rs1477262ACGTTGGATGATGCGTGAGGAGAATGAAGGACGTTGGATGAAGGCTAGTGTTCAGGAAGG

rs1477263ACGTTGGATGAACCTTCCTGAACACTAGCCACGTTGGATGCCTTGCTGCCCCATTTTAAG

rs1477264ACGTTGGATGCGTAGATAGAACCACCTCAGACGTTGGATGAAAGGCGGAGAGCACTTTAC

rs2277917ACGTTGGATGGCATTTGTTGCTAGCTGAAGACGTTGGATGTTGAACAGGAGTACCGTTTG

rs2277918ACGTTGGATGTTACGTTCCTTACTCAGTCCACGTTGGATGACCTGTCGTTTTAAACGCCC

rs2277919ACGTTGGATGTTACGTTCCTTACTCAGTCCACGTTGGATGACCTGTCGTTTTAAACGCCC

rs1978416ACGTTGGATGAGGGCGTTTAAAACGACAGGACGTTGGATGCGGGTGAGAGGATATGGTTT

rs3759728ACGTTGGATGATAGTCCCTCGCTGTTTTGGACGTTGGATGAGAAAGCACTAGGCCTTTGG

rs6574399ACGTTGGATGATGCTCTGATGCCATTATGCACGTTGGATGAGGGCACGTAAAACACATCC

rs7155336ACGTTGGATGGAGGAAGACTCGGTCTAAAAACGTTGGATGAACAATCTGACACTAGGTGC

rs7156186ACGTTGGATGATTACGGGTATGAGCCACTGACGTTGGATGGAACTGGACATTAGGTCTGG

rs7142390ACGTTGGATGTAATCAAGACAGTGTGGTACACGTTGGATGGGGTTTATTTCAGGACTCTC

rs7145875ACGTTGGATGGTCCTTTGAAGCACAAAACCACGTTGGATGCTTCATGATCTTGGATTTGGC

dbSNP Forward Reverse rs# PCR primer PCR primer rs8014635ACGTTGGATGGTCTTCTCACTCAAGAACACACGTTGGATGCAACAGAGCAAGACTCCAAC

rs8015938ACGTTGGATGCCCTGAACTCAAGTGATCTGACGTTGGATGATCTAAACAGTGTTCCTGGC

rs8015313ACGTTGGATGAAAACTGATTCTGTACCTGGACGTTGGATGGTCAGTCATTTTATAGGCAG

rs8006315ACGTTGGATGTCACTTGAGGTCAGGAGTTCACGTTGGATGCCATGCCTGGCTAAGTTTTG

rs6574400ACGTTGGATGTTATCCTTCCTCTGCCAGTGACGTTGGATGCCTTTGAACTTCCTACCCAG

rs7140816ACGTTGGATGCAATAGAGTGAGACTCTGTCACGTTGGATGATTCATGAGCCTCTCTTTAC

rs4566078ACGTTGGATGTAGAGTCTTGTTCTGTCACCACGTTGGATGAGGAGAATCGCTTGAACCCA

rs7141050ACGTTGGATGATATGTTATACATATTAGTCACGTTGGATGCAAGTTAACCATTATCAACTC

rs3049356ACGTTGGATGTACCACTGGCAGAGTAGAAGACGTTGGATGCACATGGTTTGGGTACTGAG

rs4903639ACGTTGGATGAGCGAGACTCCGTCTCAAAAACGTTGGATGTCAAAGGTAGCCTTGACTGG

rs4903641ACGTTGGATGACTCCAACCTGGGCAACAGAACGTTGGATGCTGGCTCCAGCACACTTATC

rs2364838ACGTTGGATGTGTAGTCCCAGCTACTTGTGACGTTGGATGTGATCATAGCTCACTGCAGC

rs2364839ACGTTGGATGTGGGCAACATAGCAAGATCCACGTTGGATGCTCACAAGTAGCTGGGACTA

rs4632066ACGTTGGATGGAGAAAAAAGAGATGGAGGGACGTTGGATGGCCCTGACTGTGTTTTTATG

rs2112136ACGTTGGATGTTTCTTGGGGACTAAGGCTCACGTTGGATGTAACAGGCCCTGAAGGAATG

rs4641655ACGTTGGATGCGATAGAGCAACCCTGTCTCACGTTGGATGGCCCTACACCCAGATTCAAG

rs4635269ACGTTGGATGAAAGTGCTGGGATTACAGGCACGTTGGATGCTTGCAGCATATTTCTGAGG

rs4570764ACGTTGGATGCTTGCAGCATATTTCTGAGGACGTTGGATGAAAGTGCTGGGATTACAGGC

rs759808ACGTTGGATGATGAGCTGTGATCATGCCACACGTTGGATGCCTGAACTTCATTGTGCTCC

rs7150531ACGTTGGATGATGTGCGGTGTGAAGCAAAGACGTTGGATGTTGTTTGGCCTGGTCTGATG

rs7154968ACGTTGGATGTACCCAGGTAACAAACCTGCACGTTGGATGTCCCCTATAAGGCTTTCAGG

rs7146657ACGTTGGATGTGAGTAGCTGGGACTACAGGACGTTGGATGTAACACGGTGAAACCCCGTC

rs7145859ACGTTGGATGAGGCAGGAGAATGGCGTGAAACGTTGGATGTTTTTGAGACGGAGTCTTGC

rs4903643ACGTTGGATGTATTCCATGCTGTCTGCCTCACGTTGGATGAGTTGACCTTAAAGGCTGGG

rs717682ACGTTGGATGTTTAGGGACAGAGGCTGAGGACGTTGGATGAAGTGCAGTGGCCTGATCTC

rs717683ACGTTGGATGTTGGCAAAAAAGGTGGAGGCACGTTGGATGTGATGATGGCACAGGGAATG

rs1477259ACGTTGGATGTGACTGAGACTACCTTCACCACGTTGGATGAAGTGCTCACGTAGGTTGTC

rs8019064ACGTTGGATGCCTTGCAGCAAACTTCAGAGACGTTGGATGTGACTGAGACTACCTTCACC

rs8018971ACGTTGGATGATGGTCTCACTCTGTCACTCACGTTGGATGAATTGTTTGAGCCCAGGAGG

rs1477260ACGTTGGATGAGTGTCATGGTAGCAAGGACACGTTGGATGTGCCATCTGTTTCCCATAGG

rs5809851ACGTTGGATGACAGAGAGTGTTCAGCACAGACGTTGGATGTTGGGCAACAGAGAGAGACT

rs1985149ACGTTGGATGACTGAAATCTTTGCCTCCCGACGTTGGATGGTGGTGCACTTATGTAGTCC

rs1008988ACGTTGGATGAGTGTGTCTCAGGGAATGTGACGTTGGATGCCTGGCAATTTGTTCTCTGC

rs1008989ACGTTGGATGGGAATAGCAAGTGTAACGGCACGTTGGATGACTCCAACCGCATCAGCTTC

rs8018222ACGTTGGATGATCCTCCATATGCTGAACGCACGTTGGATGAAGGTGGAACGAGAGACTTG

rs1006040ACGTTGGATGTTTAGCTCTCTCTCTGTTGCACGTTGGATGTCTTGAGCCCAGGAGTTCAA

rs1006039ACGTTGGATGTGAAGCTGGGAGTTAGAGACACGTTGGATGCCACCATGCCCAGCTAATTT

rs1006038ACGTTGGATGATAAGCCACTGTGCTCAGTCACGTTGGATGGGTAGGGTTTATTAAGTGCC

rs8009784ACGTTGGATGTGTTTTGGCTATGCTTTGCCACGTTGGATGTGACAGAGCGAGACTTTGTC

rs4903644ACGTTGGATGTTGCAGTGAGCTGAGATTGGACGTTGGATGGTGAATGAATGAATAAGGGCC

rs7149496ACGTTGGATGACAACACACAGTACTGGACCACGTTGGATGTGGGTGCATGTTAGAAACGC

rs6574402ACGTTGGATGCAGGTCCTTTGTCTGACAAGACGTTGGATGGGGATGTGCGATTTGATCTG

dbSNP Extend Term rs# Primer Mix rs7143926 ACCCAAAATTAAGGCAAAATGG CGT

rs1549071 CACACACATATATACACACACA ACG

rs8012858 CACACATATATACACACACACA ACG

dbSNP Extend Term rs# Primer Mix rs7155611 GGCACCGTTCTCTCTCTCA ACT

rs176941 CTGGGCCTCAGTTTACTCAT CGT

rs176942 AATAGGTTGGTTTGTGCCCC ACT

rs176943 CCCGTAGTCCCTGTGAAAC ACT

rs176944 AAAAGTCCACTAATCCTTCCAA CGT

rs4365221 GAGGGCAACTCAACACATTTTA ACG

rs3168952 TTGGTGGTGAGATGGACAGA ACT

rs176945 TACTATACACTCACAAAAATTGTTACT

rs176946 TTGTATAACAAAATACCACAAGCACT

rs176947 GGCGCCCGCCACTACGC ACG

rs176948 AAAACAGACCTCAGTCCTACA ACT

rs176949 CTCCCTGCAGTTCCTTGTTA CGT

rs176950 GGAGTGACATCCCATTACTTT ACG

rs176951 TCCTCCCCTCCTTGGGTG ACT

rs7156905 CTGTCTCAAAAAAGGAACCAG ACT

rs3217197 CTCCAGCCTGAGTGAGAGA ACT

rs2270443 CAGGTGTGGTGGCTCATGC ACG

rs176952 CACTGCAATCGCTGCCTCC ACG

rs176953 GGACCAGCCTGGCCAACAT ACT

rs176954 GCAGTGGCTCAATCCCAGC CGT

rs176955 CTGCCCCTCCAGCCCTTC ACT

rs3214416 CATCACGTGTTCCTAATGAAAA CGT

rs176956 AAGCCACCATGCCCAGCC ACT

rs2544566 CATCTGGGCCTCCCAAAGTA ACT

rs2544567 CATCTGGGCCTCCCAAAGT ACT, rs176957 GGTCTCGATCTCCTGACCT ACG

rs176958 GGAGTTTTGCTCTTGTTGCC ACT

rs176959 TTTTATTTGTCCCTTGTTCTTTCACT

rs1802227 AATAGTTGCACCAAGCAAGAG ACT

rs176961 TATGGCAAAACCCTGTCTACA ACT

rs176962 GGCTCACGCCTGTAATCCTA ACT

rs7401285 GGGACTCCATATCAGAAAACA CGT

rs176963 GAAAACACACGCGGGCGC ACT

rs176964 CAGTGTCCTACAAAAGTGCCT ACG

rs4903631 CTTGAGACAAGATGAAACAGTT ACG

rs4903632 ATCCTCAGGGAAACGAAAATTA CGT

rs176965 ATAAGGGCTGCCAGCTTGAT ACT

rs4903633 TAGCAATTTTATATCTCAGCATGACT

rs176966 ACCACACCCAGCTAATTTTTG ACG

rs176968 TCACACCTGTGACTCCAGC CGT

rs176969 CCGATTTACTGCATTGCATTTC CGT

rs176970 GTACAGTGGGGTGAATAGTTA ACT

rs7149198 GATATTACTCAGCCATAAAAAAGACT

rs7147918 GGATATTACTCAGCCATAAAAAAACT

rs7148685 TTGAGACCGTCTATTCAGATC ACT

rs1184232 GAATGGAAGAAAATGGTTGCAAACGT

rs1184233 TGCCCAGCCTCTTCAATTAC ACT

rs1184234 TACCAGCACTTTGGGAGGC ACG

rs7401998 ~ CCACGCCTGGCTAATTTTTTTT~ CGT

dbSNP Extend Term rs# Primer Mix rs176974 CTGGGCAACAAAGCAAGACT ACG

rs6574390 AAATTAGCTGGGTATGATGGC ACT

rs176975 AATCTAGGTGGTAGGAGATAC ACT

rs176976 TATAATTCTTTCAGCTTTTCTGTAACT

rs176977 TCAGCCTGGGCAACAAGAG ACG

rs8013727 CCTAACCATAGAAGATAATTAGAAACT

rs176978 ATGTTTTTGTTACCTCTTGTTAC ACG

rs2111829 GAATTTTGCTTGGTGAACAAAAT ACT

rs176980 GCTATGAACGCCATTTTATGTA ACT

rs5809848 TGGGTTCTGAAATCCTGCTG CGT

rs5809849 CGTGTCAGTTCCTTTTTTTTTTT ACT

rs4383070 GCCTCCTGAGTAGCTGGG CGT

rs7493652 TATACCACAAGTAACTGTTAATTTACG

rs2112133 CCACAACTGGCTAATTTTTTGT CGT

rs1963833 CTGGGTGACAGAGCAAGAC CGT

rs6574391 TGGAGAAGTGATAAACTC ACG

rs7155062 ATAACCCTTCAAATGAGCATCA ACT

rs4899674 GGCAAATGGGCTGGGGAG ACG

rs8022516 AGGCATTCTTTTGGGTATAGTA ACG

rs7140838 TCTGAAGAATACCAGACCTCT CGT

rs7141127 CTGAAGAATACCAGACCTCTC ACT

rs6574392 CTGGGCACAGCGACTCAC ACT

rs8003691 TGAAGGCCTCCATGGTATAG ACT

rs8003979 TCTGAAGCCAGTGAGGAAGT ACT

rs8010541 GCTAGCTTCAACTCTCCTGAT ACT

rs8016416 TAACTTCCTTTGACTTGCTTTTT CGT

rs8016175 GTCTGCAATCCCGGCACCT ACG

rs7154571 GTGAGGAGCGTCTCTGCC ACG

rs7158826 TCGCTCCTCACTTCCCAGA ACG

rs7159310 CATCTGGGAAGTGAGGAGC ACT

rs7401900 TGAGAACAGGCCATGATGAC ACT

rs7160355 CCTGCCAAATCCCCCTCTC ACG

rs2032781 GAGAAAAGCGGGCAGGACT ACT

rs6574394 CACCCAGCCTATTTGTATAATT ACT

rs8007598 CTCTTAACACATTTTTTTACAGCAACG

rs2267767 CTGACCTCGTGATCTGCCC ACT

rs6574395 GGCTCAGGCGATCATCGTA ACG

rs7150066 CTGCCACCCAAAGTGCTGG ACT

rs7492334 TTGTGTGTGTGTGTGTGTGG ACT

rs4359361 GCTTAGTACACTTTAAACATGAT ACT

rs4605089 TCAGGAACACCGCTTAATTTTT ACG

rs7146446 CAAGACCTCTTTAAGTAATACTC ACG

rs4346144 AGACCTCTTTAAGTAATACTCC ACT

rs7148078 GGCTTGGGTACGGGAAGC CGT

rs7148286 CATTAAGCTTGCCAGAAAATCA ACG

rs3783980 CATCTTCCTCTGCCTCCCA ACG

rs1549119 CTTCCTCTGCCTCCCATAAAT CGT

rs1984925 CAGGCACGTGCCACCACA ACG

rs1477261 AGGAGGAGCCCAAATATGAAA I
CGT

dbSNP Extend Term rs# Primer Mix rs8016447 CACACCTGGCCATGCTTCC ACT

rs7494044 CCTGGCCATGCTTCCGTATT ACG

rs2023288 AATTGTGATTGATTGATTGCGAT CGT

rs7151685 GTGAGCCACCACATCATCTG ACT

rs2112135 TCAGGTGATCCTCCTGCCT ACG

rs2161088 CCAATCACAGCCCACTGCA ACT

rs4903638 GCCAGAGTGGTCTCCAACT ACT

rs1477262 AGAGCTCAAGCTGATGTCCT ACT

rs1477263 TTTTCCTGTTGAGTTCGCATG ACT

rs1477264 ACCACCTCAGTTTTGCTGTTT ACG

rs2277917 CCTTGATAACCGCTTGGTCT ACT

rs2277918 AAAAGCTTCCCGGGGACAG CGT

rs2277919 AGCTTCCCGGGGACAGCT ACT

rs1978416 TGAGACTAGCTAATGGAGAGT ACG

rs3759728 AGCAAATCTACTGCAAACGTG CGT

rs6574399 AAGTAGAGCTGCTCCACC CGT

rs7155336 GAAGACTCGGTCTAAAAAAAAAA ACT

rs7156186 GCCACTGCACCTGGCCG ACT

rs7142390 TGGTACTGGCATAAGGATAGA ACG

rs7145875 CACAAAACCTTAACTTTTGATTTAACT

rs8014635 CAAGAACACTGGTTTTGGTTTT ACT

rs8015938 CTCAAGTGATCTGCCTGCC ACT

rs8015313 GATTCTGTACCTGGTTGATCAT ACT

rs8006315 AACATGGTGAAGCCCCATCT CGT

rs6574400 GAGATCGCCAGAGACACCA ACG

rs7140816 TGAGACTCTGTCTCAAATACTA CGT

rs4566078 CTCAGCTCACTGCAACCTC ACG

rs7141050 AGCACATAGTAAGTGCCCTAT ACT

rs3049356 GAATAGTGGAAGGTATTGAAATA ACT

rs4903639 GAGACTCCGTCTCAAAAAAAAAA CGT

rs4903641 GGCAACAGAGCGAGACTCC ACT

rs2364838 CCAGCTACTTGTGAGGCCAA ACT

rs2364839 AGCCAGACGTGGTGGCAC ACT

rs4632066 GAGATGGAGGGGGAGCCT ACT

rs2112136 GGGACTAAGGCTCGCATCC ACT

rs4641655 GGATTTCTGGGTCCCACTC ACG

rs4635269 AGCCACCGCGCCCGGCC ACT

rs4570764 GTGATTATTGGCCGGGCGC ACT

rs759808 TGCACCACACAGCCTGGG CGT

rs7150531 AGCAAAGTTAATGGGAGGCC ACT

rs7154968 AACAAACCTGCATATGTACCC ACT

rs7146657 CACCCACCACCCCGCCC ACT

rs7145859 CGGGAGGTGGAGCTTGCA ACT

rs4903643 GCTCCCTTCTGTCTACTGC ACT

rs717682 AGGCTGAGGCAGGAGAATC ACT

rs717683 AAAAGGTGGAGGCCAAAGAC ACT

rs1477259 CGGAATAATTATATCTGCCTCT ACT

rs8019064 CAGAGGCAGATATAATTATTCC ACT

rs8018971 GTCACTCAGGCTGGAGTGC CGT

dbSNP Extend Term rs# Primer Mix rs1477260 GACGAGGAGGAAAGCCATC ACT

rs5809851 CACAGCAGTGTCTTTTTTTTTTT ACT

rs1985149 TTCTTCTCCCTCAGCCTCC ACG

rs1008988 GGGGATGACCTCTCTGGAG ACT

rs1008989 GCCAGCTTGGCAGATTGAG CGT

rs8018222 TGCTGAACGCTGGTCCCC CGT

rs1006040 TGGAGTGCAGTGGCAAGAC ACG

rs1006039 CATAGCCAGACCCTATGAGA ACG

rs1006038 ACTGTGCTCAGTCTATGCTG ACG

rs8009784 ATGCTTTGCCTTAAAGTGGTG ACT

rs4903644 GCCTGGGCAACAGAGCAAG ACT

rs7149496 GATTCTGTAAGTCTGGTATGAG ACT

rs6574402 CTGACAAGAAAATGACTGCATA ACT

Genetic Analysis [0269] Allelotyping results are shown for cases and controls in Table 41. The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (A1 AF = 1-A2 AF).
For example, the SNP
rs7143926 has the following case and control allele frequencies: case Al (A) =
0.75; case A2 (T) _ 0.25; control A1 (A) = 0.71; and control A2 (T) = 0.29, where the nucleotide is provided in parenthesis.
Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 6 rs7143926218 76161268 A/T 0.25 0.29 0.216 rs15490711440 76162490 C/T 0.15 0.20 0.098 rs80128581442 76162492 C/T 0.93 0.95 0.335 rs71556112611 76163661 C/T 0.02 0.02 0.949 rs176941 4317 76165367 A/C 0.31 0.35 0.271 rs176942 4724 76165774 A/G 0.02 0.02 0.911 rs176943 4788 76165838 G/T 0.13 0.18 0.037 rs 1769445202 76166252 G/T 0.09 0.14 0.107 rs43652215780 76166830 C/T

rs31689525974 76167024 C/T

rs176945 6644 76167694 C/G 0.95 0.96 0.801 rs176946 7430 76168480 A/G 0.10 0.15 0.054 rs176947 7938 76168988 C/T 0.10 0.08 0.473 rs176948 8095 76169145 C/T 0.31 0.35 0.132 rs176949 8183 76169233 A/C 0.03 0.02 0.887 rs176950 8312 76169362 C/T 0.78 0.70 0.008 rs176951 8352 76169402 A/C

rs71569059348 76170398 C/T 0.89 0.90 0.794 rs32171979378 76170428 -/TCTC 0.29 0.35 0.036 rs22704439617 76170667 A/G 0.39 0.34 0.176 rs176952 9727 76170777 C/T 0.17 0.24 0.018 rs176953 9834 76170884 C/T

rs176954 9899 76170949 G/T 0.43 0.52 0.010 rs176955 10211 76171261 C/T 0.12 0.18 0.028 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 6 rs321441610377 76171427 -/T 0.91 0.89 0.544 rs 17695610695 76171745 C/T 0.51 0.49 0.492 rs254456610729 76171779 C/G

rs254456710730 76171780 C/T

rs17695711433 76172483 A/G

rs17695811951 76173001 C/G 0.02 NA NA

rs17695912697 76173747 C/T 0.30 0.34 0.147 rs180222712982 76174032 A/C 0.92 0.95 0.332 rs17696114419 76175469 C/T 0.51 0.47 0.158 rs 17696214501 76175551 C/T 0.82 0.79 0.192 rs740128514983 76176033 A/C

rs17696315280 76176330 C/T 0.51 0.46 0.155 rs 17696415475 76176525 A/G 0.53 0.49 0.197 rs490363115888 76176938 A/G

rs490363215976 76177026 A/T

rs17696516307 76177357 A/C 0.55 0.52 0.368 rs490363316442 76177492 A/C 0.83 0.83 0.970 rs17696617255 76178305 C/T

rs17696818948 76179998 G/T 0.23 0.27 0.246 rs17696919435 76180485 A/T 0.14 0.20 0.052 rs17697019753 76180803 C/T 0.35 0.38 0.328 rs714919820021 76181071 C/T

rs714791820022 76181072 A/C

rs714868520503 76181553 A/G 0.19 0.18 0.669 rs 118423220590 76181640 G/T 0.16 0.19 0.316 rs118423321804 76182854 G/T 0.36 0.36 0.895 rs118423421919 76182969 C/T 0.36 0.35 0.797 rs740199821990 76183040 A/T

rs17697422412 76183462 A/G

rs657439022536 76183586 C/T

rs17697523432 76184482 A/G 0.18 0.23 0.147 rs17697623468 76184518 G/T 0.86 0.80 0.087 rs17697723772 76184822 C/T 0.42 0.41 0.794 rs801372724325 76185375 C/T

rs17697824773 76185823 C/T 0.10 0.12 0.512 rs211182926274 76187324 C/T 0.02 NA

rs17698027440 76188490 C/G 0.79 0.73 0.018 rs580984828561 76189611 -IACAG 0.11 0.16 0.091 rs580984930071 76191121 -/A 0.60 0.57 0.355 rs438307031764 76192814 A/T

rs749365233008 76194058 C/T

rs211213335310 76196360 A/T

rs196383335460 76196510 A/C

rs657439137112 76198162 A/G 0.69 0.63 0.064 rs715506237285 76198335 A/G 0.17 0.18 0.878 rs489967437747 76198797 C/T 0.57 0.52 0.201 rs802251638057 76199107 C/T 0.57 0.51 0.135 rs714083838859 76199909 A/C 0.17 0.17 0.957 rs714112738860 76199910 A/G

rs657439239525 76200575 A/G 0.27 0.32 0.099 rs800369140216 76201266 A/G 0.70 0.63 0.029 rs800397940281 76201331 C/T 0.10 0.15 0.024 rs801054141453 76202503 C/G 0.38 0.38 0.993 rs801641642091 76203141 A/T 0.09 0.14 0.035 rs801617542513 76203563 A/G

rs715457142935 76203985 C/T

rs715882642985 76204035 AlG

rs715931043003 76204053 A/G 0.62 NA

rs740190043281 76204331 A/G

rs716035543716 76204766 C/T

rs203278143866 76204916 A/G 0.80 0.74 0.047 rs657439444234 76205284 G/T 0.61 0.54 0.091 rs800759844596 76205646 A/G 0.09 0.10 0.734 rs226776744871 76205921 C/T

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 6 rs657439545005 76206055 A/G 0.10 0.14 0.203 rs715006645282 76206332 A/C 0.91 NA

rs749233447178 76208228 A/C

rs435936147816 76208866 G/T

rs460508947887 76208937 A/G

rs714644648134 76209184 C/T 0.09 0.09 0.981 rs434614448135 76209185 A/G 0.83 0.85 0.368 rs714807848276 76209326 G/T 0.44 0.50 0.098 rs714828648400 76209450 C/T 0.96 0.96 0.893 rs378398048798 76209848 A/G 0.15 0.20 0.073 rs154911948803 76209853 A/T 0.18 0.25 0.027 rs198492549146 76210196 C/T 0.04 0.04 0.882 rs147726149969 76211019 A/T

rs801644751059 76212109 A/G 0.10 0.15 0.049 rs749404451064 76212114 C/T

rs202328853285 76214335 A/T 0.97 0.98 0.774 rs715168554560 76215610 C/T

rs211213554748 76215798 A/G 0.05 NA

rs216108854785 76215835 C/G

rs490363855102 76216152 C/G 0.59 0.59 0.975 rs 147726255644 76216694 A/G 0.12 0.17 0.040 rs 147726355705 76216755 G/T 0.18 0.23 0.057 rs147726455841 76216891 A/G 0.45 0.42 0.271 rs227791756623 76217673 C/G 0.30 0.36 0.039 rs227791856825 76217875 A/C 0.49 0.45 0.232 rs227791956827 76217877 A/G 0.20 _ 0.310 0.17 rs197841656892 76217942 C/T 0.79 0.73 0.074 rs375972859150 76220200 A/T 0.13 0.18 0.083 rs657439959958 76221008 A/T 0.33 0.36 0.396 rs715533660231 76221281 C/T 0.25 _ 0.250 0.28 rs715618660524 76221574 A/G 0.85 0.85 0.965 rs714239061871 76222921 C/T

rs714587562226 76223276 C/T

rs801463563230 76224280 G/T 0.07 0.11 0.062 rs801593863468 76224518 G/T 0.08 0.07 0.693 rs801531363787 76224837 C/T 0.67 0.71 0.135 rs800631565732 76226782 A/C

rs657440065989 76227039 A/G 0.75 0.70 0.099 rs714081668832 76229882 G/T 0.54 0.48 0.095 rs456607869904 76230954 C/T

rs714105070365 76231415 A/G

rs304935670886 76231936 -/TATC 0.64 0.69 0.091 rs490363973088 76234138 A/T

rs490364173103 76234153 C/T 0.54 0.66 ~0.0001 rs236483875934 76236984 C/T

rs236483975966 76237016 C/T 0.18 0.18 0.988 rs463206676273 76237323 C/T 0.66 0.66 0.961 rs211213677943 76238993 C/T 0.70 0.64 0.064 rs464165578466 76239516 C/T 0.52 0.48 0.174 rs463526978861 76239911 C/T

rs457076478872 76239922 A/G 0.55 0.68 ~0.0001 rs75980879836 76240886 G/T 0.12 0.18 0.043 rs715053180908 76241958 C/T 0.33 0.31 0.491 rs715496881509 76242559 C/G 0.03 NA

rs714665783576 76244626 C/T 0.57 NA NA

rs714585983662 76244712 C/G

rs490364383782 76244832 C/T 0.10 0.14 0.074 rs71768284282 76245332 G/T 0.11 0.13 0.624 rs71768384444 76245494 A/G 0.79 0.75 0.121 rs147725985129 76246179 C/G 0.11 0.16 0.022 rs801906485151 76246201 A/G 0.90 0.93 0.192 rs801897185296 76246346 A/C

rs147726085809 76246859 C/G 0.12 0.16 0.085 rs580985186387 ~ 76247437 -/T 0.30 0.30 0 993 ~ ~ ~ ~

dbSNP Position ChromosomeAllA2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 6 rs198514986494 76247544 A/G 0.22 0.23 0.892 rs100898889786 76250836 A/G 0.61 0.58 0.380 rs100898989894 76250944 A/T 0.14 0.18 0.172 rs801822290122 76251172 G/T

rs100604092067 76253117 A/G 0.13 0.18 0.092 rs100603992187 76253237 C/T 0.06 0.10 0.133 rs 100603892312 76253362 AIG 0.19 0.24 0.114 rs800978492824 76253874 G/T 0.13 0.18 0.037 rs490364493733 76254783 C/T 0.41 0.38 0.383 rs714949696553 76257603 ClG

rs657440296941 76257991 A/C 0.12 0.17 0.037 [0270] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1F for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1F can be determined by consulting Table 41. For example, the left-most X on the left graph is at position 76161268. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0271] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The'vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a lOkb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-$ were truncated at that value.
[0272] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.

Example 10 ERG Region Proximal SNPs [0273] It has been discovered that SNP rs1888475 in v-ets erythroblastosis virus E26 oncogene like (ERG) is associated with occurrence of osteoarthritis in subjects. One hundred sixty-six additional allelic variants proximal to rs1888475 were identified and subsequently allelotyped in osteoarthritis case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 42. The chromosome positions provided in column four of Table 42 are based on Genome "Build 34" of NCBI's GenBank.

dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs289835321 231 38783681 alt rs960818 21 882 38784332 al rs960819 21 960 38784410 a/c rs241003421 1194 38784644 a/c rs283643721 1530 38784980 al rs283643821 1673 38785123 a/

rs283643921 2096 38785546 c/t rs283644021 2285 38785735 a/

rs222668321 5873 38789323 c/t rs283644121 7256 38790706 a/

rs283644221 7988 38791438 a/

rs283644321 8222 38791672 /t rs283644421 8381 38791831 c/t rs378790621 8814 38792264 c/t rs383810821 8915 38792365 -/c rs283644521 9642 38793092 a/

rs283644621 9902 38793352 a/t rs378790821 10619 38794069 a/

rs283644721 10927 38794377 c/t rs283644821 11032 38794482 clt rs283645021 14377 38797827 c/t rs283645121 15608 38799058 c/t rs101502221 15928 38799378 c!

rs283645221 16296 38799746 a/

rs283645321 17598 38801048 a/t rs378790921 19272 38802722 a/

rs283645421 20084 38803534 a/

rs283645521 20577 38804027 a/t rs215571821 28051 38811501 a/

rs283645621 29466 38812916 a/

rs283645721 29530 38812980 c/t rs283645821 29987 38813437 a/

rs203232321 30012 38813462 clt rs205140021 30322 38813772 /t rs283645921 32216 38815666 c/t rs283646021 32516 38815966 clt rs283646121 32544 38815994 a/

rs283646221 32746 38816196 a/

dbSNP Position ChromosomeAllele rs# Chromosomein SEQ Position Variants ID NO:

rs283646321 33137 38816587 /t rs283646421 33538 38816988 a/

rs283646521 33798 38817248 c/t rs283646621 33802 38817252 a/c rs283646721 33964 38817414 c/t rs382720421 34132 38817582 a/

rs283646821 34210 38817660 c/t rs378791121 34317 38817767 a/

rs283646921 34499 38817949 c/t rs283647021 34753 38818203 a/c rs221259921 34845 38818295 c/t rs283647221 35335 38818785 c/t rs283647321 36423 38819873 clt rs188846921 36450 38819900 a/

rs188847021 36481 38819931 /t rs203232221 38447 38821897 c!

rs241003521 38784 38822234 c/t rs157333221 39387 38822837 alt rs283647421 39458 38822908 c/t rs283647521 39822 38823272 c/

rs378791421 40305 38823755 c/

rs188847121 40869 38824319 c/t rs188847221 40926 38824376 c/t rs188847321 41010 38824460 c/t rs188847421 41134 38824584 clt rs283647621 41984 38825434 a/

rs378791621 42172 38825622 a/t rs283647721 42753 38826203 /t rs970043 21 43011 38826461 c/t rs221260021 43176 38826626 a/

rs283647821 43320 38826770 /t rs283647921 43381 38826831 alt rs147587721 44142 38827592 a/

rs283648021 44383 38827833 a/

rs283648121 44726 38828176 c/t rs283648321 45087 38828537 a/

rs283648421 45141 38828591 clt rs283648521 45359 38828809 c/

rs283648621 45421 38828871 c/t rs283648721 45456 38828906 c/t rs189319921 45467 38828917 c/t rs283648821 45486 38828936 c/t rs189320021 45709 38829159 a/

rs189320121 45716 38829166 al rs283648921 47626 38831076 c/t rs188847521 49413 38832863 a/

rs283649021 49796 38833246 c/t rs283649121 49962 38833412 a/

rs283649221 50075 38833525 c/t rs283649321 50093 38833543 a/

rs283649421 50571 38834021 c/t rs283649521 50615 38834065 a/

dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs289835421 50780 38834230 a/

rs306539021 50851 38834301 -/ta rs283649621 51459 38834909 alc rs283649721 53193 38836643 c/t rs283649821 53702 38837152 c/t rs283649921 53736 38837186 a/c rs283650021 53795 38837245 c/t rs283650121 54109 38837559 a/t rs283650221 54126 38837576 c/t rs283650321 54230 38837680 a/c rs283650421 54894 38838344 c/t rs378791721 55455 38838905 a/

rs283650521 55499 38838949 a/

rs283650621 56522 38839972 c/t rs283650721 56662 38840112 c/t rs283650821 56954 38840404 a/

rs283650921 57267 38840717 a/

rs283651021 58282 38841732 a/

rs283651121 58916 38842366 a/c rs221260121 59544 38842994 c/

rs221260221 59666 38843116 c/t rs222668221 59913 38843363 a/t rs283651221 66846 38850296 a/

rs283651321 67245 38850695 /t rs199932821 67652 38851102 a/c rs221260321 67955 38851405 a/

rs378791921 67966 38851416 a/c rs283651421 68420 38851870 a/

rs102315321 70226 38853676 a/

rs102337221 70810 38854260 c/t rs221260421 72246 38855696 a/

rs222668421 73330 38856780 /t rs221260521 73457 38856907 c/t rs218730721 74389 38857839 a/

rs306541221 74638 38858088 -/aa rs289835521 74640 38858090 a/c rs283651821 75358 38858808 a/c rs383811021 75952 38859402 -/

rs283651921 76098 38859548 al rs382720721 77836 38861286 a/

rs283652021 78449 38861899 alc rs283652121 78507 38861957 /t rs283652221 80031 38863481 /t rs283652321 81695 38865145 clt rs283652421 82775 38866225 al rs283652521 82795 38866245 a/

rs383335021 84611 38868061 -!c rs283652621 84657 38868107 c/t rs283652721 84693 38868143 a/c rs383467621 85020 38868470 -/t rs283652821 85048 38868498 clt rs376136421 85100 38868550 c/t dbSNP Position Chromosome Allele rs# Chromosomein SEQ Position Variants ID NO:

rs2836529 21 85325 38868775 a/c rs2836530 21 85452 38868902 c/t rs3761366 21 85868 38869318 a/

rs2836531 21 85936 38869386 a/

rs2836532 21 85990 38869440 a/t rs2836533 21 86139 38869589 c/t rs2836534 21 86497 38869947 c/t rs2836535 21 87236 38870686 a/

rs2836536 21 87248 38870698 c/t rs3827208 21 87533 38870983 c/

rs715860 21 87912 38871362 a/

rs717231 21 88108 38871558 /t rs2836537 21 88494 38871944 a/c rs2836538 21 89598 38873048 a/c rs2836539 21 90235 38873685 a/t rs2836540 21 91287 38874737 /t rs2836541 21 91359 38874809 c/t rs2836542 21 92384 38875834 a/c rs2836543 21 92410 38875860 c/t rs881837 21 92900 38876350 c/t rs3949052 21 94495 38877945 a/

rs2065307 21 94512 38877962 a/

rs3216105 21 97777 38881227 -/a rs2073427 21 98333 38881783 c/t Assay for Verif~n~ and Allelotypin~ SNPs [0274] The methods used to verify and allelotype the 166 proximal SNPs of Table 42 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 43 and Table 44, respectively.

dbSNP Forward Reverse rs# PCR primer PCR primer rs2898353ACGTTGGATGAATGTGAATGTGGAGGTAGCACGTTGGATGCTCCCTTGCTGGTTTTTTTG

rs960818ACGTTGGATGTGGGATTTTTCCCAGAAGAGACGTTGGATGCTGTGCAGAGAAACATGATG

rs960819ACGTTGGATGCTGTCTCCCTTCTCTTTATCACGTTGGATGCATCATGTTTCTCTGCACAG

rs2410034ACGTTGGATGTTTAGAGACATTTCTCCTAGACGTTGGATGTTAGGATGATGTTAGTTTGG

rs2836437ACGTTGGATGAGCTTCTGCGATATCAGTGGACGTTGGATGTTCCTGTCAGCACATTCTCC

rs2836438ACGTTGGATGAACATGTCTTGGCCAAGCTCACGTTGGATGCCACTGTGACCTCTGGATTT

rs2836439ACGTTGGATGCCTAGTGTATAAAGTGATGCACGTTGGATGTCCTTTCTAGGCACCAATAC

rs2836440ACGTTGGATGAGATCCTAACCAACCACAGCACGTTGGATGAGGTAGGTAGATACAAGGCC

rs2226683ACGTTGGATGAATATGGCTCCTATAGACAGACGTTGGATGTTTTGGGTCACAAAATCAAG

rs2836441ACGTTGGATGTTACCTTAATAGTGCTGGCCACGTTGGATGACTTTCTGGTCAGAGAGAAG

rs2836442ACGTTGGATGCAAGGACTCTAGGCTTACAGACGTTGGATGGGGACATTTGTAGTCACTTC

rs2836443ACGTTGGATGGGGCCCCATTACATGTCTAAACGTTGGATGTTCGCTGTACTTCCTTCGAG

rs2836444ACGTTGGATGCTGCAACCAGGAATTGTCAGACGTTGGATGAGGACCCATAAAGAGGTGTG

rs3787906ACGTTGGATGTGAAAAGAGCGGAAATCAACACGTTGGATGGTAAGAAAATCATTCTGTGG

rs3838108ACGTTGGATGATGAATAAGATGGCAGGCTGACGTTGGATGAAGCTGCCCAGATAAAACAG

dbSNP Forward Reverse rs# PCR primer PCR primer rs2836445ACGTTGGATGCATTTCCAAAATTAGACGCAGACGTTGGATGAAAAAGAGAAAAACAGATGC

rs2836446ACGTTGGATGGTGCCTTGTCCTATCAAGAGACGTTGGATGAGCATCCAAGCCTGGTAATC

rs3787908ACGTTGGATGAATCACCACACTAGACCAGCACGTTGGATGCATGCAAGGGAAATGTGTGC

rs2836447ACGTTGGATGATCTCCTCTCTTTGCTCTGCACGTTGGATGGAGGAAGGTTAGGAGCTAAG

rs2836448ACGTTGGATGTGTAGGGATGTATAGGGCAGACGTTGGATGAAAGAGAGGAGATCCGTCTG

rs2836450ACGTTGGATGTGTGGGCATCAGATGACAACACGTTGGATGATCCCGTTAAATGCACCGAC

rs2836451ACGTTGGATGCAGACAAACAACTGTCACCCACGTTGGATGGTATTTCCTTTTCTCGCCGC

rs1015022ACGTTGGATGTCGAGCCAGCGTCTTTTATCACGTTGGATGGTAACAGTCGTACATTCCGG

rs2836452ACGTTGGATGATCACTGACACAGTCATGAGACGTTGGATGCCAGTAACTTTGCAGGTTTG

rs2836453ACGTTGGATGTGTATTTCCCAAGATGGCCCACGTTGGATGCCTCACTTTCTGATGGAAGC

rs3787909ACGTTGGATGACTTCTCAGTGTTCTGGCTGACGTTGGATGCGTCACTCTCTGTTTCATGG

rs2836454ACGTTGGATGAGGAATGATTCACAACCTCCACGTTGGATGGAATGTTCAAATGTAGGGTGG

rs2836455ACGTTGGATGGGTCTATTGCTGTGACATTTACGTTGGATGCATCCCAATTTTTAAGCAAG

rs2155718ACGTTGGATGAGAACTCTCACACACAGCTGACGTTGGATGTGCCTCTTATTACAGCCCTG

rs2836456ACGTTGGATGGGGATTGTCTGATCTCCTTGACGTTGGATGCCAGCTTTCCTTTGTGCATG

rs2836457ACGTTGGATGAACTCCTGGAATGAGTCACCACGTTGGATGATGCACAAAGGAAAGCTGGG

rs2836458ACGTTGGATGATCACTTAGAAGCCCAGCAGACGTTGGATGTGATGCACACTCACTGAAGC

rs2032323ACGTTGGATGGTAGCCGCACTTTGAGATGCACGTTGGATGAGCACAGAGTCGAGGAGGAG

rs2051400ACGTTGGATGACAGACCTCAGACCAAAGTCACGTTGGATGTTTGTCCTAGAGTAACCCCC

rs2836459ACGTTGGATGGCAAGAATGTTACTTTCTGGACGTTGGATGCCATCAAATAGTTGGTTGTC

rs2836460ACGTTGGATGCAATATCTGAGTTTCACCCCACGTTGGATGGTAGATGAGAATTCCGTGTG

rs2836461ACGTTGGATGGTTACCCACACGGAATTCTCACGTTGGATGCCAGATCCAGGTTCTTTCTG

rs2836462ACGTTGGATGTCTCCTCCGTATGTCTCCATACGTTGGATGATCCCGGAACTCTCTGTTTC

rs2836463ACGTTGGATGGCACTATTTGACTTGAGCTCACGTTGGATGAATTCAAGCCAGAAAGGCTC

rs2836464ACGTTGGATGGTCTTTTTCACCCCAGTAAAGACGTTGGATGATAAGCAAAAGGACCTTTGG

rs2836465ACGTTGGATGTGAGCTCTTGTGTTTTGCCCACGTTGGATGGAGAATTCTCCAGCCTTCTC

rs2836466ACGTTGGATGTGAGCTCTTGTGTTTTGCCCACGTTGGATGGAGAATTCTCCAGCCTTCTC

rs2836467ACGTTGGATGGACTCTGCTCATTTCCTTGGACGTTGGATGAAGAGTAGGGGTAGATGCAG

rs3827204ACGTTGGATGTGAAGATCACACGTGGTGTAACGTTGGATGGGGTGAATGCCAAAAAGAGG

rs2836468ACGTTGGATGTAGAGGCAGGAAAGAGCATGACGTTGGATGTTTTTGGCATTCACCCTCTC

rs3787911ACGTTGGATGTAACCCTCTTCTGGATTCGGACGTTGGATGTCATGTGCTCTGAGAGCATC

rs2836469ACGTTGGATGATTTCTCTACCTCATCCCCCACGTTGGATGGGTTGAAGTCACGTAACAGC

rs2836470ACGTTGGATGCCACTGTTAATCGTATTGCCACGTTGGATGACGGACTGAAAGCCAAATGG

rs2212599ACGTTGGATGAGGAGTTATTCTTCCCCAACACGTTGGATGCAGTGGTCCATTAAGAATCC

rs2836472ACGTTGGATGGAGTATCGTTCTCTATCATGACGTTGGATGTAAAAGAGTCAGAGCAGGAC

rs2836473ACGTTGGATGTCTCAGCCAGAGTTTTGACCACGTTGGATGAATCAACGCCTCCTCTTCAG

rs1888469ACGTTGGATGACCACCAGGAAGGGTCTGAAACGTTGGATGGAGGATCAGAGGCAGAAAAC

rs1888470ACGTTGGATGGCGTTGATTGCAGTTTTCTGACGTTGGATGTTCTTTGGCCTCCGTGTAAG

rs2032322ACGTTGGATGTGATACTCTGTTGAGCCTCCACGTTGGATGGGGGAGCAGTGATGAGTTAT

rs2410035ACGTTGGATGAATCACTTGAACCCAGGAGGACGTTGGATGTTTTTGAGACGGAGTTTCGC

rs1573332ACGTTGGATGGGGTGAACTTTACAGAGAGGACGTTGGATGCTGCCAGACAGTTTTGAGAC

rs2836474ACGTTGGATGAATTCTGCACAGGAGAGTCCACGTTGGATGCAGGAAATGAAGATGTCGCC

rs2836475ACGTTGGATGAGTTCTACATGGGAAGCTGCACGTTGGATGATATCTGTGTCTACAGGCCC

rs3787914ACGTTGGATGGGCTGAAGGCTAAAATCACCACGTTGGATGGTCTGAGAAGTAGGAATGGC

rs1888471ACGTTGGATGACTGAGGCAATTGTGTAGACACGTTGGATGTTGACTTTGTTTTGAGAGGC

rs1888472ACGTTGGATGTTGCCTCTCAAAACAAAGTCACGTTGGATGCTATTATTCTGGAAGCAGCC

rs1888473ACGTTGGATGAGAAAGTTCAGTTCTCAGCCACGTTGGATGTGTTTGCTCCTGTGAGTAAC

rs1888474ACGTTGGATGTGTTATGTGAGTCCAGGGTGACGTTGGATGTCTTGTTATGTGGGTGGGTG

rs2836476ACGTTGGATGTTACCTGTGACCTCATTTGGACGTTGGATGGAACACACAACATACGGTAC

rs3787916ACGTTGGATGAAGGCATCTCAGTCATTCTCACGTTGGATGTGAGTTTGACACAAAGAAGC

rs2836477ACGTTGGATGTTTAGCTCTCCTGGATGATGACGTTGGATGCCATGATTAGTGCATGAAGG

rs970043ACGTTGGATGTATAACTCCCCTCTCTCCTG~ ACGTTGGATGAGAGCAGACCCTTATCAGAG

dbSNP Forward Reverse rs# PCR primer PCR primer rs2212600ACGTTGGATGGAAACAGGTGTTCATTTGGCACGTTGGATGTCTGCATGAACCAGTAAGTC

rs2836478ACGTTGGATGAGCTATTGAGTGTCACTTGCACGTTGGATGCAGAAGCTTCTGACTTCAAC

rs2836479ACGTTGGATGAGTAGCCATCCTAATAGGTGACGTTGGATGAGCAAGTGACACTCAATAGC

rs1475877ACGTTGGATGAATCAACACTCCCCGTGTTCACGTTGGATGGGTACCTAGAGTAGTCCAAG

rs2836480ACGTTGGATGTACCAAACCCACTGTACATCACGTTGGATGCATAACCTAACACATTGTGGG

rs2836481ACGTTGGATGTAAGAAGTTCTTTCTCCCCCACGTTGGATGGCTGCTTCTTTCATAAGAGG

rs2836483ACGTTGGATGCACTGAGGTAATCTCCAACCACGTTGGATGGGTGGAGATATGGCTTGATG

rs2836484ACGTTGGATGAAGCCCACCAGAGTCATCAAACGTTGGATGACTACTGACCAGCTTTCCAG

rs2836485ACGTTGGATGTTCTAAGTGAAGCCCTCCTCACGTTGGATGTACAGCTGTGCAAACAGTTG

rs2836486ACGTTGGATGCATGGTCTGTTGCCTCTAAGACGTTGGATGCCCTAGCATTTTATGCATCC

rs2836487ACGTTGGATGTGAATACCCACTAGGTCTCGACGTTGGATGCCACCACTAAACTTAGAGGC

rs1893199ACGTTGGATGGGCAACAGACCATGGTTTTGACGTTGGATGCTTCCCTTCAACATGCACTG

rs2836488ACGTTGGATGGGCAACAGACCATGGTTTTGACGTTGGATGCTTCCCTTCAACATGCACTG

rs1893200ACGTTGGATGAGTTAAGTCTTCGCATAACCACGTTGGATGCCTCTCACACACTAAATCTTG

rs1893201ACGTTGGATGGTCTTCGCATAACCAAAACAGACGTTGGATGCCTCTCACACACTAAATCTTG

rs2836489ACGTTGGATGGTCAACCATGGAGCTTGAACACGTTGGATGAGAAGACATGTGGGCTTGTG

rs1888475ACGTTGGATGACCCCTGGCAAGTGAATTACACGTTGGATGGGGAGGTGGATGTTCTTATC

rs2836490ACGTTGGATGAAAGGCAGAGCTAAAGCAAGACGTTGGATGAGCACAACCCAGCAATGCAG

rs2836491ACGTTGGATGACAACTTGGAGTGGAAAGGGACGTTGGATGATCCAGATGGATTCCACAGC

rs2836492ACGTTGGATGACATATGGGCATGGAAGAGCACGTTGGATGAATCCATCTGGATGGAAGAC

rs2836493ACGTTGGATGTTAAGAGTTCCGATGCTTGCACGTTGGATGGTAATCTGGACTTCTCTTCC

rs2836494ACGTTGGATGGTGCATTCATTTGAATTGCTGACGTTGGATGCAGTCTTACTTAAAACTGAC

rs2836495ACGTTGGATGGAATTTAACGAAACTTCAGCACGTTGGATGGGATATTTTCAGGATATCTG

rs2898354ACGTTGGATGTGTAACAAACCTGCACATCCACGTTGGATGGGTACTTTCCAAATATCTGC

rs3065390ACGTTGGATGCGAGACTCCATCTCAAAAAAGACGTTGGATGTGGAAAGTACCAATAGCTTC

rs2836496ACGTTGGATGTGGAGCTTAATGTGTTCCTGACGTTGGATGGTTAGCCATGCATAAGACAG

rs2836497ACGTTGGATGAGCCGGGATGACTGCTAGACACGTTGGATGAGATGAGGCTGAAGAAGTAA

rs2836498ACGTTGGATGGGTCCTGGGAAAATAGGATGACGTTGGATGCACCCTTGCTCTTTCTGAAG

rs2836499ACGTTGGATGACTAGTCAGAGCACAGTGAGACGTTGGATGGCTCTCTCCTTCTTTGACTC

rs2836500ACGTTGGATGGCTTCCTGGTTAGTAAGAGGACGTTGGATGATCAACTCAGGGCTCTTCTC

rs2836501ACGTTGGATGACTCACAAAGGTTGACCTTGACGTTGGATGGAGGTCCAGGTTGAAAGAAC

rs2836502ACGTTGGATGGAGGTCCAGGTTGAAAGAACACGTTGGATGACTCACAAAGGTTGACCTTG

rs2836503ACGTTGGATGGAGCAATTATCAACCCTACGACGTTGGATGATTCTCCCCCTTCACTCTTG

rs2836504ACGTTGGATGGAGTCTGGGTATGGAAAGAGACGTTGGATGTTCCTAGAAATGGTG1'CTGC

rs3787917ACGTTGGATGTTTGGAGGAGGAATGCCTTGACGTTGGATGCGCCCACAAACCTAAGAGAA

rs2836505ACGTTGGATGTTTTCGACTGCTCCACTCTGACGTTGGATGGCTCTCCCTCATTGTTCTTC

rs2836506ACGTTGGATGGGCTAAGGGCATCATTTTATCACGTTGGATGGTTTGCTGATTCATGGATGC

rs2836507ACGTTGGATGAGCAAAGGTTCTGGTGTTGGACGTTGGATGAAATGATGCCCTTAGCCCAG

rs2836508ACGTTGGATGGTGTGATGATATTTTTCTCCACGTTGGATGTTTCAGGTATTCCTCTTTGC

rs2836509ACGTTGGATGTAAAGCTTTCTAAGTCAATGACGTTGGATGTCATATGATAATGGTCTCTG

rs2836510ACGTTGGATGCAGGGAGAGATCTAAACAGCACGTTGGATGGCCAAAGCTATAACACGTGG

rs2836511ACGTTGGATGAGAACCTGACTTTTGGAGTGACGTTGGATGCTTCCTCATTGGTCAGAGTC

rs2212601ACGTTGGATGCCAGCCTTTAGAACTGTGAGACGTTGGATGTGGGCTGCTGTAACAAAGTG

rs2212602ACGTTGGATGACTACAACCAGCCAGAGATGACGTTGGATGCACAAACCTTGTGTGAACCC

rs2226682ACGTTGGATGCCAAGATTGAACCAGGAAAGACGTTGGATGCACAAAAGAATTCAGGAGGTG

rs2836512ACGTTGGATGCCCCAAAACTTAGCATCCTGACGTTGGATGTGTTCTCCCTGCACTTCAAC

rs2836513ACGTTGGATGCACTGGGGTTAGCAAGAAACACGTTGGATGGACTGTGATTCACCCTGTCT

rs1999328ACGTTGGATGAGTTACAGCGCAAATTGAGGACGTTGGATGGCCTTTATGACTCCATTTCTC

rs2212603ACGTTGGATGTGGAGGGTGTCTGTGAGTACACGTTGGATGTCATGGAGCAAGGTCTGTGG

rs3787919ACGTTGGATGCCATCAGCTAGGATTCATGGACGTTGGATGTCTGTGAGTACCCCACAATG

rs2836514ACGTTGGATGCAGGTCTAACTAACTGATGACACGTTGGATGGCCTCTACTGTTATTTAAGG

rs1023153ACGTTGGATGTACAAAAGTGACCTAGAGCC~ ACGTTGGATGTTCTTGCAGGACATTGTGCC

dbSNP Forward Reverse rs# PCR primer PCR primer rs1023372ACGTTGGATGCAAATTCCAAAATTCTGGTTGACGTTGGATGCTCAGAAGTAACATGTACTC

rs2212604ACGTTGGATGCAGACTTGAGCATATACCACACGTTGGATGACCCATGTGGGAAAATGTTG

rs2226684ACGTTGGATGGGTGTTGGAAAAGGAACATCACGTTGGATGTTAATGATAGTTCCCCTCAG

rs2212605ACGTTGGATGATATGAGTGATTTGCATGGGACGTTGGATGTGCATATAAGCTGTCTGCAC

rs2187307ACGTTGGATGCACATCCTGCAGCTTTAACCACGTTGGATGCCTGGCACTTTCAAGTAACG

rs3065412ACGTTGGATGGGCTGAGATAGAATGTGCTCACGTTGGATGTCTCCTGCTTTGTTCTGGAG

rs2898355ACGTTGGATGGGCTGAGATAGAATGTGCTCACGTTGGATGTCTCCTGCTTTGTTCTGGAG

rs2836518ACGTTGGATGCACTTGTTGCTTCTTCCACCACGTTGGATGATGCCAACCTTGCTGATGTC

rs3838110ACGTTGGATGGAAGTAGTGAAGTGTTCCCCACGTTGGATGAGCCTCACTGAATCTTAACG

rs2836519ACGTTGGATGTGTTTCTCCTTCTCACTGGGACGTTGGATGAAAGGCTACAGGAACTGAGC

rs3827207ACGTTGGATGTGTAGTCTGCACCTTCACCTACGTTGGATGAGCGGCTGCTGAACATAGAT

rs2836520ACGTTGGATGCCTGCAAAGGTGTTTGCTTCACGTTGGATGGCCACCTAATTTTTCCTCTC

rs2836521ACGTTGGATGAAGAATAAGAAGCAAACACCACGTTGGATGGTTTTAGGGGAAAGGCATAAG

rs2836522ACGTTGGATGTGCATCTTTGGTTGTGACAGACGTTGGATGGCACATCTACTCTTAGCATG

rs2836523ACGTTGGATGTCTCTCTTTCTTTTCCCTACACGTTGGATGACTCTCAGTTATGATTTCTC

rs2836524ACGTTGGATGGTGTGTTGGTAGAAACGTTCACGTTGGATGGTCACCCCTTCAGATAATAAG

rs2836525ACGTTGGATGCAGAGCCGAAAACATAGTTCACGTTGGATGGTGTGTTGGTAGAAACGTTC

rs3833350ACGTTGGATGGTTGTTCCTTTTGTCTTCTAGACGTTGGATGGAATCATGTCCTTCAGTAAGC

rs2836526ACGTTGGATGATTGTGTCCTGTCCTGCTAGACGTTGGATGGACGGCTAGAAGACAAAAGG

rs2836527ACGTTGGATGGTGTTTTATGTTCTAGCAGGACGTTGGATGGATGCCTTTAGGCAAACATG

rs3834676ACGTTGGATGAAGCTGAAAAGGATGTGCAGACGTTGGATGACAGGGCATACTTCTCTATC

rs2836528ACGTTGGATGCCAAAACTCATGCGATCTGCACGTTGGATGTGGCGCTGAAGTACTCAATG

rs3761364ACGTTGGATGAAACAGCACAGCTACCATTCACGTTGGATGATGAGAAAATGTGTGTGGAG

rs2836529ACGTTGGATGAGCGGTGTTTTAAAATGTCCACGTTGGATGCAGAGCCCAAAAAAAATTTGG

rs2836530ACGTTGGATGACAGACAGTGGTCAGAACATACGTTGGATGAAAGATGCCTATAATCCAGG

rs3761366ACGTTGGATGCAGGTGATAAAAAGCAAGTGACGTTGGATGGCCATCAGTTCTTTTTTGGC

rs2836531ACGTTGGATGGCCTTCGAAAATGTCTCAAGACGTTGGATGCACTTGCTTTTTATCACCTG

rs2836532ACGTTGGATGGAAAGACAGCCTTCGAAAATGACGTTGGATGCAATGGCTCTTTGCAGTAAC

rs2836533ACGTTGGATGTTTCTGACCTCTCACGGTACACGTTGGATGTGCAGATCTGGAGGTAGATG

rs2836534ACGTTGGATGAGAAGAGGCTGGGAGAGGATACGTTGGATGTGCTGCTCTTAGGATAAGGG

rs2836535ACGTTGGATGACAGGAGGAGTTGAGTGTTGACGTTGGATGTAGAGGCACGGAGAAGATAG

rs2836536ACGTTGGATGAAAAGCATGGGTACAGGAGGACGTTGGATGTAGAGGCACGGAGAAGATAG

rs3827208ACGTTGGATGGAGGATGAGAGGTACCTGAGACGTTGGATGGGGATGATCAAACGTAGT

rs715860ACGTTGGATGTTCTGGTGGAGGTTTCTTGGACGTTGGATGCGAGACATGATCTCAAACCC

rs717231ACGTTGGATGCAAGAGACTCAAACAGTTGCACGTTGGATGTCATAGAAGTTACAGCAGCC

rs2836537ACGTTGGATGTTGGTGTGTGATCACTCTGGACGTTGGATGGAACCTAAGTTTCTCCCAGC

rs2836538ACGTTGGATGGGTTAGAGCTTACGTAATTCACGTTGGATGCTACTTGTGTCACTTCTTTG

rs2836539ACGTTGGATGTTATCCTCCAAGAGCCTTAGACGTTGGATGGGGCAAATGGAGTTCTTATT

rs2836540ACGTTGGATGCCCAGTTGGTATCAGTGTTGACGTTGGATGTGCTGAACATCGTTTGGAGG

rs2836541ACGTTGGATGCTTGCACTGACACCTTTGTGACGTTGGATGGTACTGGCGAAGACATGATG

rs2836542ACGTTGGATGAGATGAGCCATTTCCTACTGACGTTGGATGCAGCATGAGAAACTGAATGC

rs2836543ACGTTGGATGAAATGGACTTCTTCAGTAGGACGTTGGATGGATACAATTCAACCCATAGC

rs881837ACGTTGGATGAATGGATGTGGCTCTTGAGGACGTTGGATGTATGGAGGGACTTACGAAAG

rs3949052ACGTTGGATGTTTTCAACGGAAACAGATGCACGTTGGATGCCAAGTAAAATATTCAATCCCC

rs2065307ACGTTGGATGTTTTCAACGGAAACAGATGCACGTTGGATGCCAAGTAAAATATTCAATCCCC

rs3216105ACGTTGGATGACCACCATGCCTGGCTAATTACGTTGGATGGGCCTGGACAAAATAGTGAG
I

rs2073427ACGTTGGATGTTTTGCTTGGGTGTTCTGCCACGTTGGATGGGATTTACACTGGTGTTGGG
~' dbSNP Extend Term rs# Primer Mix Rs2898353 TCCTGTCTTCAGTGCTTGATTCTGCGT

rs960818 AGTAGATAACATAAAGTAACCAGCACT

rs960819 GCTATTCACCCTAGCTGTACATAGACT

Rs2410034 AAATGTAGCTGTAGTATCTTGAA ACT

Rs2836437 TTCACACTCAACAACAAACACA ACT

Rs2836438 TGGAAAGTAAGCTAGACCAAACAGACT

Rs2836439 GTATAAAGTGATGCTGCTTGC ACT

Rs2836440 AACAATTGGGATATGTCTCTCCACACG

Rs2226683 GAGAGTTAATGTGCCCTACTT ACT

Rs2836441 TAATAGTGCTGGCCATAATGC ACT

Rs2836442 CTCTAGGCTTACAGTAAACAC ACT

Rs2836443 TATAAGTTCAGGGTCACAGGTC ACT

Rs2836444 TGTGTTCTTGGGGTCGCCT ACT

Rs3787906 TAATGTAGGTGCTGAGAACTTAG ACT

Rs3838108 GGCTGATTAAAATTCTGTTTCCCCACT

Rs2836445 AGACGCAGTAAAACTTATGGAT ACG

Rs2836446 GCCTTGTCCTATCAAGAGCCAAAGCGT

Rs3787908 CATACAGTAGCTGTGGACAGC ACT

Rs2836447 ATGTATTACATTGAGAACCATGTGACT

Rs2836448 TGTATAGGGCAGGGATAAAGAC ACT

Rs2836450 AACAACAAATTTACTGATATCATCACT

Rs2836451 CTGTCACCCATTGACCTCAC ACT

Rs1015022 CTTTTATCTGCAGTTGCACCC ACT

Rs2836452 CGGGAAGATGGCTGCCTTC ACG

Rs2836453 CCAAGATGGCCCAGTAGGA CGT

Rs3787909 AAATAGTAAAATAAAAAGAGCTCCACG

Rs2836454 CACAACCTCCCAAATGAATAAATCACT

Rs2836455 TGCTGTGACATTTTAGTGCTTCTGCGT

Rs2155718 CTCACACACAGCTGGAGTTTA ACT

Rs2836456 CGTTCTGAAGGTTTTGTGTACA ACT

Rs2836457 GAGTCACCCGTCCCCTAGA ACT

Rs2836458 ACAGAAGAGCCAGCCGACA ACT

Rs2032323 TGCACACTCACTGAAGCCC ACT

Rs2051400 AAACACTATGTGACGCCACC ACT

Rs2836459 AGAATGTTACTTTCTGGATTCTACACT

Rs2836460 ATTGTAATTCTCCGTAAAACCC ACG

Rs2836461 TACCCACACGGAATTCTCATCTACACT

Rs2836462 TCCGTATGTCTCCATCCATCTCA ACT

Rs2836463 AAACTTAAATTGCTTTAATCAGCTACT

Rs2836464 AATATCTTATCACTGCTCCTGTCTACG

Rs2836465 GCCCACTTTTGTGTTTGCTTTAG ACT

Rs2836466 TTTGCCCACTTTTGTGTTTGCT ACT

Rs2836467 TTAATTTTCTTGTCTCTTTCTGTAACT

Rs3827204 CCCTCACATCTTCCCCGC ACT

Rs2836468 GCAGGAAAGAGCATGGGCATTAACACT

Rs3787911 TACATCCAAAAGCCTGCCAG ACT

Rs2836469 TCCTGCGAGATCCTGCTCA ACG

;~",- ,~"".. ....., ....
.~ . ...., , ..,m.
....~ ~.,. .,... ...
.......
..

dbSNP Extend Term rs# Primer Mix Rs2836470 ACAAGCTTAATGTTTTGTTCAGA ACT

Rs2212599 TTCCCCAACAATAGTCAGAAAA ACT

Rs2836472 TTCTCTATCATGATGCAGTCC ACT

Rs2836473 GATGATGAACAGGGCTGTGA ACG

Rs1888469 AAGGGTCTGAAGAGGAGGC ACT

Rs1888470 GTTTTCTGCCTCTGATCCTCA ACT

Rs2032322 CCTATAGGTAACGTGGCTTCT ACT

Rs2410035 AGGCAGAAGTTGCAGTGAAC ACG

Rs1573332 GAGAGGCCAGAAAGCCTTC CGT

Rs2836474 GCACAGGAGAGTCCTCAATT ACG

Rs2836475 CATGGGAAGCTGCTGAACTA ACT

Rs3787914 ACAGTGTTTGAGCCCTCCTT ACT

Rs1888471 AACTGACAGAAGAAAGAAAAATATACG

Rs1888472 TGTGTTGGTGTATAAATCAAGATTACG

Rs1888473 CAGTTCTCAGCCAGACGATC ACG

Rs1888474 GAGTCCAGGGTGCTAATTTC ACG

Rs2836476 GGTGTTAGCCCTGGGTTCTAATAAACG

Rs3787916 TCTCTTATGTAAATACAAAGACG CGT

Rs2836477 CCTCTTAAAATAGCCTGCCTTCA ACT

rs970043 GCTCCTTGACTCAAGTATTTC ACG

Rs2212600 AAAACAACTTTCTCTCCCAAAC ACG

Rs2836478 CTTGCTTATCTTCAAGCAGTC CGT

Rs2836479 CCTAATAGGTGTGAAGTGTAAAA CGT

Rs1475877 CTCCCCGTGTTCTGCATGC ACG

Rs2836480 CCCACTGTACATCTTACACTC ACT

Rs2836481 TCCCCCTGAAATCCCATAGC ACT

Rs2836483 AGGTAATCTCCAACCAAACCT ACT

Rs2836484 AGTCATCAAGCCATATCTCCA ACG

Rs2836485 CTCCTCTGGGACGTCAGC ACT

Rs2836486 CCTCTAAGTTTAGTGGTGGAT ACT

Rs2836487 TGTTGGGTTCTACACATTCAAA ACT

Rs1893199 CAGACCATGGTTTTGAATGTG ACG

Rs2836488 GTAGAACCCAACACAGAGCC ACG

Rs1893200 AGTCTTCGCATAACCAAAACAGA ACT

Rs1893201 CGCATAACCAAAACAGAAAAGAACACT

Rs2836489 CAAGAGCTCTTTTCAATTCCAG ACT

Rs1888475 GACATCAAATGATTCCCCTGT ACT

Rs2836490 GAGCCAAAGCTTTCCTGATG ACT

Rs2836491 GTGGAAAGGGCACTGTGGT ACT

Rs2836492 GGCATGGAAGAGCAAGCATC ACT

Rs2836493 TCCGATGCTTGCTCTTCCAT ACT

Rs2836494 TGAAGTTTCGTTAAATTCACTACAACT

Rs2836495 CTTCAGCAATTCAAATGAATGCACACT

Rs2898354 TCCGGCACATATATCCTGGAAC ACT

Rs3065390 AAACAAACAAACAAAAACAGTGTAACT

Rs2836496 GTGTTCCTGATGTTTCTGGAGT CGT

Rs2836497 CTGCTAGACATTGTCAGTCC ACT

Rs2836498 AATAGGATGAGTCAAAGAAGGAG ACT

Rs283649~ GAGAAGAGCCCTGAGTTGATAAA I ACT

dbSNP Extend Term rs# Primer Mix Rs2836500 AGAGGATGAGCAATTTCAGGGA ACT

Rs2836501 CAAAGGTTGACCTTGTTTTCTAT CGT

Rs2836502 AAGAACTTACATTTTATGGCTTC ACT

Rs2836503 GATTTGGGAGCAAGGGAGC ACT

Rs2836504 AGAGTTAAAGATGACTCTAGGCTCACT

Rs3787917 GCAGCCAGAGTGGAGCAGT ACG

Rs2836505 AAGGCATTCCTCCTCCAAATCAC ACT

Rs2836506 GAAAATCAAATCAGTTTCTACAACACT

Rs2836507 GTGTTGGAATATTGTTGGCCT ACT

Rs2836508 ATTCTCTACCATTTCATTCTCTTTACT

Rs2836509 TTTCTAAGTCAATGTAGGCAAC ACT

Rs2836510 CAGCTAGTTATCTTACTTCACC ACT

Rs2836511 AGCAGGTGACAACCCAGACAT ACT

Rs2212601 TAAGTTTCTGTTGTTTATATGCCAACT

Rs2212602 CCAGCCAGAGATGGGATCA ACG

Rs2226682 GATTGAACCAGGAAAGAAATAGTTCGT

Rs2836512 AATGCCAGTTGCCATAGGATA ACG

Rs2836513 ATAAGAAGATGAGTACTATTATTGACT

Rs1999328 ATTGAGGGAAGAGTAAATGATTTCCGT

Rs2212603 TGTCTGTGAGTACCCCACAATGAAACT

Rs3787919 TCTGTGGCTTCAATGCTGGG ACT

Rs2836514 ACAGACTTTAACAAAATCACTGA ACT

Rs1023153 GGGTCATCTCCTTACCTGTCCAA ACG

Rs1023372 TTCCAAAATTCTGGTTGTGTTTT ACT

Rs2212604 CTGCCCCTATACATACATAGCTTCACG

Rs2226684 AAAAACAATCTGCACAACAAATATACT

Rs2212605 GCAGTGAATATGAACAAAAAAAAAACT

Rs2187307 CAGCTTTAACCTCACTCCAC ACT

Rs3065412 AGTTACAAATCAGGTGGTGCTGG ACT

Rs2898355 GTTACAAATCAGGTGGTGCTG ACT

Rs2836518 TAGGAATCGGAGTCAATAATTTT ACT

Rs3838110 GCTGCACAATCCCCCCCC CGT

Rs2836519 CCTTCTCACTGGGTTCCTG ACG

Rs3827207 TATCACCCCTGTGTCCTGC ACG

Rs2836520 CACAAATAGATTATATATCCTGTTACT

Rs2836521 AATAAGAAGCAAACACCTTTGCA ACT

Rs2836522 CCACCCCTTCAGAGAGTTG ACT

Rs2836523 TCATATTGGTTGATCGTATTGGTTACT

Rs2836524 GATTTCAGGAATGAACTATGTTTTACG

Rs2836525 AGCCGAAAACATAGTTCATTCCTGACT

Rs3833350 CTTTTGTCTTCTAGCCGTCAG ACT

Rs2836526 AGAACATAAAACACAGAAATGCA ACT

Rs2836527 TTATGTTCTAGCAGGACAGGA CGT

Rs3834676 AAAAGGATGTGCAGATCGCAT ACT

Rs2836528 ATCTGCACATCCTTTTCAGCTT ACG

Rs3761364 CTACCATTCATTGAGTACTTCAG ACG

Rs2836529 CTTCAAAATGTGGGTTGATACC ACT

Rs2836530 GGTCAGAACATGCTGCTTTAT ACT

Rs3761366 GTGATGGCTTCTAAAAATGTAAA I ACG

dbSNP Extend Term rs# Primer Mix Rs2836531 GCATTTGTTACTGCAAAGAGCCATACG

Rs2836532 AGCCTTCGAAAATGTCTCAAG CGT

Rs2836533 CACACCCATTCCAACCCAAT ACG

Rs2836534 GCTGAAGGTTTCTGGGAGCA ACG

Rs2836535 GAGGAGTTGAGTGTTGGAACCA ACG

Rs2836536 ATGGGTACAGGAGGAGTTGA ACT

Rs3827208 CACCCACCCCAATCACCC ACT

rs715860 CTTGGTTATCCTTCAGTTTCCA ACT

rs717231 CTCATTTAGTTTATGTCTTGGTTGACT

Rs2836537 GCTCATACGCCCTTGGTCTCTAATACT

Rs2836538 AGCTTACGTAATTCAAATCAAGT ACT

Rs2836539 TTACACATTTGCACAATGAGGATACGT

Rs2836540 GTATCAGTGTTGAATGACTGGT ACT

Rs2836541 TGACACCTTTGTGAATTGCTGAACACT

Rs2836542 CCATTTCCTACTGAAGAAGTCCA ACT

Rs2836543 CTTCTTCAGTAGGAAATGGCT ACG

rs881837 GGCTCTTGAGGCCATGCC ACG

Rs3949052 ACAATTTCTCATGTTGTAAGGATTACG

Rs2065307 GGAAACAGATGCCATTTACAATTTACG

Rs3216105 GCCTGGCTAATTTTTAAAAAAAAACGT

Rs2073427 CTGCCCCCACATGACCCA I
ACG

Genetic Anal. skis [0275] Allelotyping results from the discovery cohort are shown for cases and controls in Table 45.
The allele frequency for the A2 allele is noted in the fifth and sixth columns for osteoarthritis case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the A1 allele can be easily calculated by subtracting the A2 allele frequency from 1 (A1 AF
= 1-A2 AF). For example, the SNP rs2898353 has the following case and control allele frequencies: case A1 (A) = 0.79;
case A2 (T) = 0.21; control A1 (A) = 0.81; and control A2 (T) = 0.19, where the nucleotide is provided in paranthesis. Some SNPs are labeled "untyped" because of failed assays.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs2898353231 38783681 A/T 0.21 0.19 0.560 rs960818 882 38784332 A/G 0.59 0.57 0.330 rs960819 960 38784410 A/C 0.13 0.09 0.101 rs24100341194 38784644 A/C

rs28364371530 38784980 AlG 0.14 0.14 0.956 rs28364381673 38785123 A/G 0.79 0.75 0.077 rs28364392096 38785546 C/T 0.70 0.71 0.508 rs28364402285 38785735 A/G 0.19 0.18 0.623 rs22266835873 38789323 C/T 0.79 0.76 0.312 rs28364417256 38790706 A/G 0.12 0.12 0.765 rs28364427988 38791438 A/G 0.31 0.30 0.746 rs28364438222 38791672 G/T 0.22 0.23 0.728 rs28364448381 38791831 C/T 0.19 0.20 0.807 rs37879068814 38792264 C/T 0.97 unt ed NA

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-in rs# SEQ ID Position AlleleCase Control Value NO: 7 AF AF

rs3838108 8915 38792365 -/C 0.58 0.56 0.425 rs2836445 9642 38793092 A/G 0.32 0.35 0.190 rs2836446 9902 38793352 A/T 0.12 0.14 0.274 rs3787908 10619 38794069 A/G

rs2836447 10927 38794377 C/T 0.68 0.67 0.816 rs2836448 11032 38794482 C/T 0.12 0.14 0.235 rs2836450 14377 38797827 C/T 0.70 0.68 0.460 rs2836451 15608 38799058 C/T 0.92 0.95 0.157 rs1015022 15928 38799378 C/G 0.31 0.36 0.072 rs2836452 16296 38799746 A/G 0.18 0.18 0.822 rs2836453 17598 38801048 A/T 0.02 0.02 0.836 rs3787909 19272 38802722 A/G 0.06 0.03 0.091 rs2836454 20084 38803534 A/G 0.04 0.03 0.397 rs2836455 20577 38804027 A/T 0.17 0.13 0.050 rs2155718 28051 38811501 A/G 0.78 0.78 0.950 rs2836456 29466 38812916 A/G 0.94 0.92 0.569 rs2836457 29530 38812980 C/T

rs2836458 29987 38813437 A/G 0.48 0.46 0.455 rs2032323 30012 38813462 C/T

rs2051400 30322 38813772 GlT 0.03 NA NA

rs2836459 32216 38815666 C/T 0.19 0.17 0.319 rs2836460 32516 38815966 C/T

rs2836461 32544 38815994 AlG

rs2836462 32746 38816196 A/G

rs2836463 33137 38816587 G/T 0.67 0.72 0.032 rs2836464 33538 38816988 A/G 0.67 0.67 0.991 rs2836465 33798 38817248 C/T

rs2836466 33802 38817252 A/C 0.39 0.40 0.627 rs2836467 33964 38817414 C/T

rs3827204 34132 38817582 A/G 0.45 0.42 0.213 rs2836468 34210 38817660 C/T 0.13 0.14 0.678 rs3787911 34317 38817767 A/G 0.13 0.12 0.862 rs2836469 34499 38817949 C/T 0.38 0.40 0.250 rs2836470 34753 38818203 A/C 0.73 0.74 0.939 rs2212599 34845 38818295 C/T 0.66 0.64 0.474 rs2836472 35335 38818785 C/T 0.40 0.35 0.071 rs2836473 36423 38819873 C/T 0.53 0.54 0.755 rs1888469 36450 38819900 A/G 0.45 0.49 0.175 rs1888470 36481 38819931 G/T 0.17 0.18 0.623 rs2032322 38447 38821897 C/G 0.50 0.50 0.879 rs2410035 38784 38822234 C/T

rs1573332 39387 38822837 A/T 0.57 0.58 0.609 rs2836474 39458 38822908 C/T 0.33 0.35 0.564 rs2836475 39822 38823272 C/G 0.17 0,14 0.113 rs3787914 40305 38823755 ClG 0.73 0.73 0.987 rs1888471 40869 38824319 C/T 0.29 0.26 0.175 rs1888472 40926 38824376 C/T 0.62 0.63 0.818 rs1888473 41010 38824460 C/T 0.63 0.65 0.435 rs1888474 41134 38824584 C/T 0.28 0.23 0.099 rs2836476 41984 38825434 A/G 0.46 0.44 0.379 rs3787916 42172 38825622 A/T 0.45 0.43 0.314 rs2836477 42753 38826203 G/T 0.94 0.96 0.196 rs970043 43011 38826461 C/T 0.04 0.04 0.549 rs2212600 43176 38826626 A/G

rs2836478 43320 38826770 G/T 0.76 0.75 0.914 rs2836479 43381 38826831 AIT 0.44 0.43 0.670 rs1475877 44142 38827592 A/G 0.35 0.32 0.110 rs2836480 44383 38827833 A/G 0.46 0.43 0.153 rs2836481 44726 38828176 C/T 0.42 0.40 0.434 rs2836483 45087 38828537 A/G 0.47 0.45 0.393 rs2836484 45141 38828591 C/T 0.46 0.47 0.671 rs2836485 45359 38828809 C/G 0.16 0.17 0.643 rs2836486 45421 38828871 C/T

rs2836487 45456 38828906 C/T 0.02 0.03 0.758 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs189319945467 38828917 C/T 0.62 0.65 0.220 rs283648845486 38828936 C/T 0.25 0.23 0.360 rs189320045709 38829159 A/G 0.16 0.14 0.177 rs189320145716 38829166 A/G 0.84 0.87 0.060 rs283648947626 38831076 C/T 0.29 0.31 0.502 rs1S8847549413 38832863 AlG

rs283649049796 38833246 C/T 0.94 0.93 0.731 rs283649149962 38833412 AIG 0.10 0.08 0.219 rs283649250075 38833525 C/T 0.20 0.22 0.518 rs283649350093 38833543 A/G 0.95 0.94 0.850 rs283649450571 38834021 C/T 0.72 0.70 0.536 rs283649550615 38834065 A/G 0.82 0.78 0.142 rs289835450780 38834230 A/G 0.25 0.25 0.728 rs306539050851 38834301 -/TA 0.10 0.11 0.845 rs283649651459 38834909 A/C 0.80 0.84 0.064 rs283649753193 38836643 C/T 0.65 0.65 0.935 rs283649853702 38837152 C/T 0.43 0.44 0.682 rs283649953736 38837186 A/C 0.33 0.30 0.169 rs283650053795 38837245 C/T

rs283650154109 38837559 A/T 0.36 0.34 0.234 rs283650254126 38837576 C/T 0.31 0.29 0.427 rs283650354230 38837680 A/C 0.32 0.29 0.194 rs283650454894 38838344 C/T 0.51 0.54 0.170 rs378791755455 38838905 A/G 0.56 0.60 0.137 rs283650555499 38838949 A/G 0.73 0.78 0.022 rs283650656522 38839972 C/T 0.52 0.56 0.145 rs283650756662 38840112 C/T 0.51 0.54 0.173 rs283650856954 38840404 A/G 0.53 0.56 0.376 rs283650957267 38840717 A/G 0.35 0.31 0.089 rs283651058282 38841732 A/G 0.65 0.59 0.034 rs283651158916 38842366 A/C 0.32 0.30 0.315 rs221260159544 38842994 ClG 0.45 0.46 0.568 rs221260259666 38843116 C/T 0.30 0.28 0.644 rs222668259913 38843363 A/T 0.38 0.35 0.164 rs283651266846 38850296 A/G 0.94 0.94 0.896 rs283651367245 38850695 G/T 0.23 0.22 0.713 rs199932867652 38851102 A/C 0.79 0.79 0.973 rs221260367955 38851405 A/G 0.73 0.72 0.776 rs378791967966 38851416 A/C

rs283651468420 38851870 A/G 0.52 0.54 0.319 rs102315370226 38853676 A/G 0.09 0.09 0.985 rs102337270810 38854260 C/T 0.83 0.81 0.518 rs221260472246 38855696 A/G 0.68 0.71 0.237 rs222668473330 38856780 G/T 0.83 0.81 0.462 rs221260573457 38856907 C/T 0.82 0,85 0.255 rs218730774389 38857839 A/G 0.13 0.13 0.869 rs306541274638 38858088 -/AA

rs289835574640 38858090 A/C 0.96 0.94 0.413 rs283651875358 38858808 A/C 0.10 0.12 0.261 rs383811075952 38859402 -/G 0.66 0.67 0.790 rs283651976098 38859548 AIG 0.60 0.61 0.509 rs382720777836 38861286 A/G 0.62 0.63 0.575 rs283652078449 38861899 A/C

rs283652178507 38861957 G/T 0.07 0.08 0.551 rs283652280031 38863481 GIT 0.11 0.08 0.155 rs283652381695 38865145 C/T

rs283652482775 38866225 A/G 0.05 0.04 0.321 rs283652582795 38866245 A/G 0.11 0.11 0.875 rs383335084611 38868061 -/C

rs283652684657 38868107 C/T 0.83 0.86 0.292 rs283652784693 38868143 A/C 0.08 0.08 0.936 rs383467685020 38868470 -/T 0.80 0.83 0.191 rs283652885048 38868498 C/T 0.84 0.87 0.089 rs376136485100 38868550 C/T 0.06 0.04 0.159 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 7 rs2836529 85325 38868775 A/C 0.09 0.06 0.100 rs2836530 85452 38868902 C/T

rs3761366 85868 38869318 A/G 0.06 0.04 0.179 rs2836531 85936 38869386 A/G 0.49 0.50 0.729 rs2836532 85990 38869440 A/T 0.30 0.29 0.766 rs2836533 86139 38869589 C/T 0.47 0.48 0.751 rs2836534 86497 38869947 C/T 0.87 0.87 0.874 rs2836535 87236 38870686 A/G 0.93 0.92 0.628 rs2836536 87248 38870698 C/T 0.86 0.84 0.474 rs3827208 87533 38870983 C/G 0.51 0.53 0.459 rs715860 87912 38871362 A/G 0.08 0.09 0.627 rs717231 88108 38871558 G/T 0.65 0.67 0.382 rs2836537 88494 38871944 A/C 0.43 0.40 0.239 rs2836538 89598 38873048 A/C

rs2836539 90235 38873685 A/T 0.98 0.97 0.796 rs2836540 91287 38874737 G/T

rs2836541 91359 38874809 C/T 0.07 0.06 0.403 rs2836542 92384 38875834 A/C 0.36 0.38 0.418 rs2836543 92410 38875860 C/T 0.54 0.50 0.202 rs881837 92900 38876350 C/T 0.29 0.28 0.639 rs3949052 94495 38877945 A/G

rs2065307 94512 38877962 A/G

rs3216105 97777 38881227 -/A 0.32 0.28 0.265 rs2073427 98333 38881783 C/T 0.09 0.07 0.242 [0276] The ERG proximal SNPs were also allelotyped in the replication cohorts using the methods described herein and the primers provided in Tables 43 and 44. The replication allelotyping results for replication cohort #1 and replication cohort #2 are provided in Tables 46 and 47, respectively.

dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs2898353231 38783681 A/T 0.19 0.19 0.773 rs960818 882 38784332 A/G 0.59 0.57 0.600 rs960819 960 38784410 A/C 0.07 NA 0.132 rs24100341194 38784644 A/C

rs28364371530 38784980 A/G 0.14 0.14 0.957 rs28364381673 38785123 A/G 0.80 0.77 0.402 rs28364392096 38785546 C/T 0.68 0.73 0.089 rs28364402285 38785735 A/G 0.20 0.18 0.421 rs22266835873 38789323 C/T 0.78 0.76 0.622 rs28364417256 38790706 A/G 0.12 0.12 0.946 rs28364427988 38791438 A/G 0.30 __ 0.674 0.32 rs28364438222 38791672 G/T 0.22 0.25 0.332 rs28364448381 38791831 C/T 0.20 0.20 0.908 rs37879068814 38792264 C/T 0.97 unt ed NA

rs38381088915 38792365 -lC 0.58 0.56 0.604 rs28364459642 38793092 A/G 0.33 0.37 0.211 rs28364469902 38793352 A/T 0.13 0.15 0.481 rs378790810619 38794069 A/G

rs283644710927 38794377 C/T 0.67 0.67 0.843 rs283644811032 38794482 C/T 0.13 0.15 _ 0.521 rs283645014377 38797827 C/T 0.67 0.67 0.989 rs283645115608 38799058 C/T 0.92 0.95 0.214 rs101502215928 38799378 C/G 0.30 0.36 0.076 rs283645216296 38799746 A/G 0.18 0.18 0.982 rs283645317598 38801048 A/T 0.02 unt ed NA

rs378790919272 38802722 A/G 0.06 0.03 0.110 rs283645420084 38803534 A/G 0.03 0.03 0.746 rs283645520577 ~ 38804027 A/T 0.17 0 12 0 080 ~ ~ ~

dbSNP Position Chromosome~ Al/A2F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs215571828051 38811501 A/G 0.78 0.79 0.747 rs283645629466 38812916 A/G 0.91 0.91 0.915 rs283645729530 38812980 C/T

rs283645829987 38813437 A/G 0.48 0.47 0.626 rs203232330012 38813462 C/T

rs205140030322 38813772 G/T 0.02 un ed NA

rs283645932216 38815666 C/T 0.20 0.16 0.278 rs283646032516 38815966 C/T

rs283646132544 38815994 A/G

rs283646232746 38816196 A/G

rs283646333137 38816587 G/T 0.67 0.75 0.011 rs283646433538 38816988 A/G 0.66 0.68 0.586 rs283646533798 38817248 C/T

rs283646633802 38817252 A/C 0.39 0.41 0.507 rs283646733964 38817414 C/T

rs382720434132 38817582 A/G 0.45 0.41 0.229 rs283646834210 38817660 C/T 0.13 0.14 0.736 rs378791134317 38817767 A/G 0.14 0.13 0.856 rs283646934499 38817949 C/T 0.37 0.41 0.168 rs283647034753 38818203 A/C 0.72 0.73 0.854 rs221259934845 38818295 C/T 0.63 0.65 0.636 rs283647235335 38818785 C/T 0.41 0.35 0.145 rs283647336423 38819873 C/T 0.51 0.54 0.291 rs188846936450 38819900 A/G 0.45 0.49 0.281 rs188847036481 38819931 G/T 0.17 0.17 0.949 rs203232238447 38821897 C/G 0.51 0.53 0.476 rs241003538784 38822234 C/T

rs157333239387 38822837 A/T 0.56 0.60 0.279 rs283647439458 38822908 C/T 0.33 0.36 0.330 rs283647539822 38823272 ClG 0.18 0.13 0.049 rs378791440305 38823755 C/G 0.73 0.74 0.977 rs188847140869 38824319 C/T 0.31 0.26 0.134 rs188847240926 38824376 C/T 0.62 0.65 0.247 rs188847341010 38824460 C/T 0.63 0.67 0.210 rs188847441134 38824584 C/T 0.28 0.21 0.091 rs283647641984 38825434 A/G 0.47 0.44 0.346 rs378791642172 38825622 A/T 0.46 0.41 0.171 rs283647742753 38826203 G/T 0.94 0.97 0.294 rs970043 43011 38826461 C/T 0.05 0.03 0.331 rs221260043176 38826626 A/G

rs283647843320 38826770 G/T 0.75 0.75 0.983 rs283647943381 38826831 A/T 0.44 0.43 0.752 rs147587744142 38827592 A/G 0.35 0.31 0.166 rs283648044383 38827833 A/G 0.45 0.41 0.254 rs283648144726 38828176 ClT 0.42 0.39 0.330 rs283648345087 38828537 A/G 0.46 0.46 0.797 rs283648445141 38828591 C/T 0.45 0.47 0.553 rs283648545359 38828809 CIG 0.18 0.18 0.993 rs283648645421 38828871 ClT

rs283648745456 38828906 C/T 0.03 0.03 0.955 rs189319945467 38828917 C/T 0.61 0.67 0.071 rs283648845486 38828936 C/T 0.27 0.23 0.246 rs189320045709 38829159 A/G 0.16 0.13 0.203 rs189320145716 38829166 A/G 0.83 0.89 0.021 rs283648947626 38831076 C/T 0.30 0.31 0.702 rs188847549413 38832863 A/G

rs283649049796 38833246 C/T 0.94 0.95 0.662 rs283649149962 38833412 A/G 0.10 0.06 0.038 rs283649250075 38833525 C/T 0.20 0.22 0.651 rs283649350093 38833543 A/G 0.93 0.95 0.397 rs283649450571 38834021 C/T 0.73 0.71 0.592 rs283649550615 38834065 A/G 0.81 0.77 0.212 rs289835450780 38834230 A/G 0.24 0.24 0.827 rs306539050851 38834301 -/TA 0.10 0.11 0.743 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs283649651459 38834909 A/C 0.78 0.86 0.022 rs283649753193 38836643 C/T 0.65 0.66 0.733 rs283649853702 38837152 C/T 0.44 0.46 0.576 rs283649953736 38837186 A/C 0.33 0.29 0.200 rs283650053795 38837245 C/T

rs283650154109 38837559 A/T 0.36 0.32 0.167 rs283650254126 38837576 C/T 0.31 0.27 0.206 rs283650354230 38837680 A/C 0.32 0.28 0.173 rs283650454894 38838344 C/T 0.50 0.57 0.033 rs378791755455 38838905 A/G 0.56 0.62 0.033 rs283650555499 38838949 A/G 0.72 0.81 0.004 rs283650656522 38839972 C/T 0.52 0.58 0.093 rs283650756662 38840112 C/T 0.51 0.56 0.134 rs283650856954 38840404 A/G 0.53 0.58 0.170 rs283650957267 38840717 A/G 0.35 0.30 0.136 rs283651058282 38841732 A/G 0.62 0.56 0.035 rs283651158916 38842366 A/C 0.33 0.30 0.273 rs221260159544 38842994 C/G 0.44 0.46 0.675 rs221260259666 38843116 C/T 0.29 0.27 0.571 rs222668259913 38843363 A/T 0.38 0.33 0.127 rs283651266846 38850296 A/G 0.93 0.96 0.261 rs283651367245 38850695 G/T 0.23 0.22 0.692 rs199932867652 38851102 A/C 0.79 0.80 0.618 rs221260367955 38851405 A/G 0.73 0.74 0.676 rs378791967966 38851416 A/C

rs283651468420 38851870 A/G 0.51 0.57 0.044 rs102315370226 38853676 A/G 0.09 0.09 0.699 rs102337270810 38854260 C/T 0.82 unt ed NA

rs221260472246 38855696 A/G 0.67 0.73 0.063 rs222668473330 38856780 G/T 0.82 0.82 0.992 rs221260573457 38856907 C/T 0.83 0.86 0.180 rs218730774389 38857839 A/G 0.14 0.13 0.901 rs306541274638 38858088 -/AA

rs289835574640 38858090 A/C 0.95 0.93 0.442 rs283651875358 38858808 A/C 0.11 0.14 0.248 rs383811075952 38859402 -/G 0.65 0.68 0.399 rs283651976098 38859548 A/G 0.59 0.64 0.134 rs382720777836 38861286 A/G 0.60 0.64 0.205 rs283652078449 38861899 A/C

rs283652178507 38861957 G/T 0.08 0.09 0.765 rs283652280031 38863481 GlT 0.12 0.07 0.033 rs283652381695 38865145 C/T

rs283652482775 38866225 A/G 0.05 0.04 0.539 rs283652582795 38866245 A/G 0.12 0.09 0.179 rs383335084611 38868061 -/C

rs283652684657 38868107 C/T 0.83 0.85 0.536 rs283652784693 38868143 A/C 0.08 0.07 0.444 rs383467685020 38868470 -/T 0.79 0.82 0.270 rs283652885048 38868498 C/T 0.82 0.86 0.130 rs376136485100 38868550 C/T 0.08 0.05 0.132 rs283652985325 38868775 A/C 0.09 0.07 0.214 rs283653085452 38868902 C/T

rs376136685868 38869318 A/G 0.07 0.04 0.259 rs283653185936 38869386 A/G 0.49 0.50 0.741 rs283653285990 38869440 A/T 0.30 0.30 0.921 rs283653386139 38869589 C/T 0.48 0.48 0.843 rs283653486497 38869947 C/T 0.86 0.89 0.374 rs283653587236 38870686 A/G 0.91 0.91 0.933 rs283653687248 38870698 C/T 0.86 0.86 0.945 rs382720887533 38870983 C/G 0.51 0.55 0.183 rs715860 87912 38871362 A/G 0.07 0.07 0.893 rs717231 88108 38871558 G/T 0.65 0.68 0.506 rs283653788494 38871944 A/C 0.43 0.39 0.251 rs283653889598 38873048 A/C

dbSNP Position ChromosomeAllA2 F A2 F A2 F p-rs# in Position Allele Case Control Value SEQ ID AF AF
NO: 7 rs283653990235 38873685 A/T 0.98 0.98 0.910 rs283654091287 38874737 G/T

rs283654191359 38874809 C/T 0.09 0.06 0.324 rs283654292384 38875834 A/C 0.37 0.41 0.365 rs283654392410 38875860 C/T 0.54 0.55 0.863 rs881837 92900 38876350 C/T 0.30 0.28 0.673 rs394905294495 38877945 A/G

rs206530794512 38877962 A/G

rs321610597777 38881227 -/A 0.31 0.29 0.603 rs207342798333 38881783 C/T 0.09 0.06 0.249 dbSNP Position ChromosomeAllA2 F A2 F A2 F p-rs# in Position AlleleCase Control Value SEQ ID AF AF
NO: 7 rs2898353231 38783681 A/T 0.22 0.21 0.629 rs960818882 38784332 A/G 0.59 0.55 0.351 rs960819960 38784410 A/C 0.12 0.01 rs24100341194 38784644 A/C

rs28364371530 38784980 A/G 0.14 0.14 0.989 rs28364381673 38785123 A/G 0.78 0.71 0.047 rs28364392096 38785546 C/T 0.72 0.68 0.265 rs28364402285 38785735 A/G 0.18 0.19 0.789 rs22266835873 38789323 C/T 0.80 0.77 0.342 rs28364417256 38790706 A/G 0.11 0.12 0.559 rs28364427988 38791438 A/G 0.32 0.28 0.269 rs28364438222 38791672 G/T 0.23 0.21 0.504 rs28364448381 38791831 C/T 0.19 0.19 0.829 rs37879068814 38792264 C/T 0.97 unt ed rs38381088915 38792365 -/C 0.58 0.55 0.526 rs28364459642 38793092 A/G 0.30 0.32 0.722 rs28364469902 38793352 A/T 0.11 0.14 0.425 rs378790810619 38794069 A/G

rs283644710927 38794377 C/T 0.68 0.68 0.908 rs283644811032 38794482 C/T 0.11 0.14 0.302 rs283645014377 38797827 C/T 0.73 0.70 0.314 rs283645115608 38799058 C/T 0.93 0.94 0.499 rs101502215928 38799378 C/G 0.33 0.35 0.527 rs283645216296 38799746 A/G 0.17 0.18 0.750 rs283645317598 38801048 A/T 0.02 0.02 0.934 rs378790919272 38802722 A/G 0.05 0.04 0.546 rs283645420084 38803534 A/G 0.05 0.03 0.379 rs283645520577 38804027 A/T 0.17 0.15 0.472 rs215571828051 38811501 A/G 0.79 0.78 0.704 rs283645629466 38812916 A/G 0.97 0.94 0.174 rs283645729530 38812980 C/T

rs283645829987 38813437 A/G 0.48 0.45 0.532 rs203232330012 38813462 C/T

rs205140030322 38813772 G/T 0.04 0.02 0.476 rs283645932216 38815666 C/T 0.19 0.18 0.921 rs283646032516 38815966 C/T

rs283646132544 38815994 A/G

rs283646232746 38816196 A/G

rs283646333137 38816587 G/T 0.68 0.68 0.988 rs283646433538 38816988 A/G 0.69 0.66 0.430 rs283646533798 38817248 C/T

rs283646633802 38817252 A/C 0.39 0.39 0.948 rs283646733964 38817414 C/T

rs382720434132 38817582 A/G 0.45 0.43 0.614 rs283646834210 38817660 C/T 0.12 0.12 0.879 rs378791134317 38817767 A/G 0.12 0.11 0.901 rs283646934499 38817949 C/T 0.38 0.39 0.914 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in PositionAllele Case Control Value SEQ ID AF AF
NO: 7 rs283647034753 38818203A/C 0.75 0.74 0.960 rs221259934845 38818295C/T 0.71 0.64 0.095 rs283647235335 38818785C/T 0.40 0.36 0.321 rs283647336423 38819873ClT 0.56 0.53 0.433 rs188846936450 38819900A/G 0.45 0.49 0.399 rs188847036481 38819931G/T 0.16 0.19 0.356 rs203232238447 38821897ClG 0.50 0.45 0.190 rs241003538784 38822234C/T

rs157333239387 38822837A/T 0.58 0.56 0.554 rs283647439458 38822908C/T 0.34 0.33 0.762 rs283647539822 38823272C/G 0.15 0.14 0.817 rs378791440305 38823755C/G 0.73 0.73 0.934 rs188847140869 38824319C/T 0.28 0.27 0.760 rs188847240926 38824376C/T 0.63 0.58 0.302 rs188847341010 38824460C/T 0.63 0.62 0.683 rs188847441134 38824584C/T 0.27 0.26 0.853 rs283647641984 38825434A/G 0.46 0.45 0.838 rs378791642172 38825622A/T 0.44 0.45 0.827 rs283647742753 38826203GlT 0.94 0.95 0.505 rs97004343011 38826461C/T 0.04 0.04 0.848 rs221260043176 38826626A/G

rs283647843320 38826770G/T 0.76 0.75 0.893 rs283647943381 38826831A/T 0.44 0.43 0.801 rs147587744142 38827592A/G 0.35 0.33 0.450 rs283648044383 38827833A/G 0.47 0.44 0.444 rs283648144726 38828176C/T 0.41 0.41 0.999 rs283648345087 38828537A/G 0.48 0.44 0.306 rs283648445141 38828591C/T 0.46 0.46 0.939 rs283648545359 38828809C/G 0.15 0.17 0.483 rs283648645421 38828871C/T

rs283648745456 38828906C/T NA 0.03 NA

rs189319945467 38828917C/T 0.63 0.62 0.868 rs283648845486 38828936C/T 0.23 0.22 0.913 rs189320045709 38829159A/G 0.17 0.16 0.653 rs189320145716 38829166A/G 0.85 0.85 0.947 rs283648947626 38831076C/T 0.27 0.30 0.597 rs188847549413 38832863A/G

rs283649049796 38833246CIT 0.94 0.91 0.196 rs283649149962 38833412A/G 0.09 0.11 0.493 rs283649250075 38833525C/T 0.20 0.21 0.669 rs283649350093 38833543A/G 0.96 0.93 0.211 rs283649450571 38834021C/T 0.70 0.69 0.697 rs283649550615 38834065A/G 0.82 0.80 0.510 rs289835450780 38834230A/G 0.27 0.26 0.846 rs306539050851 38834301-/TA 0.11 0.10 0.936 rs283649651459 38834909A/C 0.81 0.80 0.746 rs283649753193 38836643C/T 0.66 0.64 0.756 rs283649853702 38837152C/T 0.41 0.40 0.844 rs283649953736 38837186A/C 0.32 0.30 0.567 rs283650053795 38837245C/T

rs283650154109 38837559A/T 0.36 0.36 0.917 rs283650254126 38837576C/T 0.31 0.32 0.738 rs283650354230 38837680A/C 0.32 0.31 0.730 rs283650454894 38838344C/T 0.52 0.50 0.620 rs378791755455 38838905A/G 0.57 0.56 0.759 rs283650555499 38838949A/G 0.74 0.74 0.982 rs283650656522 38839972C/T 0.52 0.53 0.907 rs283650756662 38840112C/T 0.51 0.52 0.785 rs283650856954 38840404A/G 0.53 0.52 0.709 rs283650957267 38840717A/G 0.35 0.33 0.453 rs283651058282 38841732A/G 0.68 0.65 0.457 rs283651158916 38842366A/C 0.32 0.31 0.832 rs221260159544 38842994C/G 0.45 0.47 0.717 rs221260259666 38843116C/T 0.30 0.30 0.994 dbSNP Position ChromosomeAl/A2 F A2 F A2 F p-rs# in PositionAllele Case Control Value SEQ ID AF AF
NO: 7 rs222668259913 38843363A/T 0.39 0.38 0.801 rs283651266846 38850296A/G 0.94 0.91 0.184 rs283651367245 38850695G/T 0.23 0.23 0.949 rs199932867652 38851102A/C 0.80 0.77 0.487 rs221260367955 38851405A/G 0.74 0.70 0.289 rs378791967966 38851416A/C

rs283651468420 38851870A/G 0.53 0.49 0.363 rs102315370226 38853676A/G 0.08 0.09 0.611 rs102337270810 38854260C/T 0.84 0.81 0.315 rs221260472246 38855696A/G 0.69 0.68 0.641 rs222668473330 38856780G/T 0.85 0.81 0.216 rs221260573457 38856907C/T 0.82 0.82 0.927 rs218730774389 38857839A/G 0.12 0.13 0.685 rs306541274638 38858088-/AA

rs289835574640 38858090A/C 0.96 0.96 0.893 rs283651875358 38858808A/C 0.10 0.11 0.823 rs383811075952 38859402-/G 0.68 0.65 0.457 rs283651976098 38859548A/G 0.60 0.57 0.357 rs382720777836 38861286AIG 0.64 0.61 0.449 rs283652078449 38861899A/C

rs283652178507 38861957G/T 0.06 0.07 0.625 rs283652280031 38863481G/T 0.09 0.10 0.810 rs283652381695 38865145C/T _ rs283652482775 38866225A/G 0.05 0.04 0.419 rs283652582795 38866245A/G 0.10 0.14 0.132 rs383335084611 38868061-/C

rs283652684657 38868107C/T 0.83 0.86 0.342 rs283652784693 38868143A/C 0.08 0.11 0.209 rs383467685020 38868470-/T 0.81 0.84 0.442 rs283652885048 38868498C/T 0.86 0.88 0.350 rs376136485100 38868550C/T 0.04 0.03 0.643 rs283652985325 38868775A/C 0.08 0.06 0.271 rs283653085452 38868902C/T

rs376136685868 38869318A/G 0.06 0.04 0.473 rs283653185936 38869386A/G 0.49 0.49 0.915 rs283653285990 38869440A/T 0.31 0.28 0.446 rs283653386139 38869589C/T 0.47 0.48 0.810 rs283653486497 38869947C/T 0.88 0.84 0.149 rs283653587236 38870686A/G 0.94 0.92 0.378 rs283653687248 38870698C/T 0.86 0.82 0.311 rs382720887533 38870983C/G 0.51 0.49 0.598 rs715860 87912 38871362A/G 0.09 0.11 0.463 rs717231 88108 38871558G/T 0.65 0.67 0.588 rs283653788494 38871944A/C 0.42 0.41 0.694 rs283653889598 38873048A/C

rs283653990235 38873685A/T 0.97 0.97 0.749 rs283654091287 38874737G/T

rs283654191359 38874809C/T 0.05 0.05 0.895 rs283654292384 38875834A/C 0.34 0.34 0.998 rs283654392410 38875860C/T unt 0.43 NA
ed rs881837 92900 38876350C/T 0.29 0.28 0.811 rs394905294495 38877945A/G

rs206530794512 38877962A/G

rs321610597777 38881227-/A 0.32 0.28 0.273 rs207342798333 38881783C/T 0.08 0.07 0.700 [0277] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figure 1G for the discovery cohort. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figure 1 G can be determined by consulting Table 45. For example, the left-most X on the left graph is at position 38783681. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.
[0278] To aid the interpretation, multiple lines have been added to the graph.
The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01.
The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The generally bottom-most curve is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and T.J. Hastie, Wadsworth &
Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a lOkb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10-8 were truncated at that value.
[0279] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3' end of each gene to show the direction of transcription.
Example 11 Expression of LRCHI in Human Chondroblastoma Cells [0280] Human chondrosarcoma cells were cultured either in monolayers or in a solid alginate matrix to address the possibilty that chondrocytes would dedifferentiate in monolayer culture but would retain a chondrocytic phenotype in matrix environments (Lee, D.A., T. Reisler, and D.L. Bader, Expansion of chondrocytes for tissue engineering in alginate beads enhances chondrocytic phenotype compared to conventional monolayer techniques. Acta Orthop Scand, 2003. 74(1):
p. 6-15).
Methods [0281] SW1353 chondrosarcoma cells (ATCC, HTB-94 ) were propagated in Leibovitz's L-15 medium supplemented with 2 mM L-glutamine,l0% fetal calf serum and penicillin/streptomycin (100U/ml) as per ATCC protocol. Confluent SW1353 cells were made into single cell suspensions by treatment with trypsin-EDTA and were resuspended in 1.2% alginate (Keltone LVCR, Kelco, Chicago, USA) in 0.9%NaCI at a density of 4x106 cells/ml (10 million cells per stimuli). Alginate beads of uniform diameter were prepared by dispensing the cell-alginate suspension dropwise through a 22 gauge needle into 100mm CaCl2 from a height of approximately 2cm. After polymerization (10 minutes), beads were washed 3 times in PBS and then once with medium. The encapsulated cells were differentiated in a 24 well plate (10 beads/we11;25-SOK cells/bead) for 2 weeks under standard conditions with medium changes every 3 days. At the end of 14 days, a few randomly selected beads were stained for the presence of glycosaminoglycans by alcian blue staining suggesting a chondrocytic phenotype [46J. After 14 days, the alginate cultured cells were stimulated with either recombinant human IL1-beta (R&D Systems) or phorbol 12-myristate 15 - acetate (PMA, Sigma) alongside serum-starved controls for 3 hours (PMA) and 24 hours (no serum and IL1-beta).
Similar experimental conditions were applied on confluent plates of undifferentiated SW1353 cells to compare the effects of monolayer culture to alginate culture on gene expression. Encapsulated cells were released from the alginate beads by sodium citrate (SSmM in O.15M NaCI) treatment and the expression of target genes plus control genes (matrix metalloproteinases 8 and 13) was determined by mRNA
isolation (Dynabeads oligo dT(25), Dynal Biotech), followed by cDNA synthesis (Superscript II, Invitrogen) and semi-quantitative PCR using standard molecular biology techniques and manufacturer's protocols. PCR
was performed using a standard protocol of 30 cycles. LRCHI forward primer: 5'-CCAAAGATCAGGACATGGATA-3'; LRCHI reverse primer: 5'-TGCTGTTTGTGGTAGGAGAG-3'; MMP8 forward primer: 5'-CAATACTGGGCTCTGAGTGG-3'; MMP8 reverse primer: 5'-GGAAAGGCACCTGATATGC-3'; MMP13 forward primer: 5'-ATATCTGAACTGGGTCTTCC-3';
MMPl3 reverse primer: 5'-GACAGCATCTACTTTATCACC-3'; GAPDH forward primer: 5'-ATCATCTCTGCCCCCTCTG-3'; GAPDHreverse primer: 5'-GAGGCATTGCTGATGATCTTG-3';
Single band PCR products were resolved on 2% agarose gels and visualized by ethidium bromide staining. cDNA levels were normalized for cell number differences by the housekeeping gene, GAPDH.
Control cDNA is composed of an equimolar mixture of 56 cDNA preparations from various human cell lines and was used to verify that the selected primers only amplified a single predicted product.
Results [0282] Analysis of LRCHI expression in alginate cultured human chondrosarcoma cells treated with inflammatory stimuli, IL1-beta and PMA revealed substantial increases in the expression of the known IL1-beta responsive gene, MMP13 [52], in both IL1-beta and PMA
stimulated cells.
Interestingly, MMP8 was strongly upregulated by IL1-beta but weakly upregulated by PMA, suggesting that MMP8 may be regulated by different inflammatory stimuli and pathways than MMP13. LRCHl expression after IL1-beta and PMA stimulation was unchanged from controls.
This suggests that the effect that LRCH1 has on the etiology of osteoarthritis may be via an inflammatory independent mechanism, possibly involving compressive stress. There were no differences in expression of LRCH1 or control genes in monolayer cultured SW1353 cells compared to alginate cultured cells suggesting that SW1353 cells retain a chondrocytic phenotype even in monolayer culture conditions (data not shown).

Example 12 Ire Vitro Production of Target Polyp~tides [0283] cDNA is cloned into a pIVEX 2.3-MCS vector (Roche Biochem) using a directional cloning method. A cDNA insert is prepared using PCR with forward and reverse primers having 5' restriction site tags (in frame) and 5-6 additional nucleotides in addition to 3' gene-specific portions, the latter of which is typically about twenty to about twenty-five base pairs in length. A Sal I restriction site is introduced by the forward primer and a Sma I restriction site is introduced by the reverse primer. The ends ~f PCR products are cut with the corresponding restriction enzymes (i.
e., Sal I and Sma I) and the products are gel-purified. The pIVEX 2.3-MCS vector is linearized using the same restriction enzymes, and the fragment with the correct sized fragment is isolated by gel-purification. Purified PCR product is ligated into the linearized pIVEX 2.3-MCS vector and E. coli cells transformed for plasmid amplification. The newly constructed expression vector is verified by restriction mapping and used for protein production.
[0284] E. coli lysate is reconstituted with 0.25 ml of Reconstitution Buffer, the Reaction Mix is reconstituted with 0.8 ml of Reconstitution Buffer; the Feeding Mix is reconstituted with 10.5 ml of Reconstitution Buffer; and the Energy Mix is reconstituted with 0.6 ml of Reconstitution Buffer. 0.5 ml of the Energy Mix was added to the Feeding Mix to obtain the Feeding Solution.
0.75 ml of Reaction Mix, 50 ~1 of Energy Mix, and 10 ~g of the template DNA is added to the E.
coli lysate.
[0285] Using the reaction device (Roche Biochem), 1 ml of the Reaction Solution is loaded into the reaction compartment. The reaction device is turned upside-down and 10 ml of the Feeding Solution is loaded into the feeding compartment. All lids are closed and the reaction device is loaded into the RTS500 instrument. The instrument is run at 30°C for 24 hours with a stir bar speed of 150 rpm. The pIVEX 2.3 MCS vector includes a nucleotide sequence that encodes six consecutive histidine amino acids on the C-terminal end of the target polypeptide for the purpose of protein purification. Target polypeptide is purified by contacting the contents of reaction device with resin modified with Niz+ ions.
Target polypeptide is eluted from the resin with a solution containing free Ni2+ ions.
Example 13 Cellular Production of Tar e_g t PolY~eptides [0286] Nucleic acids are cloned into DNA plasmids having phage recombination cites and target polypeptides are expressed therefrom in a variety of host cells. Alpha phage genomic DNA contains short sequences known as attP sites, and E. coli genomic DNA contains unique, short sequences known as attB sites. These regions share homology, allowing for integration of phage DNA into E. coli via directional, site-specific recombination using the phage protein Int and the E. coli protein IHF.
Integration produces two new att sites, L and R, which flank the inserted prophage DNA. Phage excision from E. coli genomic DNA can also be accomplished using these two proteins with the addition of a second phage protein, Xis. DNA vectors have been produced where the integration/excision process is modified to allow for the directional integration or excision of a target DNA fragment into a backbone vector in a rapid in vitt~o reaction (GatewayT"' Technology (Invitrogen, Inc.)).
[0287] A first step is to transfer the nucleic acid insert into a shuttle vector that contains attL sites surrounding the negative selection gene, ccdB (e.g. pENTER vector, Invitrogen, Inc.). This transfer process is accomplished by digesting the nucleic acid from a DNA vector used for sequencing, and to ligate it into the multicloning site of the shuttle vector, which will place it between the two attL sites while removing the negative selection gene ccdB. A second method is to amplify the nucleic acid by the polymerise chain reaction (PCR) with primers containing attB sites. The amplified fragment then is integrated into the shuttle vector using Int and IHF. A third method is to utilize a topoisomerase-mediated process, in which the nucleic acid is amplified via PCR using gene-specific primers with the 5' upstream primer containing an additional CACC sequence (e.g., TOPO~
expression kit (Invitrogen, Inc.)). In conjunction with Topoisomerase I, the PCR amplified fragment can be cloned into the shuttle vector via the attL sites in the correct orientation.
[0288] Once the nucleic acid is transferred into the shuttle vector, it can be cloned into an expression vector having attR sites. Several vectors containing attR sites for expression of target polypeptide as a native polypeptide, IvT-fusion polypeptide, and C-fusion polypeptides are commercially available (e.g., pDEST (Invitrogen, Inc.)), and any vector can be converted into an expression vector for receiving a nucleic acid from the shuttle vector by introducing an insert having an attR site flanked by an antibiotic resistant gene for selection using the standard methods described above. Transfer of the nucleic acid from the shuttle vector is accomplished by directional recombination using Int, IHF, and Xis (LR clonase). Then the desired sequence can be transferred to an expression vector by carrying out a one hour incubation at room temperature with Int, IHF, and Xis, a ten minute incubation at 37°C with proteinase I~, transforming bacteria and allowing expression for one hour, and then plating on selective media. Generally, 90% cloning efficiency is achieved by this method. Examples of expression vectors are pDEST 14 bacterial expression vector with att7 promoter, pDEST 15 bacterial expression vector with a T7 promoter and a N-terminal GST tag, pDEST 17 bacterial vector with a T7 promoter and a N-terminal polyhistidine affinity tag, and pDEST 12.2 mammalian expression vector with a CMV
promoter and neo resistance gene. These expression vectors or others like them are transformed or transfected into cells for expression of the target polypeptide or polypeptide variants. These expression vectors are often transfected, for example, into murine-transformed a adipocyte cell line 3T3-L1, (ATCC), human embryonic kidney cell line 293, and rat cardiomyocyte cell line H9C2.
[0289] Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, yet these modifications and improvements are within the scope and spirit of the invention, as set forth in the claims which follow. All publications or patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference.
[0290] Citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. U.S. patents and other publications referenced herein are hereby incorporated by reference.
Nucleotide and Amino Acid Sequence Examples [0291] Table A includes information pertaining to the incident polymorphic variant associated with osteoarthritis identified herein. Public information pertaining to the polymorphism and the genomic sequence that includes the polymorphism are indicated. The genomic sequences identified in Table A
may be accessed at the http address http:l/www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=snp, for example, by using the publicly available SNP reference number (e.g., rs552). The chromosome position refers to the position of the SNP within NCBI's Genome Build 34, which may be accessed at the following http address:
www.ncbi.nlm.nih.gov/mapview/map search.cgi?chr=hum chr.inf~query=. The "Contig Position"
provided in Table A corresponds to a nucleotide position set forth in the contig sequence (see "Contig Accession No."), and designates the polymorphic site corresponding to the SNP
reference number. The sequence containing the polymorphisms also may be referenced by the "Nucleotide Accession No." set forth in Table A. The "Sequence Identification" corresponds to cDNA sequence that encodes associated target polypeptides (e.g., Q96FX2). The position of the SNP within the cDNA
sequence is provided in the "Sequence Position" column of Table A. If the SNP falls within an exon, the corresponding amino acid position (and amino acid change, if applicable) is provided as well. The amino acid found to be associated with OA is in bold. Also, the allelic variation at the polymorphic site and the allelic variant identified as associated with osteoarthritis is specified in Table A. All nucleotide and polypeptide sequences referenced and accessed by the parameters set forth in Table A are incorporated herein by reference. Genomic nucleotide sequences for KLAA0296, Ch~ona 4, Chnom 6, ELP3, LRCHI, SNWl and ERG regions are set forth in SEQ ID NO: 1-7, respectively. A polymorphism in Table A designated by "AA" is present in the genomic nucleotide sequence of SEQ ID NO: 28, which follows Table A.

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rM M N M d'M

f~
~

: N
~

WO O r r r N ~ ' rN N N N N N ~

a~
U

U

tf7 bl7 O ~" U O
N N f~ ' :
U

y , N E ~ M M U ~ C%~ ~

00r ~ C O r 1~~
O D ~
d' r n n n a ,.~, a ,.T' a AA ~enomic sequence (SEQ ID NO: 28) TCATTAGCTTTTTCAGTTTTTCACATTCCTGATACAGACGTAGGAGTGCTCGTATTTTGGATTTTGCATCCAACTTGTA
CTTAGTT
TTAAATTCTGCACA[A/G]AAATGTTCCACTAACTTTTCATCGAAGTTTTTTCCTCCTAAGAAAGGATCAAAAGCTGTT
CCCAGTA
CCTAATTTGGTTGAAACAACAAATAGTCTGGTT
[0292] Following are genomic nucleotide sequences for a KIAA0296 region (SEQ
ID NO: 1), a ch~om 4 region (SEQ ID NO: 2), a ch~~om 6 region (SEQ ID NO: 3), a ELP3 region (SEQ ID NO: 4), a LRCHI region (SEQ ID NO: 5), a SNWI region (SEQ ID NO: 6), and a ERG region (SEQ ID NO: 7).
The following nucleotide representations are used throughout: "A" or "a" is adenosine, adenine, or adenylic acid; "C" or "c" is cytidine, cytosine, or cytidylic acid; "G" or "g"
is guanosine, guanine, or guanylic acid; "T" or "t" is thymidine, thymine, or thymidylic acid; and "I"
or "i" is inosine, hypoxanthine, or inosinic acid. Exons are indicated in italicized lower case type, introns are depicted in normal text lower case type, and polymorphic sites are depicted in bold upper case type. SNPs are designated by the following convention: "R" represents A or G, "M" represents A or C; "W" represents A
or T; "Y" represents C or T; "S" represents C or G; "K" represents G or T; "V"
represents A, C or G; "H"
represents A, C, or T; "D" represents A, G, or T; "B" represents C, G, or T;
and "N" represents A, G, C, or T.
KIAA0296 ~enomic sequence~S~ ID NO' 1) >16:31076951-31174000 1 ccccaccccccaacagctgcacagtctggagcgaatatacacgcccaccacccacacacc 61 caagacccaatacacttttttaaactttatttttacttctatttatttatttttaattat 121 tttttaaaaatctaattagagatgaggtcttaggctgggcacagtggctcatgcctgtaa 181 ccccagcacttcgggaggccgaggcaggcagatcacgaggcgggaggatcacgaggtcag 241 gagttcRagaccagcctggccaatatggtgaaaccccatctctgctaaaaatacaaaaat 301 gagctgggcgcggtggtgtgcacctgtaatctcagctacttgggaggctgaggcagaatt 361 gtttgaactcaggaggcggatgctgcagtgagctgagatcgtgccactgcactccagtct 421 gggagacagagcgagactacgtctcaaaacaaacaaacaaacaaacaacaacaacaaaaa 481 cagagataaggtcttggcatgttgcccaggctggtctcaagtcctgggctcaaaggattc 541 tcctgcctcagcctcccaaagtgctaggattacaggcgtgaaccactgcacccaccctac 601 ttttttttttttttttttttatacaggatctcactctgtcacccgggctggagtgcagtg 661 gcaagatcactgctgactgtacccttgacctcagggactcaagtgatcctcctgcctcag 721 cctcctgagtagctgggactacaggagagcgccagcacacctgggtaattaagatttttt 781 ttgtagagacagacgctatgttgcccaggctgctctcgaactcctggcttcaagtgatac 841 acccttggcctcctaaagtgbtgggatcacaggcatgagccactgcacctagcctaatat 901 agttaatatccccgtcaaggctgctcagagggcctgagaggaacaaagggctcagctctg 961 gagagctccacccccagcgccaatctctctaaatggcctctttcctctccatattccacc 1021acaaggcttggagtccagcttcctgtgaccttaagtcaccattccaaagccctgcgatct 1081cacccagagaccacaagtgaaataatattataatcctgagaagtttagtggaccaagatg 1141gcatgccatcaagacgctgagaaacaaagaggaagatgggaccagggggcccagaagacg 1201ctggaacccacagtattaaaagctcagagaggctgggcacagtggctcacacctgtaatc 1261ccagcactttgggaggccaaggtgggtggatcacttgagcccaggggtttgagaacagcc 1321tgggcaacatggcgaaacccagtctctaccaaaaaatatacaaaaattagccaggcatgg 1381tggtgcgtgccttagtaccagctacttgggaggctgaggcaggaggattgactgaacctg 1441agagcacaccactgcactccagcctggatgacagaaccagacctgacctcaaagagaaga 1501aaaaaaaaaaaaaaaaaaagcccagaggggagggYaccctcaacagttttccagcccctt 1561ccacatccttcctaacctcacttgatagtgttcaagtcctaccttaggcaaggcagaaat 1621tataggaccaagccgccaaatggggaaattgagtcccagagagaagtaatgcattattta 1681agatcccatgcaggactatgagtcaggggtccaagagcccttccaccgtgtgccactcag 1741agacacagagtaggagggggaagggggtcgggtggcaggggacaaaagatgcaggaggca 1801agcagcagtgactgaagaggcagaggctgacatgaaagacccaggagcagagaatctttc 1861cttatcatctccaggggacaccactgggcagggcttggcctccggaaaaaccctgcattc 1921cctctgtgggttcatcagggcaccactctcctactagctgggttttttttttttgttttg 1981ttttgtttttgagacagagtcttactctgtcacctaggctggagtgcaatggcgtgatct 2041cagctcactgtaacctccacctcccatgttcaagcaatcctcctgtctcagcctcccaag 2101tagctgggattacaggcacctgccatcatgcctggctaatttttgtatgtttgtagagac 2161agggtttcgccatgttggccaggctggtctccaactcctggcctcaggtgatctgcctgc 2221ctcagcctcccaaagtgctgggattacaggcatgagccaccacaccctgcctgagctggg 2281ttttaacaggaagaggagaagagccaaaactcctcacatagaatcacacagcacttgaca 2341gtttccaacctcatcatcactgaagtttagagcagccgatacccaYaaagatgatctccc 2401catccccctacagttacccactgtgcagagggagatccacacttagagacaggaagcgat 2461ttccagaagtccatagcaactcagtcccaggaatctaggtttcctgaccagggcatagca 2521gaaagggtccattcctttccttgcttgtaccttcacagaagcttcctggacagagccctg 2581gggtccaggagacctgttattcattcccggctatgctgagacttgctgagtgaccttggg 2641gactccttctagagaatataagttccacgagtgcaggaatttttgtctattagtccttga 2701tgtatctccagccctagaacagtgtttggcccatactatgtgcccaaaaaatatccatta 2761aatgactgaatgttgctgtgcatggtggtgcatgcctgtaatcccagcactttgggaagc 2821tgaggcagaaggattgcttaagcccaggagttagagaccagcttggacaacatagtgaga 2881ccgcatctcgtaaaaatttttaaaaataaaaaatgagtgaatatctagatagccaggatt 2941agagaagtgtcacagtcagaaagcctgaagcctaaagaagaccaaggaaccaggggcttt 3001atcctcagatacatgaaagcctgaaattctgtccacaagtatttatagagggcccgtaat 3061gttcttggtactgggctaggaactccccagattcagttaagaacaaagtcattacctggc 3121ctcagatgcaaggcaggggctggggggtgtgagtggcagggaggcagcgtgatcaataca 3181aacacttttcttagcctgagctgccctgacatggtctgacggctcacaaggtggtgagtg 3241cagccgggctgcagtgttcaaggagggcgccggctggccgcccacctgtcagaggctgcg 3301ccagaaggatgcggaagaagagatttctgccttggctgaggtcacttcccacccccagat 3361tccctgcccacacaaccctgcaattttctgacgctgacgactcggatcctattatttccc 3421gattttcaaggtcccatgatgctgacagccccaaatgctaagtcgtcagtccgcccacgc 3481cctggacccgaaagcaataaaggcgaggtcagcaagggtcctaccacccactgcctcgaa 3541aggcctctgggggtggtcggcgcgcccctccccacctcgcgggggccgtgtgggcgtcgc 3601tcggtcgttggggtgccggggacgtcgtgatgagaacggcgtcccagagacggcggtgac 3661agagccgggacacgtgacagtcacagggtcacattctgcggtccacgagtttgggaccgg 3721gctggtcacgtgacgcggtgggggcaccatggggtgatgtgagatgcgggtgtctcggat 3781tacgtacaaatgacgtattcctaccccttttggcaaccagatttccgttggaagatgcaa 3841cggttccggtgacggtagcaagttctcgcgtccaggcatctccgcttccgctcggggcgc 3901aacaacttccgactccaccttcccagcctcgggcaaggaagagacgcgaccatgtgcgca 3961tgccccgaatttatcacggaggggcggggctgaggctgcgggagctggagcggggaagaa 4021aagggaattccaacctgtggaaccttggggggtccccggggtcggcgccttcccattgac 4081tgtgggcggtgcaagggacggagcctctggcggctcgtgggggtgttggggtccgcaggg 4141ggagggaggggagtgtcagagtgtgagcggggtacgggaattccaaatttgagggcctcc 4201cggctctggcgccggggagggagagctcaggccgccatgcgggacaggacccacgagctg 4261agacaggtgagacgccagggcagcggggatggggacgggcggacgaactggaacgcagga 4321cttctggtcttcgggatagggaggggtggctgatggccaggaaggaaagtcccggaagcc 4381tgtgggtcctgcggggtaagagccgcagcgaaacggtggtgccaatgactccgggcctgg 4441cagggggatgacagctcggacgaagaggacaaggagcgggtcgcgctggtggtgcacccg 4501ggcacggcacggctggggagcccggacgaggagttcttccacaaggtaaggggctggggt 4561ctccgcctggattcgcgagggtgtaggaggacccgaggagtagcgtggtctggagtaccc 4621catatctctttcagccctctcggtcaccctccccaggtccggacaattcggcagactatt 4681gtcaaactggggaataaagtccaggagttggagaaacagcaggtcaccatcctggccacg 4741ccccttcccgaggagagtgagtgaaaccccggctgcagggcgcatgctccgccccaggga 4801ttgtgggggttgtagttccacgcaggtggtggccagagtggtttgttgaggtgggggctg 4861ctgtttgggagtcttggccttctcttattcaggcatgaagcaggagctgcagaacctgcg 4921cgatgagatcaaacagctggggagggagatccgcctgcagctgaagggtgagctcctggg 4981acctcagacagatccttccctctgatcctgccctgttgttggtatatctggggagtgtgt 5041ggcccagagaagccagtgatatatccaggtcacacagcaggcctgggtctagcatctgtc 5101tcctggcctccaggccattgtactctccacagcacaagtccgcctctcaggttcttttat 5161ttacaatgaaaccatttacttacacagttatcgctgcccactgggcattctttgggcagg 5221gagatggagttttgttaggtggcctctgcatacctatgggaactcagtgatgtaatgcaa 5281agaaaaataaacttactttctcctcttagaggctcagccttagtcattttatgataaatt 5341atatttccctaaaaatcctatggagacaagtacccccaatacccctgtgtcttcccacag 5401ccatagagccccagaaggaggaagctgatgagaactataactccgtcaacacaagaatga 5461gaaaaacccaggtgggttttttttctcagaaatgaggacatttcagcaaatgtttcatga 5521agtattagatgacaggtgtatgaaggaagggcctgcagagatcatggagtccaattggat 5581gacttttccaaatggggaaactgagctcagagagagaaagaacttgctcaaggtcaggaa 5641gccaggtctcctgatgctcagtccggttataacaccctgctttattttcttccattcaat 5701aggaagttactgtgaccccagacaagacctagtcttggctgtgggacacatgttttcttt 5761tctttttttgcctcagcctcctgaatagctgggattacaggcggacacccccatgcccag 5821ctaatttttgtagttttagtagagactgggcttcaccatgttggccaggctggtttcgaa 5881ctcctgacctcaggtgaccctcctgcctcggcctcccaaagtgctgaattacaggcgtga 5941gccaccatgcccagctgggacacatgttttctgggagtcaagatgaggagttagggttca 6001ataggggataaagacattactcacgtgggacctggtggctaacggcgctgcccagggaag 6061gagagtgagaagtcataaatgactggcaggtttcctatctatgtgacagggacatcctta 6121gtcccacaggtggaattcaagaagtcaggaagaggaacttccttggggcaacactgaaga 6181ggaactcccctggtgtgatatcttatttttttaattattattatttttttgagatggagt 6241ctcactctgtccctcaggctggagtacagtggcacaatcttggctcactgcaacctccac 6301ctccttcaagcgattctcctgcctcagcctcacgagtagctgggattacaggtgtgcacc 6361accacacctggctaattttttatatttttggtagaaatgaggtttcaccttgttggccag 1fR

6421 gctggtctcg aactcctgaY ctcaactgat ccacctgctt tggcctcgca aagtgctatg 6481 attataggca tgagccaccg cgcgcggccc ctggggtgat atcttagtaa ggagatttgc 6541 agtgatctga ctggccctct ctgggtcccc agtgaggagg ataccaggag gtcagggttg 6601 gagtagttgg gcccagggct cagcagggac cccagattga agatggagca gcttgggcat 6661 cttggaaggg tgaagctgga accaggaaag cagatgtatc tctggaaaag gaactccaag 6721 gaatgagcat atttaaggcc tcagaagaag gggcaaggca gagcagatgc cccagaacca 6781 gtgtttctgg ggaagcctgt ggtggtgatt ggcatgagtg gttgagggtc catgtgggcc 6841 tgttgcacct gtttcgccca ggcaacatgt tcatctctag gcgtaggagc tgtggtgtag 6901 gcagcgaggt tggcattcag caagcattca gcagttacat attgggtgcc tactgtgtgc 6961 cagacctttt tggaactgtt taggatacag cagtgaacca gtgatccctg tcctcatgga 7021 acttcccttc tggtgtagac aatcaccata ataaataagt gaattattta gaacataata 7081 agcattaagg aaaaaagagc aggggaagag ggactaagca tgctggagga ggtagagttg 7141 cagttgaaag caggtggagg aagcttcatt cagaaggtaa catctgaaca agagacttaa 7201 aggtgtttgc tgggaatgag cattctaggt agaaggaaaa gtgaatgcaa aggcttaagc 7261 tgagagtgtg ctttgtctag ggaggggtaa ggagaccagt gtggatgggc agaggaaggg 7321 aacagtaaga ggaagtaaga tcagagaggt catgggagaa ggagagatca tagagggcta 7381 gccaggcacc gtggctcacg cctgtaatcc cagcactttg gaggctgagg tgggaggatt 7441 ggttgagccc aggagtttga gaccagcctg ggcaatatag tgagaccccc cccccttttt 7501 tttttttcct ttgagacagg gtctcactct gttgcccagg ctggagtaca gtggtgccat 7561 ctctgctcac tgcaacctcc gcctcctggg ttcaagccat tctcttgctt cagcctccca 7621 agtagctggg actacaggcg cccaccactg caccaagcta atttctgtac ttttagtaga 7681 gatggggttt caccacgttg gccaggctgg tcttgacctc ctgacctcag gtgatccacc 7741 tgcctcagcc tcccaaagtg ctgggatcac aggcatgagc caccgtgccc ggccaaccct 7801 gtctctatta aaaataaaaa taggccaggt gcagtggctc acgcctgtaa tggaggccga 7861 ggcaggtgga tcacaaggtc aagagatcaa gaccatcctg gccaacatgg tgaaacccca 7921 tctctactaa aaatacaaaa attagccgtg cgtggtggcg cgtgcctgta gtcccagcta 7981 ctcgggaggc tgaggcaaga gaattgcttg aacccgggag gccaaggttg cagtgagccg 8041 agattgtgcc actgcactcc agcctgggca acaagagtga aactctgtct caaaaaacaa 8101 ataataaata aataaataaa taaataaata aataaataaa taaaaaagat catggaggac 8161 cacataggcc tgataagggc tttggctttt agtctaagag aaatggggga gcctgtcaag 8221 gtcatcacaa ggtggttaag gtggcagatc ccgcataaga gctcatgcta tttgctcact 8281 gtactatggg gttgccgagg caccgaccgg gcagggatcc tcccaggggc actcagccta 8341 tattcttcat ctttagcatg gggtcctgtc ccagcaattc gtggagctca tcaacaagtg 8401 caattcaatg cagtccgaat accgggagaa gaacgtggag cggattcgga ggcagctgaa 8461 gatcagtgag ttgtgcatgc ccagcctggc ccgcaggggc aggtaatccc aacccaaccc 8521 tgagcctggc cttttccttc acagccaatg ctgggatggt gtctgatgag gagttggagc 8581 agatgctgga cagtgggcaa agcgaggtgt ttgtgtccaa tgtgagtggc cacagccagc 8641 ccctctctgc tgtgcctccc atcccctctg agtcctgtcc gtttctcgac ctcctgggct 8701 caggtgatcc tcctgcctca gcctcccgag tagctgggac tataggtgca agccactgca 8761 ccccgcttgc tgtggccctt tctgattaag ggcaccctga ggcctctaag ggaattaatt 8821 agcctgcctg gagtcaccca tcagattcca ggctgagggc tccccagaag ctcaacagga 8881 gtttctgacc tgctgtcggt ctccctgtga acagttgccc cactcctgtc caccccccag 8941 atcctgaagg acacgcaggt gactcgacag gccttaaatg agatctcggc ccggcacagt 9001 gagatccagc agcttgaacg cagtattcgt gagctgcacg acatattcac ttttctggct 9061 accgaagtgg agatgcaggt gggtgccccg cgcagcccca gacgtgagac caggctcagt 9121 ccaaactgcc agMctcccgc caYccttaga ttctctccct gaggcttttg tgtcttccag 9181 gtttggccat gcccccagat tggtgcttat tcctatcctt agctgtaccc cgagaatggc 9241 acctgcctct gctgctacac agatgcccac tcccttctgc atagcaccct gccccctctc 9301 caaaacttga gcctgcccag gtctggcccc agccctcact ccccctccac taacagcatc 9361 cacccttata cctctcagag gtccagtcag agttgcccta gaggggctgc ctcctaacat 9421 ctgtacaagg ctggggtggg ggcggcgttc ccctggccct ggttgtgagt Wgagttgagc 9481 ttccagccct gtcctggagg agctggcctc agtcatgcta cagccaatgc ccttttgcag 9541 ctgagactta caggaaagag atctcattca gtaggagtac tgagacctga ggctggtggt 9601 gccaggagga ggcagggata gggagggctt tgcagcagct gtagataggc ctggaagaat 9661 gggtaaattc agacagattt gtgaaggcac agttcaccat ctgtgaaagg tatgagccat 9721 ttgaggccct tagctccaag ctaccactgc agatagaggt tgtatgggat aagtgagcag 9781 gggacaaggg actacatgat agaaggggcc tggaagccat ccccaaggag tctgaacttt 9841 tgtcagatca agtcttgccc ttgtctttgt tagtgcaatt tttttttcct gccaggaatg 9901 ttcttcagtc atctggggtg gggtgggcaa aggcatcctt acctccctga accaccccat 9961 cctctgagca gggggagatg atcaatcgga ttgagaagaa catcctgagc tcagcggact 10021 acgtggaacg tgggcaggag cacgtcaaga cggccctgga gaaccagaag aaggcgagga 10081 aggtgagcct cccaggcccg gccactgccc caggcaccct gtgtgacttc cctgaccccc 10141 tcctctccca cagaagaaag tcttgattgc catctgtgtg tccatcaccg tcgtcctcct 10201 agcagtcatc attggcgtca cagtggttgg ataatgtcgc acattgttgg tgagatgttg 10261 tgggctgccc cctggcctgc cccagccctg gccccagccc tccctcctcc ctcagaccct 10321 gttctccctc ctttccttac aggcactagg agcaccagga acccagggcc tggccttctc 10381 tcccagcagc ctggggggca gggcagagcc tccagtcgga ccccttcctc acactggccc 10441 ctatgcagaa gggcagacag ttcttctggg gttggcagct gctcattcat gatggcctcc 10501 tccttcaggc ctcaatgcct gggggaggcc tgcactgtcc tgattggccg ggacacacgg 10561 ttttgtaaaa aattaaaaaa caaaaaaaga gcatagaaag ccctgtgcac gtgtgttcct 10621 ggaagggctg gcccaaggct tccgggcatc caacctcctt acctcctgga cgtccccagg 10681 gccaggtctg gccctggctg ctcaggtcaa actgccaggg gtgctgtgcc cacagcaggc 10741 tggttctgcc tttctgcacc cccataggaa tgggtgggca gggaggggta acaccggcat 10801 ctagctcctg gctcagtact gtccccggga aaggaccact gtgagtatct gtcttggaaa 10861 tgatgaggct gaccaggcca ggctgggacg caggtgagat gggggtttgg gtggcatcag 10921 tgggccttct tgtggcccag aggaagaggc accatgaaaa aatgcctaat tgaggctgtc 10981 actttggatg cagtggatag ggatggtctg gtttcagcag ggatgacatt ggagtgggat 11041 gttaagctgg ggaagaggtt gccagtcaga aagcacagga ggccgggccc tgtgaccaac 11101 aaaagcatca tcttttacat aagcgtttag gcagggtgtg gtggctcgca ccagtaatcc 11161 cagcactttg ggaggcccag gcaggaggat ctcttgagcc caggagcttg agaccagcct 11221 aggcaggatg gggcaacctc ttctctttag agaataataa ttttacaaat tagccaggcg 11281 tgatggcaag tgtctgtcgt cccagctact ccagaggctg aggtgggagg atcgcttgag 11341 cccaggagat taaggctgca gtgagccatg gtcatcccac tgcactccat cctgggtgac 11401 agagcgagac cctgtctcaa aaataatagc aatcatcatc agtagcagca gcagcagcag 11461 cagcagcata gagagccagt gatcctggat cagtgcacct ggttgctgag ggttacctgg 11521 ctgaagcagg tggtggcagc agaaaagcct gacctctgat ttcttccata aggtacctga 11581 aatccaagcc ctgactaaat ttcttttttt cttttttttt gagacagagt cttgttcttt 11641 tgcceaggct ggagtgcagt ggcactatct cagctcactg caagctccgt ctcccaggtt 11701 cacgccattc tcctgcctca gcctcccgag tagctgggac tgcaggcacc cgccaccaca 11761 cccggctaat tttttgtatt tttagtagag acggggtttc accgtgttag gatggtctcg 11821 atctactgac atcgtgatct gccctcctcg gcctcccaaa gtgttgggat tacaggcgtg 11881 agccaccgcc taaatttcta agggctccta gtcctgatgc ctaatttctg gagtggacgt 11941 ggctcctgtt ccccgacacc tagagttttt gtttgtttgt ttgtttgttt tgagacagag 12001 tctcgctctg tcgcccagcc tggggtgcag tggcgcaatc tcggctcact gcaagctccg 12061 cctcccgggt tcacgccatt ctcctgcctc agcctccaga gtagctggga ctacaggcgc 12121 ccgccaccat gcccggctaa tttttttttt ttttttgaga cggagtcttg ctctatcgcc 12181 cagactggag tgcagtggtg cgatctccgc tcactgcaaa cttcgcctcc cgggttcacg 12241 ccattctcct gcctcaggct cctgagtagc tgggactaca ggcacccgcc accgcgcccg 12301 gctaattttt tgtattttta gtagagacgg ggtttcatcg tgttagccag gatggtctcg 12361 atctcctgac ctcgtgatcc gcccgcctca gcttcccaaa gtgctgggat tacaggcatg 12421 agccaccgcg cccggccccc gacacctagt tttaaagggt aagccggctc ctggcacctg 12481 cctacttgca gtagggcggc gcctagctct gacctccaag gtctggggac tgcgtcgcag 12541 ccgcccagtc catcccactt tcaatcttac aggcccctgc tgttgctgcc gctgccgccg 12601 ctcccagctg cccagtctgg cgggctcagt cccgcgttgc catgtgtggg agaccgcgtc 12661 gcgtaagcgc tggatgtggc ttcgctgatg cacattggac cgggctctgg actgggctag 12721 gggaagggca ggagggcgga attgggcccg agggccaggc ctcgccgacc cccgactgcg 12781 cctcccggtg gccccgcagc gcctcccggt ggccctggag tgcaggtctt accgtccgag 12841 atcgtccgca actgggcgag ctgtgcatgg ggcgtggcta aggccgtggt ttggttacga 12901 ttggccagcg ggacttaagt gttgtctctg aagagcatgg acattagtct ggagggtcct 12961 ggaagagtga tccccgcccc accatcaaat ggcgcttagg tctaggaagc gggtgtgggt 13021 ggggccttag ggcgaggcgc agacataccc cgaagtggtt ggattgtata ccgcaagggg 13081 ctggatcgaa ccccccaaag acactggaag gctgtgtggc tgaggagggc ccggcagatc 13141 cagtgtgtcS tgggctttac aggaaagagc tccaccttct ctggagtgtg cagatgcgat 13201 ctaggtgtgt ccacccgatg ggagctgcgg gccgggcaga tgctgcccca gtacaaagct 13261 gatttggacc tggggcctct ggacttccct gattctctgc ttgcatctcc agcaaagtcc 13321 tgtcccgttg gctgccttca tccactctct cacttctctg ccttcagagt aaaattgcaa 13381 gatctgtggt gcttactggg atctgataga gtctctcggc atccactgtc tatgcagcgg 13441 gtgtccacct gcagcggggg ccatgtgcag cggggggcca cgtgcagtgt gtgcctcttc 13501 ttagccatgc tggacagcgc cgcccctgaa aagcagctcc ccggtttcac ccagaaagcc 13561 atccagaacc tcctggaaaa ggtggcctga tggccaagtg gcctcggatg ccaggctcaa 13621 tcctttgaac ttttcctgtg ggctgtcagg acccatagaa ggtctttgag caggtgagtt 13681 tggagcagat ctggtaggca agcgaacaga tggatgYgtg cactggagat tccgtgggtt 13741 cccctgtgta catctcttcc ctttgggaaa ctgccctgag tgaggggcta agggcaggat 13801 ttgcattgaa atcctagctt tgctgctgtc agcccaactt ttaggcaaca gggtcttggt 13861 ttgatgtgac atttccaagt ccatcttgta tcacaacctg tcagctgcag ctcacttatt 13921 caatctattg tggttcaagt tcccaagaaa atgaatcagt ctggtctgct ctccagatca 13981 gattacgttt acttgcctag gaattgtctg ccctttaact caagactttg cactgttgtt 14041 cacatttgta atcccagcac tttgggaggc caaagcagga gtattgcttg agcccaggag 14101 ttcaagacca gccagggaaa tataacaaga ccctatctct acaaaaatta aaattaggtt 14161 gggcactgtg gctcatgcct gtaatcccag cactttggga ggccctggca ggtggatcac 14221 ctgatgtcag gcgttcgaga ccagcctgac caacatggtg aaaccccgtc tctactaaat 14281 acaaaaagtt agctggatat ggtggtgcag gcctgtaatc ctacttggga ggctgaggca 14341 gaagaatcac ttgaacccgg gaggtggagg ttgcagtgag ccgagattgt cccattgcac 14401 tccaacttgg gcaacaagag caaaactccc tctcaaaaaa aaaaaaaaaa aaaaaaaagc 14461 caggtRcatg tcagtggtac gtgcctgtgg tcccagctac ttgggaggct gaggtgggag 14521 gattgcttgg gcctggggtt gagaccacag tgagccaata ttgcaccact gcactccagc 14581 ctggacaaca gaataatacc ctgtctcaaa aaaaaaaaaa aaaaaaaaga aaaaaaagaa 14641 aagaaaaaga ctttgccctt gagtcaagac tttacccttt tacccttggc taagatggat 14701 gtaggaagtg acatggtaca aaatgctgca gcagagcgtg tgtatgtgct ggaagaggag 14761 ttgactaggg cagtgattga catctctgtt ccagatattt gcttaccttc cctgctgggc 14821 ccctccctat aggagcatta tatgctcatt ccctacttac aataggtttg gctataggac 14881 ttgctttggc cagtggaata tgggtaggaa ggcaaaatat cggccgggcg caatggctca ~~n 14941cacctgtaatcccagcactttgggaggatgaggcgggtggatcagctgaggtcaagagtt 15001cgagaccagtctggccaacgtggtgaaaccctgtctctactaaaagtacaaaattagcca 15061ggcatggtggcacgggcctgtaatcccagctgctaggaaggctgaggcaggagaatcact 15121tgaacccgggaaggaggaggttgcaatgagcccagatcatgccattgcactccagcctgg 15181acaaaaagtgaaactccgtctcaaaaaaaaaaaaaaaaggtaaagtatcacttctgcata 15241gaagctttagggcaccattgagtactctagcagcttccagtctcttctccctctgctcag 15301gctcataaacctggcagtttccagatctagacttctctttcagcctgcaacccagaatga 15361caatgacatgaagctgggctacagcctacctataaaatgatgcagaatttaagaaataaa 15421tctctcttgctgtgagccattgatatatggaggttgtttgttagcacatccaaatgttta 15481aacaaactgttacagaattaatacccagaagtggtgtgctgcaacaataaaaattgagcc 15541tcagccgggcacggtggctcacacctgtaatcccagcattttgggaggccaaggtaagtg 15601ggtcacctaaggttaggagtttgaaaccagcctggccaacatgacaaaaccctgtctcta 15661ctaaaaatacaaaaaaaattagccaggcatggtggtaggtgcctgtaatcccagctagag 15721gctgaggcaggagaatcgcttggacccaggaggcagaggttggcagtgMgtcaagattgc 15781gccactgcactccagcctgggcgatggagtgagactccatctcaaaaaattaaaaaataa 15841aaataaaaatattattaaaaattagccaggtgtgatggcatgtgcctgtagtcccagcta 15901cttgggaggctgagatgggaggatcacttgagcccaggaagcagaggttgcagtgagcca 15961agattgcaccactgcactccagcctgggtccaaaaaaaaaaaaatceccagccaggcatg 16021gtggctcatgcctgtaatcccagcactttgggaggctgaggtgggtgctgaggtcaggag 16081tttgatactagcctggcaaacatggtgaaaccctgtctccactaaaaatacaaaaattat 16141ccaggcatggtggtgggcacctgtaatcccagctactcaggaggctgaggctggagaatc 16201gcttgaaccttggatgcggaggttgcagtgagccaagatcaagccactgcactccagcct 16261gggcgacagagcaagactatctcaaaaaaaaaaaaaaaagcctaaactatgtaaactata 16321tgacattgacgttgagctggacagtggctggtaagggaactgtcattggaagttggaaag 16381atggtgacgtgtgttatgcaatggtgaatcgtttggttaaactgtaagcttatgaccaaa 16441tgagctttaggctttaggtaaagaactggggaaagggagtattggtagcatgctgtcact 16501actattgcatgcatttgaggagttactagaagaaagagatgactcagaaattaaatggtc 16561agtttataagcagaaatggaagagaatatagaaattcgaggcaagtgatccacattttca 16621gtaaaagatacaactgagaaagtccttgagccacaaggttttcgtttttgtttttgagac 16681agtcttgctcttgtttccaaggccaccttctgggttcaagcctttctcctgactcagcct 16741cccaagtagctgggattacaggcgtgcaccaccacgctcagctaatttttgtattttcag 16801tagagacaggtttcaccatgttggccaagctggtcttgaacttctgacctcaaatgatcc 16861tcccacctcRgcctcccaaagtgctgggattacaggtgtgagccactgcgaccggctgag 16921ctacaagttttgattaaaagtcatctttgtggcaagggccatatcaagtatatggctatt 16981atgccctttgtaaaaatctccaaactgatcaaagtggttcctaataaatcctctcagcta 17041gtcaagatgattcaaaggaaagaggttaagagtgtaactcaccttggctgggcgtggtgg 17101ctcacgcctgtaattccagcactttgggaggctgaggtgggcggatcacctgaggtcagg 17161agtttgagactagcctaaccaacatggagaaaccccgtctctactaaaaatacaaaatta 17221gccaggcatggtggtgcatgcctgtaatcccaactacttgggaggctgaggcaggagaat 17281tgcttgaacctgggaggcggaggttgcagtgagccaagatcacccatggcactccagcct 17341gggcaacaagagtgaaactccatctcaaaaaaaaaaaaaaatgtagcttacctgagggag 17401tcagtaggctcaactacagttaagtctaacgtcatggttatgtctgaaaagaattatggg 17461tatgctgttgacccatggatctgaatggagtaaaatacgtaagttcagttttggagggaa 17521ttgccctgcttcccctgcctaacaccccctcaccctgacaaaaagccaccaggttaaatc 17581ttgaccatgagtgttcaatacttagtatgatttttaggtccccaagtttctttctttttt 17641tttatttcggagaccgggtctcactctgtcacccagcctggagtgcagtgatgcaaccac 17701agctctctataacctcgaacttctgggctcacacgatcctcctgcctcagcctcccaagt 17761agctgggactacaggcccatgccaccccagcaggctaatttttgtttttcaaattttttt 17821gaaacaaaatctcactctgccacccaggctgaagtgcagtggcacgatcttggctcactg 17881caacctccgcttcctgggcttgagtgatccacttacctcagcctcccaagtagctgggac 17941tacaggtgtgcgctaccatgcccggctaatttttgtatttttttggtagagacagggtct 18001tgctatattgcccaggctggtctcgaactcctgaactcaagcgattcacctgtcttggcc 18061tcccaaagtgctggcattataggcgtgcagtgtaccaccatgcccagcctatttttgttt 18121tgttttgctttgttttgttttgagatgaagtcttgctctgtcactccagctggagtgcag 18181tggcacaatcaagcctcactgcagcctctacctctagggctccagtgatccccccacctc 18241agccttctgagtagctgggactacaggcatgcgccaccacacctggctaatttttctatt 18301tttttctggagaggatttcagcctgttgcccaagctggtcttgaacttctggtcttaagg 18361agttctccctcgttggcttcccaaagtgatgggattacaggtgtgagccaccatgcccag 18421cctaatttttgtatttcaggtttttttttgttttgttttgttttgtttttagtagagatg 18481ggggtctctgtatgttgcccaggctggcctcaagcaatccttgcctcaagtgatcctcct 18541gcctYagcctctcaaaatactgtgattgcagatgtgaaccaccatgcccggcctgggtct 18601ccaaatttcttttttttttttagagacggagtctcgttctgtcacccaggctggagtgca 18661gtggtgtgatctcggctcactgcaagctctgcctcccaggttcacgccgttctcccgcct 18721cagcctcccgagtagctgggactacaggYgcccgccaccatgcccggctaattttttttt 18781gtatttttagtagagacagggtttcactgtgttcgccaggatggtttcgatctcctgacc 18841tcgtgatctgcccgcctcggcctcccaaagtgttggggttataggcgtgagccaccgcac 18901ctggccatgggtctccaaatttctatgggcatgaaggagactgagaaagctactctactt 18961cagaaagacataaccaccagtgtcctctcaattgtggccaaggagaataagtggaaaagg 19021gtggtttactctaagggcagagccaagaacatggtgaagaatgaactagggaactcttcc 19081cactcccagggaaaagtgggggttcttctcaacatctgcccaKcagcactttagacttag 19141tggggcccagagcctgctgtgtgtctcctgtccttccttccttttttttttttttttttt 19201 tttttgagac agagtttcac ttttgtcacc catgttgtag tgcaatggca ctatctcggc 19261 tcactgcaac ctctgcctcc tgggttcaag cgattctctt gcctcagcct cccgagtagc 19321 tgggactaca ggtgcatgcc accacgcctg gctaattttt ggttttgggg ttttttgttt 19381 ttgtttttga gacggagtct tgcactgtcg cccaggctgg agtggaatgg cacgatctcg 19441 gctcactgca acctctgcct cctgggttca agcgattctc ctgtctcagc ctcctgagta 19501 gctgggacta caggggcccg ccaccacgcc cggctaactt tttgtatttt tagtagagac 19561 cgggtttcac tatgttggcc tggctggtct tgaactcctg accttgtgat ctgcccccct 19621 cggcctccca aagtgctgga attacagacg tgagccactg cgcctggcta atttttgtat 19681 ttttagtaga gacaggtttt caccgtgttg gccagggtgg tctcaaactc ctgacctcag 19741 gtgatccacc ggcctcggcc tcccaaagtg ctgggattac aggcatgagc caccgcaccg 19801 ggccctgtcc ttccttctga acgggagtgt gctctgctgt tctcctgtcc ttgttctgct 19861 ttatatgttg gatgtgttcg tgtgtgtgtg tgtgtagaaa tggggcacag gtaacttgtc 19921 tctgtctctc tcttattttg tagctcatag gtctctgaat caagagaagc cacatctgga 19981 cctgatatag aagagactat tagagatcct gggcttgagg ctgattccat gtcagatggg 20041 tcacttaggt ggtctccctt gggaagggga tgcatttatt ttgcatatgg aagaaaatgc 20101 aaaggcagta tttgtaagga agagggcaga cgggggaaga ttttataatt gttcaaaaac 20161 attcactggg atgtgtgtgg tggctcacgc ctataatccc agtgctttgg gagggtgaag 20221 caggaggatc acttgaggcc aggagtttga gaccagcatg ggcaacatag tgagacccta 20281 tctctacaaa aaataaaaca ataaaaaaaa attagctggg cgtggtggtg cttgcctgta 20341 gtcctagcta cttaggaggc tgaggtggga ggatcactta agctcaggag gtagaggctg 20401 cagtgagtta tgattgcacc atgcacctat gcactccagc ctgggcaaca caacaaaaca 20461 ctgactctaa aaaaacaacc aacaaaaaaa aatcacatgt attcactggc cctctctttg 20521 gggacctgct acatagaatg gttttttgtc cccagttcac tgacatcagg tatggctatg 20581 tggcttgctt tagaccatgg actttgagtg gaaatgacat gtgccacttc cacgaggaag 20641 ctttaaaagc cgtcatgggg tctgccacct ttcctctctt cggtgtctgg agacggaaag 20701 ttccagcttg agacttttcc ttcagacagg gctctRgaat gaagatagca tagaacagag 20761 tggtcccatg gaggacatgg atatgagtga gaaatcaaca tggtgttgtg agcccctaag 20821 atttgggggc tgctattact gcagcgtaac tggatcccag ctgatagatg cagcctccct 20881 gtgggatacc ctgctcaggt atcctttccc atcaccatga caactgacac accataatga 20941 gctatgctga tgttaggaag tctccgcctt tgctcctctt cagagctgtt caccctcagg 21001 tcctaaccag tgagcctatt tctttttttc tttctttYtt tttttYtttY tgagaWggag 21061 tcttgctctg tcaccaggct ggagtgcagt ggtgcgatct cggatcaatg caacctctgc 21121 cttctggatt taagcaaata ttgtgcttca gcctcctgag taggtctgga actcctgacc 21181 tcaggccatc cgccagcttt ggccttctaa agtgctggga ttacaggcat gaaccaccgt 21241 gcccagccaa gccgagtctt cttgattctt gctggcattt ggcaactagt agcagctgct 21301 cacaggaact gtaaaaacat ctggtggggc ccagaccttc tagcatcaac atggtgccta 21361 gtaaatatca atctcacatg catcctgaga tgcattaaaa agaagctgtc caggccgggc 21421 acgggggctc acgcctgtaa tcccagcact ttgggaggca gaggcgggtg gattgcttga 21481 gcccaggagt ttgagaccag tctaggaaac atggcaaaat cctagctcta tttttaaaaa 21541 gggggggaaa aagaaataaa aaagctgggc atggtggttc acacctgtaa tcccaacact 21601 ttgggtggct gaggcaggtg gatcacttga gagaccagcc tggtcaacac catgaaaccc 21661 catctctact aaaaatacaa aaattagcta cacctcatgg tgcacNcctg tagtcccacc 21721 tactcgggag gctgaggcag gagaatcgct tgaacctggg aggtggaggt tgcagtgagc 21781 ccagatcacg ccactgcact ctaacctggg ctagagagtg agactctgaa aaaaaaaaaa 21841 aaaaaaaaaa gagaaaagaa cataatgttt ggccaggcat ggtgccttac acctgtaatc 21901 ccagcagttt gggaagccga gggggcggat cacctgaggt tagttcaaga ccaacctaat 21961 caacatggtg aaacccatat ctactaaaaa aaaaaaaaaa attagccagg cgtggtggtg 22021 gatgcctgaa atcccagcta cttgggaggc tgaggcagaa gaattgtttg aaccctggag 22081 gcagaggttg cagtgaaccg agattgtgtc actgcactcc agcctgggcg acaagagtaa 22141 aactccgtct caaaaacaaa acaaaacaaa aaagaatcat aatggttagt aagtgaaaat 22201 tctgaattag tttgtgtatg tgtattgttg catataatag agacccaaat taactgtggc 22261 ttaaataaga tagaagttta tttctctctt ctataaaagt ccaagttagt atgatggatc 22321 tttccatgaa atcattagga gccagatttt ttgtatcatt cattcattca ttgattcatt 22381 actaccatta atagagacaa ttttctgcac cattcaggct ggagtgcagt ggtgcaatca 22441 taattcactg taacctcaaa atcctgggct ccagcgattc tcctgcctta gccccaacaa 22501 agtagcaggg actacaagca catgccacca cgcctggcta atttttcttt ttcttttttg 22561 tagaggtggg gtgttactat gttgcccagg ctggtctcaa actcctggcc tcaagtgatc 22621 ctcctgcttc accctcccaa agctctggga tgacaggcat gagccactct gcccctccag 22681 gtctttttta tcttgttgct gttccatccc tagggcgttg ccctcaccca catgatccaa 22741 tatgattcac caccacttcc acagtctggc ccttctgagg ggtgatggtt tgccctttgc 22801 cctaaagagc atgattcaga agtacagatc atttttgctc taatccccat agccaggatg 22861 tagtcatatg gctacatccc gatgaaagtg ttgctgagaa atagaatctc taccctgagc 22921 agctttttgc ccagataaaa gttcagttac tctgggagaa gggtagaatg gatactgggg 22981 gaccataagc tgttgccacc acacacattg aatgttaacc catcccaact gtatcaattt 23041 ttCCttCCtt tCCttCCttC CtCCCtCCCt CCCtCCCtCC CtCCCtCCtt CCttCCttCC
23101 ttCCttCatt CCttCCttCC tttgttCCtt tCtttCgaCa gtCtCCCtCt atCCCCtagg 23161 ctggagtgcR gtgttgccat ctcggctcac tgcaacctct gcctcccagg ttcaagcaat 23221 tctcctgcct cagcctcctg agtagctggg attacaggcg tgctccacca tgcccagcta 23281 atttttgtat ttttagtaga gacaggattt ccccatgttg gccaggctgg tcttgaactc 23341 ctgccctcag gtgatccacc cacctcagcc tccaaaagtg ctgggattat aggcgtgagc 23401 cactgccttg gcctcaaacg gtatcaattt tctgttactg atttaaccaa ttatcataca 23461 ctcagtggtt taaaaccaca cacatttact ttcttacagt tctggaagtc agaagttcaa 23521 aatcagtttc attgagccaa tgtctggtgt cagcagggct ggtttttgtt ggtggctctg 23581 gtggacaatg tttccttgcc ttcttcagct cttttttttt tttttttttt tgagacaggg 23641 tctcgctctg ttacccaggc tggggtgcag tggtgcaatc atagctcact gcagcctcca 23701 tctcccaggc tcaggcgatc ctcccgtgtt agccttctca gtagctggga ccacaggctc 23761 acgccaccac gccctgctaa ttttgtttat tttttgtaga gatgaggtct cactccattg 23821 cccagactgg tctcaaagtc ctggattcag gagatcctcc tgcctcagcc tcccaaaggt 23881 ctgggattac aggtgtgagc cgttgcaccc caccctcttt cagtttagaa aggctacctg 23941 tattccttgg ctggtgggtc catcctccat tggaaagcac atgaatccat ctctgccttc 24001 atcatcactc cactttctcc tctgagactt attcctcctg tgtgcctctt aggaggatgt 24061 tcatgattac ataccgccct cttggataat cctgaataat ctctccatct caggatcctt 24121 cacattttca aaatcccttt caccatataa cgtgacattc acagattcca ggaataggac 24181 gtagacatat ttaggggggt tctctattca gcctactgta ccatgccatt ccacacttaa 24241 ctccttcact catttattca taaaatatgt attgagcaag acctgtgtgc caggcattgt 24301 gttaggtgct agagaaatag aggtgaaaat acagacaagg cctctgcttt catggagttt 24361 atattctagt gaagaggaca agtaaatagc taagctattc tttttttttt tttttttttt 24421 tttgagacgg agtctccctc tgtcgcccag gctggagtgc agtggcgcaa tctcggttca 24481 ctgcaagccc cacctcctgg gttcacgcca ttctcctgcc tcagcctcct gagtagctgg 24541 gactacaggc gcccgccacc acgcccagct aattttttgt atttttagta gagacggggt 24601 ttcaccgtgt tagccaggat ggtctcgatc tcctgacctc atgatccacc cgcctcggcc 24661 tcccaaagtg ctgggattat aggcgtgagc caccatgccc ggccaagagc taagctattc 24721 taagctataa cgtgtattat caaaacaatt aaggccaggc acagttgctc acacctgtaa 24781 tcacaacact ttgggaggct gaggcgggtg gatcatttga ggtcaggagt ttgagaccag 24841 cctggccaac atggtaaaac cctgtctcta ctaaaaatac aaaaaaatta tccaggtgtg 24901 gtggtgcatg cctgcagtcc cggctactcg ggaggctgag gcacaagaat aagaattgct 24961 tgagtgggga ggtggaggtt gcagtgagcc aagatcatgc cactgcacta caggctagga 25021 gacagagWga gaccctgtct taaaaaaaaa gcaattaggc caagtgcagt ggctcatgcc 25081 tgtaatccca gcactttggg aggccaagga gggcagatca cgaggtcaag aaatcgagac 25141 cagcctggcc aacatggtga aaccctgtct ctactaaaaa tacgaaaatt agctgggtgt 25201 ggtggcgcgt gcctgtagtc ccagctactc gggaggctga ggcaggagaa tgccttgaac 25261 ccgggaggtg gaggttgcag tgagccgaga tcacgccact gcactccagc ctgacgacag 25321 agtgggaatc catctaaaaa aagaaagaaa gaaattggct ggagaatcgc ttggacccag 25381 gggtggaggt tgccatgagc tgagattgtg ccactgcact ccagcctagg caacaagagc 25441 aaaactccgt ctcaaaaaaa aaaaaaaaaa tcccagcact ttgggaggcc aaggagggca 25501 gatcacgagg tcaagaaatc gagaccagcc tggccaacat ggtgaaaccc tgtctctact 25561 aaaaatacaa aaaattagct gggtgtggtg gcgggtgcct gtagtcccag ctacttggga 25621 ggctgaggca ggagaatggc atgaacctgg gaggcggagc ttgcagtgag ccgagatcac 25681 accactgcac tccagcctgg gcaacagagc aagactctgt ctcaaaaaaa aaaaaaaaaa 25741 gaaaagaaaa gaaattaaac agtgtgatgt gacaaaaagt gatagggggt tggagacagc 25801 ttttctgttg gatggttagg aatggcttct tagaaaagat gactgacaca tgggaggctg 25861 atgtggcaga tcacgaggtc aggagatcaa gaccatcctg gctaacacgg tgaaaccccg 25921 tctctactaa aaaatagaaa aaattagccg ggtgtggtgg cgggcgcctg cagtcccagc 25981 tactaaggag gctgaggcag gagaatggcg tgaacccggg aggcagagct tgcagtgagc 26041 tgagatcacg ccactgcact ccagcctgga cgacagagcg agactccatc tcaaaaaaaa 26101 aaaaagaaag aaaagatggc tgacacagag ggcagagctg agagccaaga gggcagaaaa 26161 gagccataga aaaccatttc caggcctgga agcctaaagg aatttcccag ctggatttgc 26221 agttgctttg gattggtgac tcctttttac ctttcattgt taggggacct gcaggttcct 26281 ttgcctgctg tgcagctaca gctccattac accaagacaa tagggatgca gcagagagag 26341 ttactggtgc agggcaccta gtgcagagat gggaagaggc cctcaaatct atctccccga 26401 gcaattctgg gagagggttt ctaaggggac tgtggagggt aggggattgt ggagggtaag 26461 gttttgggca actgggtcat tgattgattg ggggaaggat gtagaagctg cgtttttggg 26521 ggaattagct ccttgtgggg tccttcaggt cagctgagtc agtagttcca tgaggacctg 26581 aaggaatctc ttttcttttc ttcttcttct tctttttttt tttttttttt gagatggagt 26641 ctctctctgt cgccaggcta gaggtgcagg gggtcgcagg ctagaggtgc agtggcatga 26701 tcttggctca ctgcaacctc cacctcccgg gttcaagcaa ttctcctgcc tcagcctccc 26761 aagtagctgg gactagaggt gcgtgccacc acacccagct aatttttgta tttttagtag 26821 agacagggtt tcaccatgtt ggccagggtg gtctcgatct cttgacttcg tgatcggccc 26881 ccgccccacc ctcggcctcc caaagtgctg ggatcacagg agtgagccac ggtgcccagc 26941 cttaattttt gtattttcag tggagacggg gtttcaccat gttgatcagg ctggagtgca 27001 atggtgcaat cttggctcac tgcaacattc gcctcctgga tttgaatgat tctcctgcct 27061 cagcctccca agtaactggg attacaggaa tgcgtcacca cgcccggcta attttgtatt 27121 tttttagtag agacggggtt tcaccatgtt ggtcaggctg tcttgaactt ctgacctcaa 27181 gtgatccacc tgctttggcc tcccagagtc tgaaggaata tctcaaaggg aacacttaat 27241 gttgtgtaat gtccaggttg tgatccatag agcagttaaa ggtaaaggta actataattt 27301 tttttttttt tttttagaca gagtctccct ctctgtcacc caggctggag tgcagtttca 27361 cgatctcggc gcactgcaac ctccgcctcc ctggttcaac caattctcct gcctcagcct 27421 ctcaagtgtg tgctgccatg ccaggctaat tttttttttt agacggagtc ttgctctgtc 27481 acccaggctg gagtgcagtg gcacaatctc ggctcactgc aacctccggc tcctgggctc 27541 aaacaatgtg ttttttcccc tagtactttg gtgtttgatt atcttttttt tttttttttt 27601 tttttttttg agatagagtc tcgctctgtc acccaggctg gagtgcagtg gtgcaatctt 27661 agctcactgc aagctctgcc tcctgggttc atcccattct cctgcctcag cctcccaagt 17'~

27721 agctgggact acaggcaccc accaccacgc ccggctaatt ttttgtattt ttagtagaga 27781 cggggtttca ccatgttagc caggatggtc tcgatctcct gacctcatga tctgcccgcc 27841 tcagcctccc aaagtgctgg gattacaggc Rtgagccact gcacccagcc tggtgtttga 27901 ttatctatta tgtcaaacag gctgggttta gtggctcacg cctgtaatcc cagcactttg 27961 ggagactgag gtgggaggat cacttgagcc caggagctga agaccagcgt agcaatgtag 28021 caactccctg cctctacaaa aagttaaaaa atttagctgg gtgcaccagY agaccagctc 28081 ctcaggaggc tgaggaggga ggatcactcg agcccaggag ttcaaggctg cagtgagctg 28141 tgatcatgcc actgtactcc agcccaggca atggagcgag accctgtctc aaaataaata 28201 aaacatgaag aatgtcgaac acattatctg gtttttgttt ttgttttctt tttttgagat 28261 gttgtctcgc tctgtcaccc tggctggagt gtagtggtgc gatctcggct cactgcaacc 28321 tctgcctccc gggttcaagc gattctcccg cctcagcctc ccgagtagct gggactacag 28381 gtacgtgcca ccatgcctgg ctaatttttg ttattttttt tttttcagta gggacagggt 28441 ttcgccatgt tggccaggct gttctgaaac tcctgacctc agatgatcca cccacctcgg 28501 cctcccaaag tgctgggatt acaggtgtga gccatcgtgc ccggcctgtt ttaaaaaacc 28561 atattggccc aactcggtgg ctcatgcctg taatcccagc actttgggaa gccaaagcag 28621 gaggattggt tgagcttagg agtttgagac cattctgggc aacatggtga aaccctgtct 28681 ctgcacaaaa atagaaaaat ttgccacctg tgctggtgtg tgcctgtagt cccagctact 28741 ctcaaggctg agggaggagg attgcttgta gagcctggga agtcggagct gcagtgagcc 28801 atgatcacac caccacactc tagcctgaca gaatgagacc ttatcccaaa agaaaaaata 28861 aatgatattg tattatatgt gaactttgaa ttatattgtg ttgtatctga agtttgaatt 28921 ttcacgttat gtttaaaaat cttggctggg cgtggtgggt cacgcctgta atcccagcac 28981 tttcggaggc caaggcgggt ggatcacctg aggtcaggag ttcgagacaa gcctggccaa 29041 catggtgaaa ccccgtctct actaaaaata caaaacttag ccgggcatag tgacatgcac 29101 ctgtagttcc agctactcgg gaggctgagg caggagaatc gcttgaaccc aggaggcaga 2916T ggttgcagtg agctgagatc gtggcattgt actccagtct gggcaacaag agtgaaactc 29221 catctaaaaa ataaaaaaga aaaagaaaaa ataatacaag aaattagccg ggcgtggtga 29281 caggcacttg tagtccctcc cagctactca ggaggctgac gcaagagaat tgcttgaact 29341 tgggaggtgg aggttgcagt gagctgagat cgtgccattg cactctagcc tgggaaacaa 29401 gagcaaaact cagtctcaaa aataaatagc ttgaacccgg gaggcagagg ttgcagtgag 29461 ctgagattgc accacttcat tccagcctgg gtgatagagc aagactctat ctctaaataa 29521 ataaataaat aatcctttag gatggcaatg aatttaagga ctaaactagg gagaatcgac 29581 tttttttttt aaaatggagt cttggtctgt cgcccagact agggtgcagt gggcgccatc 29641 tcggctcact gcaacctcca ccttccaggt tcaagggatt cttgtccctc agcctcccaa 29701 gtagctggga ttacaggcac ccgccaccat gcctggctaa tttttgtatt tttagtagag 29761 atggggtttc accatgttgg ctatggttgg ccaggctggt cttgaactcc tgacctgagg 29821 tgatctgcct gcctcggcct cccaaagtgc tgggattaca ggcatgagcc actgtaccca 29881 gcccattcga cattatttat ttatttattt atttatttat tttttgaggt ggagtctcac 29941 tctgtcgccc aggctggagt gcagtggcac aatctcggct cactgaaacc tccgcctccc 30001 gggttcaagc cgattctcct gcctcagtct cccgagtagc tgagattaga ggcaaccacc 30061 actatacccg actaattttt gtatttttca gtagagatag ggcttcacca tgttggccag 30121 gctggtctcg aactcctgac gtcagttgat cctcccacct cagcctccca aaatgctgga 30181 attaaagctg taagccagcg ggcctggtgg acatctttta ataatcagtc tttccattca 30241 ggtatatggt atatgtctcc atttacttag gtcttatttc atatccttca ggttggagct 30301 atcatttctt ttcatacagg ttttgcacat ttcttgtgag gtttattcct tcatggtcca 30361 tggattttgt tgtgaattgg gaatcctttt tccaccaagt atattttcta atttgttact 30421 ttagtataca ggaaagataa ctaattttta tctgcagttt attatctatg aaaggataaa 30481 agtagaacta ctcagtaaaa ggtttccata atcaaataag tatgggctaa acaaagctaa 30541 acagatgtgt tcactgctgg acttatcaat gcttgtgata attttttttt ttttttttga 30601 ggcagagttt tgctctgtag cccaggctgg agtgcagtgg cgggatcttg gctcactgca 30661 acctccacct cccgggttca agtgattctc ctgcctcagc ctcccgagta gctgggacta 30721 tggcatgcac caccacatct ggctaatttt tgtaatttta atagagacag ggtttcacca 30781 tgttgactag gctggtctca gaactgttga cctcaggtga tctgcctgcc tcagcctccc 30841 aaagtgctgg gattacaggt gtgagccacc accaccaggc aattgaagac gtatattcta 30901 tgaagaaatg ggtagatttt aatgaacaat accccttttg tgggcagatt cctaagtccc 30961 aggccctcac aacaaagggg cagtgggcct ggagatgcca gcttcagctg ccagagggac 31021 tgctcctcca gggccacccc agcccacttt tgatcaccaa gttttgatca ccaagaatcc 31081 caagaagggc acagggaatt tcctttctta cctgcccatg aaaccttttg tcactagaca 31141 tcctgaaaca tactttggga aactgcatcc aaagaccctt ctagtttcaa atctgtggat 31201 ccaggggtct ccactgaacc ttacctgatg cccaaactcc cacccattca ctcccaacca 31261 gaacacagaa gatgacctgg tgccaaaatg aaagctttaa tgagtgttac tcctagacag 31321 tcacgtctca gcttctgcca gcctccactg tcccagctct cttagctggc cgacagggga 31381 gctagttgct gaggggtagg gatctggagt ctaaagagca gagccaggca aaaggaggta 31441 caggaagccc ccgatggggg ctgggctccc ggagtgtggt gctggggggt catgggcttc 31501 aggccggccc ctcttcaggc attcctagca aagccaccag gggctccagg ggtgtggggg 31561 tccccatggg cacagggtgg gtgcgttcat gcttgcgcaa gtcgctggca ctcaagaagg 31621 ccttgggaca atgggggcag gtgtaggggc gcactgagct gtgagtgcgg ctgtgtttgc 31681 gcagcccagc ccggtcagag aagctcttgc cgcactRggt gcaggggaag ggccggagct 31741 ccgggtgtga gcgctcgtgc cgacgcagca gcgtcattgt ggagaaggtc tccttgcact 31801 ctcggcacac aaactggggg ggcttctcgt cagcctcctc accccccgcc tcgcctgccc 31861 cttccaaggg accaggagcc tcccggacac cagcatcttg gcattccaca tgctccaccg 31921 tcatgcccac cacctgccac tgtgtggcca tcacaccacc tgactccggg ggcagcccta 31981 gcagccctgc tggagggtcc cccagccccg cccctgctRc cggggcggct gaactctcac 32041 ctgccacgcc cacaggcagc gccaacccca ccaccagctc ctgtgcaggg ggcacacccg 32101 cggcctcact gcttcgatgg gtccgctcgt gcttcctcag gctcgacgac accacaaagg 32161 atttcccaca tgcgttacag tggaaggggc gctcccccga gtgcacccgg ctatgcttcg 32221 tgaggctggc acgctcggcg aaggctcgcc cgcactcctc acagcggaag ggccgctggc 32281 cagagtgcac cagcgcgtgc cgcttgaggt cccaggaYgc cacgaacgtc ttgtcacatt 32341 gcaggcactt gaacggccgg tcgcctgtgt gcacacgccg gtgcatggcc aggtccgccg 32401 gctgccggaa gtccttgccg cacttctcgc agtggtatgg cttcacccct tcatgggcgc 32461 gctggtggcg acggaagctc gaggggtcgg agaacatgcg gccgcagcgc gggcacagga 32521 agggcttctc ccccgagtgc gtgcgctcgt ggctctggta ggaactgagc tgcgtgaagc 32581 ccttgccgca ggccgggcag cggtagggct tctgtgccgc gtggatgcgc tggtggcacg 32641 tgagcgagga tgagcgggag aagctcttcc cgcactcgga gcagaggaag gggcgctcgc 32701 cggtgtggga cctgcggggg tgtggaggac ttggcatgaa ggcgacagac ccataacgtg 32761 accccactgc ctgtctgggc tgtactttag gggctcccca aacgttcgtg ggggcctagg 32821 cttaatcccc taagagccac atggctgcac cccagaggaa gaagccttca ggctggctgg 32881 gtgtctctat tccaaagacc tgtctctgca cattaaagac caagatatgg gccgggcgcg 32941 gtggetcacg cctgtaattc cagcactttg ggaggccgag gtcaggagat cgagaccatc 33001 ccggctaaca cggtgaaacc ccgtctctac taaaactata aaaaattagc caggcgtggt 33061 ggtgggtgca tgtagtcccR gctactcggg aggctgaggc Rggagaatgg cgtgaacccg 33121 ggaggcggag cttgcagtga gccgagatct tgccactgca ctccagcctg ggcggcagag 33181 cgagactccg tctcaaaaaa aaaaaaaaaa aaagaaaaag aaaaaaaaaa aagaccaaga 33241 catggccagg cgcggtggct cacgcctgta atcccagcac tttgggaggc cgaggcgggc 33301 ggatcacctg aggtcaggag ttcaagacca gtgtgaccaa aacggagaaa ccccgtctct 33361 actaaaaata caaaattagc cgggcatggt ggcgcatgcc tgtaatccca gctactcgga 33421 aggctgaggc aggagaatcg cttgaacccg ggaggcggag gttgcggtga gccgagatcg 33481 cgccattgca ctctagcctg ggcaacaaga tcaaaactcc gtctcaaaaa acaaacaaac 33541 aaaaacaaaa caaaacaaaa cagaaaacca agatacgtgt cctccgcctt ttttttcctg 33601 ttccccaggc tggaatgcag tggcctgacc atagctcact gcagcctcga cctcccaggc 33661 tcaggccatc ctcccacctt atcctcccaa gtacccggga ctagaagtgt acatccccac 33721 gctcgggtaa tttttttatt tttatagaga cgaggcttgc tgtgttgccc aggctggtct 33781 tgaactcttg ggctcaagca atcctcctgc ctcagcctcc caaagtgctg gaattatagg 33841 cgtgagctat tgtgcccagc ctagaaacat gtcattaatg tagaggctga gaaaaagaaa 33901 aaaaaaaatg acctagacaa accaggcccc actcacacct cctggtctcc acaaaagacc 33961 ctcagaactg cccaactcca aaccccgccc cctttccagc tggcctacaa cggaggccaa 34021 tctgacccaa tcccattctc agagatcaac ctcaaggtgg ttgccacctc tgcccaatca 34081 ggggcaccaa tttctcccac atgcctagcc cctccccttg gatctgccat gcccaccttc 34141 ccattggctc actttaccct gagactcaaa cccaggcccc attggctgca gcaacgctgt 34201 cgccctgccc cggaaggcgc cctgccccgg aaggcRCCCt caccgctcat ggttgcggag 34261 gtccttgagc tccgcatagg ctttRccgca acgctcacag ctgtagggcc gcaggccagc 34321 gtgagtacgc cggtgcttgc ggaacactga agggtcagca aagctcttgc cgcagtcggc 34381 gcaggcgtaa ggccgctcgc ctgtgtggcc acgctggtgg atcttgagct tggagagcgc 34441 gccataggcc ttcgggcagt gcgcacagcg gaagggcagt tcgccagcgt gcgaggccag 34501 gtgcacgcgc aggcacacgg gctgcatgaa gcggcggccg cactcggggc acggaaaggg 34561 cttctccccc gtgtggctgc gcccgtggct gcgcagctcg ggtgccgtct tgtaggcctt 34621 ggggcatagc ggacacgcat agggcctagg cttggccgcg gagcctgaca ccttctcccc 34681 actggcttcc tctgccttag cttctgtctc tggctttggc ttcacctcgg CCaCCtCttC
34741 agagcagtct gccggcccat gtgtggcagc gtggcgcgct gccctgggcg cgtttggaaa 34801 tgtcttggta caggacaSgc acttgtagcg gcggcccgag cgcttgtagc cgggggctgg 34861 ggaccgggcc tctgcagcct ccacttccat ggccttggtg aacggggttt ctctgcaaga 34921 gaagcaaagt tagaccaaag ccacatacct tcgccactcc tgaaagcctc agagagaacc 34981 ctatctcatc tgcatttctc acctcggaac ccacacatcc ttcctgccca gcattcctgg 35041 ctctgacatc ctgcgttcgt ttcctccctg atctgctcat tgaagaaagg agttggacca 35101 agtgtccgca gagccactaa gaaaggaggc tgagggtcac aaaagattca cctacacgtc 35161 cccccccScc cccaacgggc ttttccaaac actgtggcat tcccagaggc ccaggttcca 35221 tctgtctcac catcttcctt cttcagctca gtgtccaaga actatgccag gataaagagt 35281 gtacccagac gtgggcctgg cctgaaggtc tccaagcgcc cagaaaagac agacctggga 35341 ccagaaaagg gctgagccaa tgggctaaat ctggtagctg gcactgtctg gaagtgacag 35401 gtccccagca tttgtgtttt ctttcctcct ctggatggtt agtcctcaga gacagcaact 35461 gttcacacag aattctggcc ttgcacagct gtacgggcct ccgccccaga ctggaatctg 35521 tccactctct gctctggaat cttgttggcc tgttcccaca actctggtaa tggagaatca 35581 ctcaaggcag cctgagccat tgctagcagc tggaagcctc tttctgagtc ataactgatg 35641 tatctgatct aacatggcct cctgggatac cagctctagc tgagatccct actttctggt 35701 ccagaaccca gacgccctcc acccagctgc tcctggggat catggttggg aggaaacagg 35761 attaatggct gtattagtct taacaccagc tcatcctccc tgggggatga agggaagagg 35821 attatggcag atccacttaa ggagtgctca gcagctgctg ctgggggaag gggtctgagg 35881 agtgggggct gcagggagcc aggtgtgccc agaggctagg gggcctacgt tctacttgca 35941 gccctgtgga ttactatgag acctcagtga aatgagtgtt gtttataaga ctatttccgc 36001 ccggctgggc gtggtggctc acgcctgtaa tcccagcact ttgggaggcc gaggggggcg 36061 gatcacgagg tcaggagacc gagaccatcc tggctaacac agtgaaaccc cgtctctact 36121 gaaaatacaa aaaaattagc cgggcgtggt ggcgggcgcc tgtagtccca gctactcggg 36181 aggctgaggc aggagaatgg tgtgaacctg ggaggcggag cttgcagtga gccaagatcg 36241 tgccaccgca ctccagcctg ggcgacagag caagactccg tctcaaaaaa aaaaaaataa 36301 aaagactatt tcctcatctg gacacgttag gggttggtgg cttctaagtt atgacactgg 36361 ggttcaggag gaggaaactg agctgagcca cgagggtgct aggggaaata cagagactca 36421 gggcccctta tgccaggaaa gggcgggaga agcagcttac ctggttgacc cagggaggac 36481 acaggagccc ctgacgcgtg gcaagggcca catccttaaa gtcagcaccc ttctgcctga 36541 aatcccggcc tcaggcctgc acgctgccct ccctccccaa ccccatgcag ccggtcttct 36601 cccaaaagta atgaatgatg tttcctgttc cctgctcaag aactttccat ggcttccacc 36661 acaccatgca aatccccagg tccttcctgc ttgttccaaa tctgacaagt ccttcactgg 36721 agccccactt ccaccaggag gatcctcaag catctcccct ttgggtttgg ccccaatccc 36781 acaaaactcc atcttattct cacttggtta tttcactttt cccactaaat cctagggctt 36841 agccaggtgt ggtggcatgc gccttaagtc ccagctacgt gggaggctga ggcgggagga 36901 tcctgtgaac ccaggggttc gaggctgcag ggaactatga tcgtaccact gcgctccagc 36961 ctgggcaacc tggtgagacc ccatctctac taaaaataaa aattagcaga tgtggtggca 37021 tgtgcctgta gtactgccta cttgagaggc tggggtggga ggactgcttg agcccaggag 37081 ttcaaggctg taccactgca ctccagcctg ggagacaggg caagacactg tctcaatcaa 37141 tcaatcaatc aataatcaat cctggggctt gaagataagt taaagggact gaattctaac 37201 ctttctgatg acttgaattc ttcctacagt ttccaaggga tccctcccta tttctggatg 37261 aggtactcac tacctcttcc agacggtttc tggagagtct gcctgataat gttcctcctt 37321 aataaaaatg atagcttggg ccaggttcag tggctcacac tagcactttg ggagaccaag 37381 gcgggtggat cgcttgagcc caggagttca agacaaggcg ggtggatccc ttgagcccag 37447. gagttcaaga ccagcctggg cgatatagca aaatcccatt tctacaaaaa atacaaaaat 37501 tagccaggca tggtggagca tgcctgtact cccagctact ccagaaggct gaggtaggag 37561 aaatgcttga gcctaaggag actgaggttg cagtaagcca agatggtgcc actgcactcc 37621 agcctggcaa cagagtgaga ccccatctca aaaataaata aataaataaa tgataaaaaa 37681 gatagttcac atttactgag cactcgccaa ataccaggca gtatcctaaa ctccttatgt 37741 gtattagctc agttaccctt catggcaacc ccatgaggaa agttctatta ttccattttc 37801 acagataagg gaaccaaggt ccagagaaat ggttcagtat tttgttaagt gcccagtccc 37861 tgaagccaaa ctgtctggct tcagattttg cctccatcac ttcccagctg atgtgaccgt 37921 gtgtaatgta ctgcatgtct tagaacctca gttttctaat ctgaaaaatg gagataatga 37981 Yagtacttac ctgacagagt tgggtgagga atgaatgagt caaaaataat tactgtcctc 38041 aattatcaaa gcgtcttctt agagccagac acattgctgg gtgtgctggt ttatttaatt 38101 taatgtctta taScttYctg agatagggat tcttgtccct actttacaga ggaataaatc 38161 gaggttccaa gagttaagtg acttgcccat ggtcccacaa tgggtaacct aagcagctgg 38221 gacttcagtc caggtgttta atttgcctta agttgctggg gtcttgctca gtggtctggg 38281 gcctcttacg cttgtctgct gcctccgcca gccccacagt gaccagaacc ctgagctcag 38341 gtcatacctg tgtcttctct catccttgca gaactgccct gagaccctgg ccggcaccct 38401 ttatgtctct gcttccctct cagagggctt gacccagtgg ttctgagctc tggcccttct 38461 actgcctctt gccagctctg ICgtctcagcc ttcctatctg tgagttagac accaggtagc 38521 tggaggggaa atccctcctc ccatggcact tcccagggga aaaggtaggg gagtgccagg 38581 ttggtctcag catgcgccca gctacacaaa gaggScaggt aggctaggtc tctgtctaac 38641 atcccaccat taaaaaaaaa aaaaaaaaaa atatatatat atatatatat atatataatt 38701 tttgagatgg agtcttactc tgttgcccag gctggagtgc agtggcgcga tcttggttca 38761 ctgcaacctc cgcctcctga gtagctggga ctacaggcac ctgccaccac acctggctag 38821 ttttttgtat ttttagtaga gacggggttt cactgtgtta gccaggatgg tctcaatctc 38881 ctgacctcgt gatccgaccg cctcggcctc ccaaagtgct gggattacag gcgagagcca 38941 ccaMgcccag actttttttt ttttttttat taaagagctt gaggtaggcc tcaggaatct 39001 gtattttaaa tacactctgg atcattccag ccaatacttt tgtttgtttg gttttgaaac 39061 aagatctcac tctgtcgctc aggctggagt gcagtggtgc agtcatggct tactgcagcc 39121 ttgacttccc agactcaagc aatcctccca cttcagcctc ccaagtagct gggactacag 39181 gcatgcacca tcatgcctgg ctaattttta ttttattttt agtagagatg aagtcttgct 39241 atgttgcctg ggctggtcta gaactcctgg gctcaagtga tcctcccMcc gcagcctccc 39301 aaagtgctgg gattacaggc gtgagccacc gtgcctgccc aaccaatact taagaaccaa 39361 acacacatcc ttaggtctcc acgagctctc aggagaggag cattttaagt gttcactaca 39421 cctctttttc agatattgag attaaggtcc ccacaaagga aaaactgtac acaaggacac 39481 acagctggtc aaggagccag actcgaaccc aagtctccat tctctccccc aggttgaatc 39541 atgagacttc ccactgctcc caggaaaaag accaatatct tttccatggc cagcatagcc 39601 ccaaaccatc taaatcctgc ctacctgggc agatcacttg aggccaggag tttgagacca 39661 gcctggccaa catggtgaaa ccccatctct actaaaaata cacacacaca cacacacaca 39721 cacacacaca cacacacctg cctacctcac ctcccactcc tctccctggc ccactgggct 39781 ctacccacag aggcctcctt tcttctcctc aaagagctaa attccttccc acctcagggc 39841 agtggcacta gcagttccct ctgtctgagc cactcttctc ccacgatctt tgtgtagctg 39901 tcttttttgg tgttatttgg atctcagctc ccagtcacct cctcaaaaag agctttcttg 39961 accacctttc cttttcttcc ccccttttaa tattccaaat tttttccttt tttaaccaac 40021 caaggagcac tgaatgacta cctttctcaa tgctatcttt acccctgata atcattctct 40081 atctactctt tattattatt attatttttt gacggaatct catgattatc tatcaagcag 40141 ttctcctgcc tcagcctcct aagtagctgg gactacaggt gcccgccacc acgcccggct 40201 attttttttt tttttttttt tttgagacgg agtctcactc cgtcacccag gctggagtgc 40261 agtggcacaa tcctggctca ctgcaagctc cgcctcccgg gttcatgcca ttctcctgcc 40321 ttagcctcct gagtagctgg gactacaggt gcccgccacc acgcccggct aattttttgt 40381 atttttagta gagacagggt ctcactgtgt tagccaggat ggtctcaatc tcctgacctc 40441 gtgatccacc tgcctcggcc tcccagagtg ctgggattac aggcgtgagc cactgcaccc 17~

40501 ggcccaatcc cggctaattt ttgtattttt agtagagatg gggtttcacc atgttggcca 40561 ggatggtctc gatctattga cctcgtgatc cgcccgcctc ggcctcccag agtgctggga 40621 ttacaggtgt gagccaccgc gcccggccct ttttttgaga cggagtctta ctctgtcccc 40681 caggctggag tgcaatggca caatatctgc tcactgcaac ctccgcctcc cgggttcaag 40741 cggttctcct gcctcagctt cccgagtagc tggaattata ggcgcccgcc actacatctg 40801 gctcattttt gtatttttag tagagagagg atttcaccat gttggccagg ctggtcttga 40861 actcctgacc tcaagtgatc cacccacctt ggcttcccaa agtgcttgga ttacaggcat 40921 gagccaccgc acccagccct ctttactttt taaaaaatgt ttttattttt atttatatat 40981 ttatttttga gacagagttt cactcttgtt gccaaggctg gagtgcaatg gcaccatctc 41041 tgctcactcc aacctccgcc tccccggttc acgagatttt cctgcctcag cctcccgagt 41101 agctggaatt acaggcatcc accaccacgc ctggttaatt ttttgtattt ttagtagaga 41161 tggagtttca ccatgttggc caggctggtc tcgaactcct gacctcagat gatccactgc 41221 ctcggcttcc cagagtgctg ggattacagg catgagccac cgtgcctggc ttatttttat 41281 ttattttatt atttattgtt attattattt gagacagagt ctccctctgt tgcccaggct 41341 ggagtgcaat ggtgtgatgt cagttcactg cgacctctgc ctccYgggtt caagcaattc 41401 ttctgcctca gcctcccaag tatttgggat tacaggtgcc tgccaccaca gccagctaat 41461 tttttgtatt tttagtagag atggccatgt tggctaggct ggtctggaac tcctgacctc 41521 aggtgatcca cccaccttgg cctcccaaag tgctgggatt acaggcttga gccaccatgc 41581 ccggcctatt tatttcattt ttatttattt attttctttg agagaaagtc tttgttgccc 41641 aggctggagt gcagtggctg catctcagct cactgcagcc tccacctccc ggattcaagt 41701 gattctccag cctcagcctc ccgagtagct gggactacag gcgaaagcca tcacacctgg 41761 caaacttttg tatttttagt agagacaggg tttcaccaca ttggccacgc tggtctcgaa 41821 ctcctgacct caagtgatcc gaccgcctca gcctcccaaa gtgctgggat tacaggcgtg 41881 agccaccgtg cctggccttt atttttattt agagattggg tctcactctg tcaccctgga 41941 gtgcagtggc tcaatcatag ctcacttcag cctcaaactc ctgcactcaa gcaatcctcc 42001 tgagtagcta ggactatagg cacccaccac cacacctcgc taatttatta aaaattcttt 42061 gtatatagag atggaggtct cactacgctg ccgacagtgg tctcaagaac tcctggcttc 42121 agatgctcct ccactWtggc ttcctaaagt gctgtgatta caggcatgag ccacagtgac 42181 cagcMcccct cctctctaat ttcctttatg gtgtcatctg gacaatactc cttgcaagct 42241 taccatgggc aaggtatcat tctaagcatt ttgtgcataa tactcaacta ctcaagccaa 42301 ctgcacagct gcctagcagt tcattatgag tgaatgtttg tgttccctgt ccRttcatat 42361 attgaaattc taactctcat tgtgactgta tttggagaca aggcctttat ggaagtaatt 42421 aaggctgaat gacRtcataa gggtatggcc ctggtccagt aggattagcg ttcttatgag 42481 aagtgacacc acaaagaaac aagcttacta gtcacggtcc cagccagtgt tcaaatccca 42541 aacacctgct ctctgagccc tgactattgc tttgctagca ttacacatct tatggtttgg 42601 ctgttaattc ttcatcacca gcaccagagt ccaggctggc aaagggctag gaaaccgatc 42661 atctgcctcc tctacaccca gaaccctgtg tggtgaccca aaacaaatgg aaagaaccaa 42721 cctcagatga aatttgaacc caggtctgta gcctctgcct cctccacagt aggagtttgt 42781 gagaatgtcc accaataact gtttattaac taaattcctc cacctttcca actccacaag 42841 gctcaactat tgccccaata tcccacagtg ggctccctgt cgtggcgatg aagccttgct 42901 ttgcctcact actggcttag gaaggggatg aagttctgct gtctcactag gcaagcaaag 42961 attcaatttc caaaaatcct aggctaggac cctggggcag ggatgaggag aaaaaggagg 43021 cacctcaatc ttcccatctc taaacaagca gtcaccacac aggcctcacg gccaggagtg 43081 acgtagtgag cggatgaacc ctgcagaagt gagcgctaat catatcctag gcctcctacc 43141 gggccagttc acaacctgat cccaacctac ttttccagcc tcagctccag cgacagagtc 43201 ctcctcccgg cagcgaccga acctccagcc acaattctca atcctccacc tctagatgca 43261 gtttcctggg ctcggggagc ccttgcctgc cttctccaac gggaaagccc ctttacatcc 43321 ttcaagaacc cccttcccta gtgccctcag gaatacttta tggcagtaga gaggtaaggg 43381 ccccacgccg ctctggacct cagtttcctc atcagtaaaa tggggtccct taagtttgtg 43441 ggagtttgaa gggcggtggg gcctacgaag cgcgccgagg agccgagagt tgcagaaacc 43501 cggagctcct cgctcctcgc aaccgtctgt acgcggcgcc cccgccagcc aggcagcccc 43561 tggagggcag gaccccggtt ataagcctca gaaaacgtgg cttcggagga cgtggcaagg 43621 aggactgaac gaaggatgag gagatgaaca aatgaatgga cggaaggccg aatgagggac 43681 aaaggcttgc aagatggcgt tctctaggac cgcgggagtg gtggccgggc ctcagcaggg 43741 gagggggccg ccggcgcctg ggatcttgca gcgcgggcca cgcgaccggg acaaaaaccc 43801 aaaacatggc gggctctagg acccccggga ccacaccgcg ccgggccagc agccgcgcgg 43861 gccgagcctg ggtgtccgca gcccagaacc gcggagacag ccggcgggtt ctaggacctg 43921 ctgggcccgc aatgcgcccg gggccgctca cagcccgccc cgcccgcgct gctcgcgctg 43981 ggccaacccg gcccgccctc ggcgcccgca gggaaactga ggccagctcg gatcgtggcc 44041 gcgtgggagc tgcccggggc cctcgcggct tcccgccgac gtttcctacc tgatgagact 44101 tgtgctgact ccgtggcgtc ggcgtcggct cctcgcaccg acggagcccg gaccctgcca 44161 aacaggggcc ggcgctagga cccagcgggg ggcggggagg tgggaccggt ggcgcggcga 44221 gcggaagtga gggatcttcc tcagctagga aggaagggaa agttcccggg gaacctccag 44281 cctatggcgg cagagaagca tcttgcaaga ggtctctgtg tgtgctgagg caaggggacg 44341 ccaggcaggc tgacggtata cgcccgcctt gtgttagtct ggggccaggt caccggcaat 44401 gtcttcaaga accagaaggt gggaggacaa aaaggccatg ctcaagctct gcaaaaccta 44461 agtccaatta tattccacaa catttccttt aatagcaagg agtgggtttc acgaagtttt 44521 ctccatctgc cttgggaaaa gtcctccaga gagccccacg aaaagtgtca ccaaagtacY
44581 gtggccaggg ctgtagaatc tttttctccc tttctgcgcc tattcaatat gcaccggaac 44641 gattctagct gctcttgccg gaagtgtggc tagcWtagcg tgcaaagacg ccgcgttgtg 44701 acctacgtgg gcggagtcag ccgtgcagac ctagaactta gcgccggaag tgtgtctgcg 44761 taaaactgcg gctcggaggc gggacaggca gtgctcccga agcggaagtt tcgcggggaa 44821 gcttttgcac ctaaggacac ttcctgtttc ctagtaacaa taggaagtgt ccgtagagct 44881 gggagtagac tcctggctca tgccagctgc gccctctttt ctctacctcc ttcctcttcc 44941 ccccttctcc tttccctctt tcccttccct cccacctccc gggaaccctg gctgagtgtg 45001 cgtgtgtggg agcgcgagag ccccccgaca gccacccctt ggggcgcgcg gctgcagtta 45061 gggtaagggt cccagtgcgc aggcgcgctc ttgttcgcgg tccccaactg acgcgcccgc 45121 ggcgggaagg agagggggcc gccggtgcga ggtaggcgtc ctgagaggaa attggcagac 45181 gagatgagtg aggtcagagg acttcattgg tggttgacta ggggagggga cttttgatca 45241 aaggggcttt gtgaggtgag aattccgggg gcaggttcag tgaaggggtt tacggtcgga 45301 gacagttgta ctggggtccc atgggaagaa gagtcagagt tggagaagga caagacgatg 45361 tagggggcat gagagagcaa gggctttggg atgaagaccg cctcagtcag ggggtttgct 45421 gttacgtgaa ctagaataac aggcattgcc gtgtgttctg aggattgagt aacacaatga 45481 atatagttag cacagtgcct ggcacatggt aatataatac tcttcatgag ttgctgtcat 45541 catcagtatt aagagaggag gcagaagaaa aaaatgagaa agactggtga gggtaagatc 45601 aggaggcatg ggagagaaaa ggtaggcaat gaagtgacat tacaacctgg tattgatgtt 45661 attcccaaga tggaagatag tttgagttca agggaagtag ataaaagaag tcgctaagag 45721 agtcttttgg ggttttttKt ttttttgaga tggagtctcg ctctgtcacc caggctggag 45781 tgctgtggtg ggatctcagc tcactgcaac ctccacctcc caggttcaag cagttcttca 45841 gcctcagcct cctgagtagc tagaattaca ggtgcccacc accacgcccg gctaattttt 45901 gtatttttag tagagacagg gtttcaccat gttgtccagg ctggtcttga actcctgaac 45961 tcaggtgatc caccagcctc ggcctcccaa agtgctggga ttacaggcgt gagccaccac 46021 acctggccca gttaagagag tcttaactct cttaactctc ttgtcacaag gaaaagagac 46081 cttgtgacac tgaaatgact cggggtggtg ggggaacaag ccagcccttt ccctgaagga 46141 ggcctctaac ctctcctctc aggtcctcag ctattaactg gaggaaacag ctgctttttc 46201 agtgcttctc agctactctg tttagctgag agatgaagta ggaagatttg gacttctctt 46261 attgaaaggc ctagagaagg ttttggtgtc cttttaagat gtcacagaaa atttttgttt 46321 caggattgta gggagcagat tcctactgtt cttaaaggac agtaatgcct tttgagtctg 46381 gtctgaagaa cataacaggt ctgtgatcag aagtaggttg catctctctc aactttaaYt 46441 tccttagcta tacctgtagg gatgacttaa gcctagggga gctcctatat ttgggaagct 46501 tgtgcacagg gaagccttaa atgatggtgc ctgcagattg gatctagtag aaattaggtc 46561 cttgggcatg gatgcttggg gaacctctca gtgacctcag gtgaacttgt tgctcgtaga 46621 gccaagaggc gaagttaatt caggccttcc ttttgaccac tgccccctct tcctaggcct 46681 tggcccctcc accagaggaa ggtgctgcca cgtgtctgct ccttctgaac ctccaggttt 46741 ctgctacgtt gccccatgga ggacacaccc ccctcactca gctgctccga ctgtcagcgc 46801 cactttccca gcctcccaga gctctctcgg caccgagaac tgctccatcc atctcccaac 46861 caggacagtg aggaggctga cagcatccct cggccctacc gttgtcagca gtgtgggcgg 46921 ggctaccgtc accccgggag cctggttaac catcgtcgga cccacgagac tggccttttc 46981 ccctgtacca cctgtggcaa ggacttctcc aatcccatgg ctctcaagag ccatatgagg 47041 acacatgctc ctgagggccg ccgcaggcac aggcccccac gccccaagga agccactcca 47101 cacctccagg gtgagacggt gtccactgac tcctggggcc aaaggcttgg ctctagtgaa 47161 ggctgggaaa accagacaaa acatacagaa gagacacctg actgtgaatc tgtacctgac 47221 cccagggcag cttcgggtac gtgggaagat ctgcccacca gacaaagaga aggcttggca 47281 agccacccag gtcctgagga tggtgcagac ggctggggac cctccactaa ctctgccaga 47341 gcccctcctc tccccatccc agccagcagc cttcttagca acttggaaca gtatctggct 47401 gaatcagtag tgaacttcac agggggccag gagcccaccc agtcccctcc tgctgaRgag 47461 gagcggcggt acaaatgtag tcagtgtggc aagacctaca agcacgccgg gagcctcacc 47521 aaccaccgcc agagccacac gctgggcatc tacccctgtg ccatctgttt caaggagttc 47581 tctaacctca tggctctgaa gaaccactct cgactgcatg cccagtatcg gccttaccac 47641 tgtccccact gcccccgtgt cttccggctc ccccgggagc tgctggaaca ccagcagtcc 47701 catgagggtg aaaggcagga gccacgctgg gaggRgaaag ggatgcccac caccaatggg 47761 cacacagatg agagcagcca ggaccagctc cccagtgcac agatgctgaa tggctctgcg 47821 gagctcagca cctctgggga gctggaggac agtggcctgg aggaataccg gcctttccgc 47881 tgtggggact gtggccgtac ttaccgccat gctgggagcc tcatcaacca tcgaaagagc 47941 caccagacag gtgtctaccc ctgctcactc tgttctaagc agctgttcaa tgcggctgcc 48001 ctcaaaaacc atgtgcgggc tcatcacagg cccaggcaag gagttgggga aaatgggcag 48061 ccatcagtcc caccagctcc cctgctgctg gctgagacca cccacaaaga ggaagaggac 48121 cccaccacca ccctggacca tcggccctat aagtgcagtg agtgtggtcg tgcttaccgc 48181 caccggggga gcctggtgaa ccatcgccac agccatcgga ctggagagta ccagtgctca 48241 ctctgtcccc gcaagtaccc caatctcatg gccctgcgca accacgtgcg ggtacattgc 48301 aaggctgctc gccgaagtgc agacatcggg gctgagggtg cccccagcca cctcaaggta 48361 gaactcccgc ctgacccagt ggaggcagag gcagccccgc acacagatca ggaccatgtg 48421 tgcaaacatg aagaagaggc cacggacatc accccagcag cagacaagac agcagcacat 48481 atctgtagca tctgtgggct gctctttgaa gacgctgaga gccttgaacg tcatggcctg 48541 actcatgggg caggggaaaa ggaaaatagc agaacagaga ccacaatgtc acctcctagg 48601 gcctttgcct gccgagactg tggaaagagc tatcgccact caggcagcct tatcaaccac 48661 aggcagaccc accagacagg agacttcagt tgtggggcct gtgccaagca cttccacacc 48721 atggctgcca tgaagaacca cttgcgccgg cacagtcggc ggcggagcag gcggcatcgg 48781 aagcgggctg gcggtgccag cggtgggaga gaagccaaac tcctggcagc ggagagctgg 48841 acccgggagc tagaagacaa tgaaggcctg gagtctcccc aagacccttc aggggaaagt 48901 cctcatgggg ctgaaggcaa cctggaaagt gatggggact gtttgcaggc tgaatctgaa 48961 ggggacaaat gtgggcttga gagggatgag acccatttcc agggtgataa agagagcgga 49021 ggcactgggg aaggactgga aaggaaggat gccagtttac ttgacaactt ggacatccca 49081 ggtgaggaag gtggtggcac tcacttctgc gatagcctca ctggggtgga tgaagaccag 49141 aagccagcca ctggccaacc caactcctct tcccactctg ccaatgctgt cactggctgg 49201 caggctgggg ccgctcacac atgctctgac tgtgggcatt ctttccccca tgccactggc 49261 ctgctgagcc acaggccctg ccacccacca ggcatctatc agtgctccct ctgcccgaag 49321 gagtttgact ctctgcctgc cctccgcagc cacttccaga accataggcc tggggaggcg 49381 acctcagcac agcctttcct ctgctgcctc tgtggcatga tcttccctgg gcgggctggc 49441 tacaggcttc accggcgcca ggcccacagc tcctctggca tgactgaggg ctcagaggag 49501 gagggggaag aggaaggagt ggcagaggca gcccctgcac gcagtccacc actgcagctc 49561 tcggaagcag agctgctgaa tcagctgcag cgggaggtgg aagcgctgga cagtgcaggg 49621 tatgggcaca tctgtggctg ctgtggtcag acctacgatg acctggggag cctggagcgt 49681 caccaccaaa gtcagagttc tgggactact gcagacaagg ctcccagccc cttgggagtg 49741 gcaggtgatg ccatggagat ggtcgtggac agtgtcttgg aggacatagt gaattctgtc 49801 tctggagagg gtggagatgc caagtctcaa gagggagcag gcaccccctt gggagacagc 49861 ctctgcatcc agggtgggga aagtttgttg gaggctcagc cccgcccctt ccgctgcaac 49921 cagtgtggca agacctatcg ccatgggggc agcctggtga accaccgcaa gatccaccag 49981 actggagact ttctctgccc tgtctgctcc cgctgctacc ccaacctggc tgcctaccgt 50041 aatcatctgc ggaaccaccc tcgctgcaaa ggctctgagc cccaggttgg gcccatccca 50101 gaggcagcag gtagcagtga gctgcaggtt gggcccatcc cagaaggagg cagcaacaag 50161 ccccagcaca tggcagagga ggggccgggg caagcagaag tcgagaagct ccaggaagaa 50221 cttaaagtgg agcccctgga ggaagtggcc agggtgaaag aagaggtgtg ggaggagacc 50281 actgtgaagg gggaggagat agagcccagg ctggagacYg ccgagaaggg ctgccagact 50341 gaagccagct ctgagcggcc cttcagctgc gaggtgtgtg gccgatccta caagcacgcc 50401 ggcagcctca tcaaccaccg gcagagccac cagaccggcc actttggctg tcaggcctgc 50461 tccaagggct tctcaaacct catgtccctc aagaaccacc ggcgcatcca tgcagatccc 50521 cgacgtttcc gctgcagcga gtgtgggaag gccttccgcc tgcggaaaca gctggccagc 50581 caccagcggg tccacatgga acggcgtggg ggtgggggca cccgaaaggc gactcgggaa 50641 gatcggccct tccgctgtgg gcagtgcggg cggacctatc gccacgccgg cagcctcctg 50701 aaccaccRgc gcagccacga gacgggccag tacagctgcc ccacctgccc caagacctac 50761 tccaaccgca tggccctgaa ggaccaccag aggctgcact cagagaatcg gcggcgacgg 50821 gctggacggt ccaggcgcac agctgtgcgt tgcgccctct gtggccgcag cttccctggc 50881 cggggatctt tggagcggca cctgcgggag catgaggaga cagaaaggga gccagccaat 50941 ggccagggag gcctggatgg cacagcggcc agtgaggcga acctgactgg cagccaggga 51001 ctagagaccc aattgggtgg tgctgagcca gtaccccact tggaggatgg agtcecaagg 51061 ccaggggagc gcagtcagag ccccatcagg gcagcaagct cagaagcccc agagccactg 51121 tcctggggtg cagggaaggc aggtgggtgg ccggtaggtg ggggactggg gaatcatagt 51181 ggagRctggg ttcctcagtt cctaactagg tcagaggagc cagaggacag tgtccacagg 51241 agtccttgcc acgctggtga ctgccagctc aatggaccta ctctgagtca catggatagc 51301 tgggacaaca gagacaacag ctctcagctg cagccaggga gccactcctc ttgcagccag 51361 tgtggcaaga cttactgcca gtcaggcagc ctcttgaacc acaacaccaa caagacagac 51421 cgacactatt gcctgctctg ctccaaggag ttcttaaatc ctgtggccac aaagagccac 51481 agccacaacc acatagacgc ccagaccttt gcctgtcctg actgtggcaa agcctttgag 51541 tcccaccagg aactggccag ccacctgcag gctcatgccc ggggccacag ccaggtgcca 51601 gcccagatgg aggaggccag agatcccaaa gccgggactg gggaggacca ggtggttctc 51661 cctggtcaag ggaaagccca ggaggcccca tcagaaaccc ccagaggccc aggagagagt 51721 gtggagagag ccaggggagg acaagcggtg acgtccatgg cggctgagga caaggagcgg 51781 cccttccgct gcacccagtg cgggcgctcc taccgccatg ctggcagcct gctgaaccac 51841 cagaaggccc acaccacagg gttgtacccg tgctccctct gtcccaaact tctccctaac 51901 ctgctgtctc ttaagaacca cagcaggacc cacacggacc ccaagcgcca ctgctgcagc 51961 atctgtggca aggcctttcg gacagctgcc cggctggagg gccacgggcg ggtccatgca 52021 ccccgggagg ggcctttcac ctgcccccat tgtccccgcc acttccgccg ccgaatcagc 52081 ttcgtgcagc accagcagca gcaccaggag gagtggacgg tggccggctc cggtaggggg 52141 catgaagggt cccaggagga ggtgggcaca cagtggaggg ggaagtccag ccccaaagtc 52201 ggtgggggag caaggagtga gaggagagag ccccggggat tctaagaggt gggtgggggc 52261 ttggctatgg ggtgagagaa gtagcttgag gatgtgctga gctgagcacc cgcaagtcag 52321 gtataacaaa tagcagggtg ggttgggcag cacgtggggg cgtggtcagg ccgaggctgc 52381 tacctgggct cctccattac actgtagcca gaatggaatg gtctttctgt tcaggggaag 52441 gtcactgggt accccctggc tgctgtgtct ggaaaccctc ctgagtcagc cagtaaagta 52501 atgacttcca gagaaaaaga ggaagccatt ggtttggtct aggttccatt ctttcctgga 52561 gcaggccggg tgccagggaa caagggatgg ggcatgggct ccacggcttc cctgctgact 52621 tggccacgga aactggttca ctggttggca ccctactccc tgtccctctt tccctgcgcc 52681 ttgtctctgc tgctcctctc cttggaaact agacctctgg tccttccctg tcagtgttgc 52741 tcccatctct tctctaacct ttattcagcc ccttttccct ctgctgccaa cggccttttt 52801 aggatccaac caaaccaccc tttctacctg cgcaccctgc caccctctgc acacctttaa 52861 ctggaggact gagtcacaga taattgtttc cttgaagtcc aggcccagct gcagcaacaa 52921 cagtcattag cccgtgtcac atccctgatc agagggcatc tccgtgggga atcgcctcca 52981 cccagcactg ctggaagccg cRgctgccag ggagtggggc ggccggttcc ctcagcagga 53041 cctgggctgg cctctccacc tccYctagta gaggcggacc cattccatct agtggccacc 53101 gagggtgggt ggccctgaga tggtgggccc ttgacaggcc ttgtcagagc agagggcagg 53161 tgggagtcac ctgaaagctg aaggaatggc tttaaggata gaagatttct catgacctca 53221 agggatatga gggaggagcc agtttgccag ggctgggaaa ataattagga ggcctagaat 53281 ccctgttctc atctgggcct ccggggccag gggcagggga atggcctgca gggctgggag 53341 ggggtacacg ctgtgcgggg tctgcccctc agttggtgac ctcctctctc tctcccccca 53401 ggagccccag tggcaccagt gacgggcaga ggggacttgc cattgccccc tccacccacc 53461 cccacgaccc cactcctgga tccttcaccc cagtggcctg cagacctcag cttctccctc 53521 tgaacttcaa gtctccaaag atcagaatct gggggaggga gcgcgtgcag ggaggggctt 53581 gatctccaca ttttctcagg agtagttcgg gcatccccat atcttctcct ctccccYtgt 53641 gaagaggacc cagatctggc ttctttccca aggagggggt ggggtgttcc tcgcgtccct 53701 gtccttgaag gacctccttc ccccagcctc atcaccgtgc tcttctcagc gccaccctca 53761 gcagccagat tgcaacacca gggagaggcg gatgcagagc cccaccggtg ggaaagttgc 53821 ctgtggaagg gagccttttg ctacaatttg taacttattt tctaaagtct attttgtaac 53881 aatttattta agtttaaaaa aaggaaaact gctgcccccc aaaaaaagaa attttcaaaa 53941 caacgtggct ggcgtgattg tatctgaaag ggtaaaggag gaggaaagct gagacgcctg 54001 cttggtagca gagttgggtg tgggagtgtc cacagacacc cctgtcctgc agggtgggga 54061 gtgggcacct gtggccccag gcaggttcct tcccacagct gctgggcttc tgggcctgcc 54121 ctggtgcctg gaatcacaca tgacagggtg gggaggacag gggcagtaat gccatttgcc 54181 tgcctgcatt ctcttgtcct gagaatggcc aggtcccctg tcagcagctg gttggttggc 54241 ctgtggggaa ggaaggaggg tggagttgtc ctcatcctca cggctttggt ccctccctcc 54301 ctccccattc ctcgaaggaa cagggtctgt cttggccgcc atgacagatg agaatactga 54361 ggctcaaagc ggttgagcag cctgctccaa gtcacacgat gacaaagaac cagaatctga 54421 atcaaatggg tctgcctgtt gctccaccct acccaaggca gctggagtgg gttagaacgg 54481 cacgttctca ctggagagag aagggtcctg gagaggcagg gtttggcagg aggccccggg 54541 gccacatact tatgttggcc aggcagcttc caggctcagc ctcgggctct ggttcctcgg 54601 cgaagtagac ctgccagtcc aaactgctga cccagtcctc ataggcaggg agcgcggtga 54661 agaccgccgg cctggcgggg ccttggcaag catctccgaa gctgtgcagc ccggccagga 54721 accatgtgcc cctcacctca tgcaccagtg gtgccccaga caggccctgt caggggtcag 54781 gtgacactgg gtgacttttt ataggcagct gtgcaggacg gtagagcagg ctagggaacc 54841 tctggctgtt tgggggctaa ttggcaaaaa ggcttagttt caggtgggag gtgggtccag 54901 aggccaagcc tggaaggtcc gttcttgagc tattgggtga ggggatgcca ggggcctgtt 54961 aggtaaggtg tgggggcctg gggctcacct cacagctggg cagctcaccc acagcactgg 55021 tacacaccat ccccggcaga atagggctgc catcaccccc aggagctgca tgcagccggc 55081 tgcaggccct aggccccagg agggtcacgg gcactgtctg gagggagctg atgcctgtgg 55141 agcaagggaa agctggctgc cccggcctgc aggttggatg gacagcagcc ctggccctgt 55201 gcccacctac ctgctcctgg gcgggcccgt cccagaaccc agccacgctc cccatcaggc 55261 aggtggtggt cagSataggg caggcagagg ggccgcaggc tggctcccag tgtcacaggc 55321 tgggccagca gcaggagggc catgtcgtag cccccctcag ggtgggtgta ggctccatgc 55381 aggatgagct gcttcaggcc ccactcctcc ggtctggtcc ccagccctac gctccattcc 55441 tctggggcct ggcgcctgtg cagaggcagt gtggacggca ccaggtgaca gggctgccgg 55501 caggggcagg gggcacagca gagagggatc caagactcac ccaatgaagc agtgggcagc 55561 agttagcacc gcctcctctg acaccagggc tccgccacag gccagctgtc cctggtgcat 55621 cagcctggcc tcccagggcc atggggaggg tgctcctgcc tggggacctg ctgtcctcaa 55681 ggatccacag gctgaaacag ataagtgcct catctgactt cttgctaagc acttcccact 55741 tcccatcaaa tcctcacagt agcttttgaa attgaatttt gttcccctca ttactgaagg 55801 taaccaaagt tccagagagg ttaaRagact tccttgctct gtaactacag gcaagtggca 55861 gacttgcgat tcgcaagcca gggcctgagc ttttagccct gttggtctga tgggacccct 55921 gtcccagcct cgtgggaatg cccctacttg tcactcccct gctccacccg tctgcaccct 55981 ccaggMtggg cctgcctccc gtattcctga ctcattagtg catctcttat catcaagaca 56041 taatatccgt cccaggaatt actttgcatt caatttgcat gccagtcact taatgccgga 56101 attctgactg ggagccctac cctgtgcagg ctcgctgggt ccctgctgga agcctgccac 56161 ttccccagaa acccaagtca ggtctcagag attcctcttc tcacctaaac tccaaacctg 56221 tagagttcca aagtgcctgt gcctctcagc cctaacaggg ctgttcccat cccagggggt 56281 gaaagagccc cctaattagg ctcggcggtg tggatgccta tgccagttct ctagtcctaa 56341 ctgaggtttg cttcacagtg gcttctgccc actcccagca tgccccactc gtacctacac 56401 agctgtcctc atcactcatc tccggggtct ctgggctctg ggccaggaaa gctgccccct 56461 gaactcgagc ctgcagccag gaactgtgag cagctgtgtt ggtcagcagc acaggagcgt 56521 cctcctgggc acagcttgat gcaaagctga tgatgccagc ctgaacccag tgtccgtcag 56581 gctcgaggca cagcacaggg cccccggaat ctccctggag ccaggcaaca aagccaagga 56641 cagatgcctg agcccagcta tggcagacac cctctgattg cagStctttc ccccagtcct 56701 gtgagtccaa cccccagccc agggttaggc ccctcccctt ctgctccttc tcttctccct 56761 atcagacctg acaggggccc tgcaccccag gctgggggcc cccacatagc atcccaggcc 56821 gggccgggtt ggacaggtgt cgctggtgca gctggttgta gatacagtta catgtggggc 56881 gactgatgag acgcaggcgc agattgcgta gggtcccagg agctggtgaa agagacgggg 56941 ctggggctag agtctgggat ctgggaagca agggagactg gaagccagga cagttgggag 57001 ctgagactgt gacgctgggc aagcagagtg cctctccgag cttcagtctg ggccagcact 57061 taccatcact ggtgtcctga tcccagccag tggcccagca ggaggctcca aaggggaagc 57121 gatgggcggg ctggggcagg cagaggggtg tgtgggtcgt ggggtgggcg agctgcagca 57181 gggccaggtc tgagccctgg ctgtagtggt tataggccct gggcaactgc agggcagcca 57241 cccccacctc ttcggcccca gggctgagtc cctcacgctg cagagaaccc aggaccactg 57301 accaggaatt cagttctgtt gctgctgccc tggaagggga aggacaaggt ccaggctgct 57361 gagtgcaagg gtagacagtg acaccatggg agaccccaca ggtaggtgga agatagcaga 57421 gagcactcca cggctttttc tttttgaggt agggtctcgt cctgtcgccc aggctgcagt 57481 gcagtggcat gaccatgact cactacaagc cttgacctcc caggctcaag cgatcctccc ~Rn 57541 acctcagcct cgtgagtagc tgggactaca ggcgtgcacc accatgcctg gctaatttta 57601 cagtttttgt agagacatgg tcttgctatg ttgcacaggc tagtcttgaa ctYttgggst 57661 caagcgatcc tccctccgtg gcctcccaaa gKgctgggat tacaagcgtg agctactgtg 57721 cccggcctca gtctgtgact ttaagcgagg tcattccctt gcaacctgag ttttYtgatt 57781 tgtaaatctt ctaccatgaa aggtggttgt tacaattaac ttgacaatat gtacccagta 57841 catggcagat tctcagtaaa tggttcttta ttattactct agaggcaggg actagccttg 57901 tggggcttga gacaaattgt ccactcccca gagccggaga ccctgcctga ccccagccat 57961 gacttacttt tcaaagcagt gggcagcagt gaggacccag gtgtctgcca ccagggagcc 58021 gctgcagatg tgggctcctt gcctcctcac actggcctgc cagggccact cgccagggac 58081 tgtgttgccc tcctgaggct tgggggggcc ggggccacgc tgtccacagg ctgtggaaag 58141 gagttagtca cactgacagc agatacctgt cctgacctca ccccagtccc aacccagacc 58201 caagtaagac ctaggccccg tgtccccaga ccttaccacg ctgagcggct tgaagacctg 58261 ggaagagaga gacacaggta agatgcaggg actccaggcc tgcctagctt tggggaggag 58321 aggggatggg ctggggggcg ggcccagggt ccttgcctgt gactctgatt accttaccag 58381 cccctcccag aatgaaaata tttatatgag gccgagacag cttttattgg aacctattca 58441 gtgtgcacac tcagtaatta attctccttc agctgtgctc agcactctgg ggcttggggt 58501 tcagcttggg agtaggccag ccctcctcca ggcttcagaa cccccaactc ctgcccccgc 58561 cactgagtca gccaggcggc ctgtgtgtgt agagagcatt agcttaattg tcctcttagc 58621 agcagaggcc taagaggaag gattagaggc ctgcatcatt tccaagtggg gagggcccca 58681 agaaatggag acttacctca ccctggtcta gagactcagt cttccccacc ttcccagaaa 58741 ctgtctgaga gcccgccaga gagagggccc ctgcccaccg cccctcacag gcacacaggc 58801 accccatgag acagctgagc caggctgccc agaggatgga tgaaaagaaa gggaaactga 58861 ggccagagga gcccagagtt tgcctgacgt cattgtggaa gtcgaggggg aggcaggcac 58921 aggacacacg caggcagcac ctcacacaca cacaagacca caggccccgc caacgcaaac 58981 tgcagctggc ccgagaaaat ctcatccatg ttgacacagg tggccacata taccacccca 59041 cagagtccta cggagttaca tccccactgg tggactgtcg cccacaggcg gtccccccac 59101 caagaagcag ggactgctgg ggcagagatg gcccctgagc ccccaccagg ccacacccat 59161 accccagcac atggcggctt accctccatg aggactgtgg cacccgcgat gagcagcact 59221 gggccccagc accacttcat gctgccccgg gccactctgc cacctgtgct ccactctgag 59281 agaggccacc tgggtctccc tggctccacc tctgctccac ctccagttgg ctaggattca 59341 gctgtctgct tgccctagcc agcagttcct agctctgggg ctgtggctgt gtgaccctag 59401 gcttgtcacc acccctctct gggccttagc cgtggagcca aattgtctgg gtttaaatct 59461 gtttccttac tacttgagtg gcctgggaga gctaacctgc ctgtgccttg tctgagaaac 59521 agttgttgaa tggaaaacgt ctcaatgaca gcctggcaca gggcaagctc actcccagca 59581 tgaaagtgcc atcctggaac catggagggc acgtgggcag ctcctcccag tccccacttt 59641 tcatttccac tcccccactt ctcttccagc cagggctagg tgggtttcac atgccttctc 59701 ccaggtctgc tcagagacag tgtgtgccag gctgagtggt gaggagccag cacccactgc 59761 tgcttgctcg ctgtgagcct ttggcaaatc ccagtatctc cctgggcctg ctggcttcct 59821 gggaaacagg gtgacagcgg tgcccacctt cctcataggc gcagaggact cggtcaggcg 59881 ggaagaacac tttggcgcgt gcctcctctt cctcttccca ctcctaactc aggctggccc 59941 agaccattca agaaccctga ccccaagaca gaggcagctg tgggtaaggt ttagcatata 60001 ttatagatgc tggccgggca tggtggctca cgcctgtaat cccagcactt tgggaggcca 60061 aagcaggcag atcacctgag gtcgggagtg cgagaccagc ctgaccaaca tagagaaaca 60121 ctgtctctac taaaaataca aaattagcca ggcctggtgg cgcatgcctg taatcccagc 60181 tactcgggag gctgaggcag gagaatcact tgaacctggg aggtggaggt tgtggtgagc 60241 cgaaattgtg ccattgcact ccagcctgga caacaagagc gaaagtccgt ctcaaaaaca 60301 aaccaacaaa aaaaaaagca tatagatgct ggagccagat ggaccaggtg gattcaaatc 60361 ctgagagcct cctgcagtag ctgtgtgatc tcaggcatac taattagcca ctctgtccct 60421 atcatcaaga tagggataat aatagtaccc acctcataaa tcactgtaaa gattaaacga 60481 gtttaacacg ttaacacaag tttttttttg ttttttgttt ttttttggag acggtcttgc 60541 tctgttgctc aggctggagt gcagtgatca tggctcactg cagcctcaac cttctgggct 60601 caagcagtct tcccgccagc ttcccgatta gttgggacta taggtacata caccaccatg 60661 cctggctaat tttttttttt tttttttttt gtagagacag gggtctcact attttgccca 60721 ggctggtctg gaactcctgg cctcaagtga tcctcctgcc ttggcctccc aaagtacagg 60781 gattacaggt gtgagccact gcaccctgcc aacacaagtt cttaaacagt gcttggcatg 60841 taggtaagtg gtcagggcat aataggcaaa acaaaaacct tcacaacctg gccctgaccc 60901 tccaaggcta ccaatactgg cttggaatgg tcgataaggc aactggaggg gttaaagtta 60961 aactcaagga agaacttccc agcaagcatt tacagaacca gaagggcagc ctgcccttcc 61021 aggtgtgtgc tcagccttcc caggagagga ggcctggctc ctgtgggcag caggagcgag 61081 ctgccagcct gtttcctggg ggtgggggcc aatggtgccc caggccttgc tgactccaca 61141 cactggagat gagactaccc ataaccaccc ttcccagcag gccctccact ctccctctga 61201 ctcacccttc ccagctccag agaaggcaac accgagggag gcccagcacc acagtccatg 61261 gcagacacat ggttcagact tggctgattg atctaagaaa ctttattgct caRaaccttc 61321 cctccctggg caatggaaag agctttggag accagcccat ggggacagag tcagaggcac 61381 tgggtgtaaa aaagagcgag cgtgtggcac atttggtcca ttgtcatgtg Ygggtatggc 61441 aggaggaggg ggtaatctag aagccccaca tctagggcct tctagggacc cagatatgcc 61501 cccttaggca aggctcacat gccaaagcaa agcagatgag gtcagcctgg cttgggttga 61561 gggctcagtg cctcttagcc ttgccctggg gttcttggac cttccggaaa ctgagccaca 61621 tcaggctcac gttgatagca taggtggtga tacaaacaat gcagaaatca tagagcacga 61681 agaacaggat ccaggccaRg tagacagaac cagcgagaga caccagggag ctcagcagca 61741 tcaggacaga ggcccagcgt gtccgcaggc aacctgcaag gcagaagagg gtccggtgtg 61801 ggcttcaggc actggccacc tcccgaacac tccatgatgt cactgcacta cctagatgcc 61861 aggagctgct gggaagggtc tctaaaacaa gaggctccag ggcagatgtg gtggcttacg 61921 cacgtattcc aaacactctg ggaggccgag gtgggaagac tgctttaggc taggagttca 61981 agaccagctt gggcaacata gaaagacccg atctctatca aaaatttaga aattcagctg 62041 ggcacggtgg ctcatgcctg taatcccagt attttgggag gccaatgggg gtggatcacc 62101 tgaggttagg agttegagag cagcctggcc aacatggcaa aaccccatct ctaataaaaa 62161 tacaaaaatt agccgggtgt gttgatgggc acctgtaatc ccagctgctg gggaggctaa 62221 ggtggagaat cgcttgaacc taggaggtgg aggttgcagt gagccgagat catgccacca 62281 cattccagct tgggcagcaa gagcaagact tcgtctcaaa aaaaaaatgc ccggtgaggt 62341 tgactcacgc ctgtaatcct agcactttgg gaggccaagg cggatggatc accaggtcaa 62401 gagattgaga ccatcctagc caacatggtg aaaccctgtc tccactaaaa atacaaaaat 62461 tagctgggcg tggtgacacg cgcctgtagt cccagctact caggaggctg aggcaggaaa 62521 attgcttgaa cccgggaggc agaggttgca gtgagccaag atcgtgccac tgcactccag 62581 cctggtgaca gagcgagact atgtcgcaaa aaaaaaaaaa aaaaaaaaaa aaaaattagc 62641 tgggtgcagt gacatgccta tagtcctagc tactcaggag gatcgcttga gccaggttac 62701 agtgagctat gattgtgcca ctgcactcca gcctgggcaa cagagcaaga ttatttctta 62761 aaaaaaaaaa aaaagaaggc ttcaacaggt cccctccaag ggactggtct ctgaagctct 62821 tgccattgcc cagggaggga aagttctgag caataaaatt tcttaaataa atcggccaag 62881 tctgaaccat gtgtcagcca ggaccRtggt gctgggcctc cctcagtgat gccttctctg 62941 gagctgggaa gggtgactca aagggagcgt gggagcctgc tgggaagggt ggtaatggat 63001 agtctcatct ccggcatatg gcatcagcaa ggcctggggc gccatcgtct tccactccct 63061 tggttcctct ctctgttctt atgggactag atacaaattt tcctgctgag cactaaatga 63121 gacaaaagat agctcatgct cagcttctcc ttaaaaagga atttcggcat cttttccaca 63181 aaactggggt gttggtgggg catggtagct cacgcctgta atccccccag cactttggga 63241 ggctgaggca gacagattgc ttgagaccag cctgggcaac atggcgagac accatctcta 63301 ccaaaaaaaa acaaaaacaa aaattagctg ggcatagtgg tgcacgcctg tgattccagc 63361 tgcttgggag gctaaggtgg gaggatccct tgggcaggga ggcagaggtt gccatgaact 63421 gagatcacgc cagtgcacac taagggcatc ctagacctca ctttgggcaa cagagccaga 63481 ccctgtctca aaacaacaac aaacaaaaaa cctggggacc taggatgtct ttaagggccc 63541 ttcagcctct aacagtactt aaaccaatta aaagactcct gttagttacc tccccacatc 63601 cccacccgca ggacgctcSg tgatgagcag ctagctggct gtcagctgtg tggatcacca 63661 agattgcatg gagtggggct gagctgacca agggggatga ggggcggggc ggggcgggca 63721 gggagggggc ggagccactc acctaacaat agctgtagtg tgtagaagat gcaaccgaat 63781 atgctgttgg attgattgag gatgctgtcc tgtcccagca catgctccac cagcccgaaa 63841 cccctgcccc acctggcaga ggggtggggt ggggtggaac caggttagga ctgtcaaccc 63901 agtgccttgg accctgcccg agaaaggtga tttccaagaa gccacctggg ctatcctctg 63961 ttccccgacc tcccatccta gtccaagggt cgatgatctc ctggcaccgg gcacctttgg 64021 ccacgtcagg attccatgtc actgacccta tcctcccctc tccccagacc aggcccggac 64081 gtggctactc cgtaggccct gcttttcatc ttagacctta agtaagtctc tttttttttt 64141 tttttttttt tttttttgag acggagtctc actctggccc aggctggagt gcagtggcgc 64201 gatctcggct cactgaaacc tccgcctccc gggttcaagc gattctcctg ccttagcccc 64261 cccgagtagc tgggattaag gcacccgcca tagcgcccga ttaatttttc tatttttggt 64321 agagacaggc tttcaccatg ttggccaggc tggtcaactc ctgacttcaa gtgatccatc 64381 cgcctcggcc tcccaaagtg ctgggattac aggagtgggc caccgcgccc ggcccttaag 64441 taattcttaa aatggcaagg ctggtataac ggttcactcg gttttgcatc agagactggg 64501 agtcgggggc agattatctt tgccctggac cccagaatct ccagctccct ggccactcac 64561 tcgcctcctc tgtattccgt cattatgcta acgcctggcc atcacgcaca gccagaccgg 64621 gccaccttgt tcctgggcgc agccatcgcc aacacccccc ttcMcctgcg cgccgtcctt 64681 gagaccatcg tcaatctcta ccgccatcct gcctccccgc ctttcctggt caccgttatt 64741 ccttggcatc caattcacgt gcgagtcccc ggaataatcc cagtccccag cactgtctgg 64801 tcccttgcct cgcactctta tttcgaacac cagtatcgct gggtagctca gcccctgtgc 64861 aacgaccccg cgagcagtcc agccccgtgt ccgttccccg ggcacaccga tcccagactc 64921 cagaataatc atctggcatc ctggccgccc tgctccgagg ccccacgcct cccactcccg 64981 tgcacacctg gaggagaaga cgcgcgaaca gctgatggcg gtgcccacgt cgcagagcgc 65041 gcggtaatcc cggtcccggg cgcgcgccgc cttcacgtgc agcgcgtaga gcgagagcac 65101 taagcccgtc aggcaaagag cgagccgcac ccagccaggg ctcccccagg tgctgcccat 65161 tatctccagg ttccgcccga ggcgcccgcg gagaaaacca gccacggagc aggggccggg 65221 cggcgaatgg ccgcgcccct cctggccctc tgactcggcg attggccggc cgtgctcgca 65281 ctccacgacc caaatggctg ttccagggcg ctagtcaagc gggcgagtta ggaaaacagc 65341 gaagaatgcc gggactagtg aagcgggtaa gggacgtgcg gaatcgcggc cccagcggct 65401 gccaggcatg atgggagttg tagtcggcgc ggctgcaagg catcaaggga aatgaagtct 65461 ccacagattt aaaaactgtt ggccgggcac ggtggctcac gcttgtaatc ccagcacttt 65521 gggaggccga ggctggcgga ttacctgagg tcaggagttc aagaccagcc tcgccaacat 65581 ggtgaaaccc catctcaact aaaaatacaa aaattagccg ggcgtggtgg cacatgcctg 65641 taatcccagc tactcgggag gctgaggcag gagaattgct tgagccgggg agccggaggt 65701 tgcagtgagc cgagatcgtg ccactgcact ccagccaggc cgacagagtg agactctgtc 65761 tcaaaaaaaa aaaagaaaaa aaaaagtgtg ttagtgtggt taacagcatt tgcgcttacc 65821 ctatgccaag tcctgttgta agaattgcag catccgggac ctagagacca gcggatcagg 65881 ggatccagcg aatacggcga tccgattcgg gaaccaagca tttcccctga aactatttca 65941 ggcaccattc gggctgcagc ctcccatcct cccgggtcct gcctcaccag tgcttcctgg 66001 tggtcggtct ccctttctcc catacattca cagaaccact cctttggcca cacacaccct 1261gaaggaaaagctggaatactgtgagagacttaccagtggcctgtctgcgtgtaactaact 1321cctcatcccgacttggtcacgcaaaggacaggtgaccatacctccaggaaggtggaaagg 1381ggccctacatgagtgagaggctcaagtcctgcccaagtggaatctgtgattctgtgatct 1441aaagaaagtttgtggctatttttagaaactaaagtttatctcatattgacacaaactcaa 1501aaatcaatgatactttgagatatgtcatatcacaaaaaagatttctcctctagtacatta 1561tcatttaaccaatacaaacaggtctgggccaggtgctgtggttcatgcctataaacccag 1621cactttgagaggctgaggggggtggatccctagagcccaggagtttcaggccagcctggg 1681caacatggtgaaactctgtctctaccaaaagtacaaaaattagccaggtatagtggcaca 1741cacctgtagttccagctactaaggaggctaaggtgagaggaccactgagcccagggacgt 1801agagactacggtgagacatgattataccactgcactccagcctgggcaacagagggagac 1861cttctctcaaaaagaaaagaaaagaaaaagaaacaggtctaatttgttcatctaagcaat 1921gataagatttatatgaacataagttgctttattgatgaaaaattgaacataatctaatca 1981agcctctaaatttaactgccaatttataggaaaagacaggacagaacctacaggaatgca 2041atcatttatatctagaatgtggaagattctgcatgacaaacgacttggattcttcaacat 2101gtaaatttcaaggaaagagagagagagagagataaaaaggcttgtttccagatttgaatg 2161acatgttaatagacatttatgagacaatcaaggaaatttgaacatggactgcatattgaa 2221tgttgagggattatagttaatttttaaaggtacaattgtgatactgtgattatattttta 2281aatgcgatcattatcttttaggagcactaaaatatttactaataaaattataggatttac 2341ttcaaaataaacaacgataataagattaccatgaatagtggtgggtgaaatatacaaggg 2401gcttatttgacatttccataataaaaaacacgaatgaataacaaagcattatagaaattc 2461aagtaaaaaatagctcgtgcttagtaataaatcaaagcgtgctggacactttaaataata 2521aacaaagataagatcttgccctctagaaaacagctctaattcaggacagacttgctcaca 2581tcagatggaagagtcagaatgagatgtgctgagtagaaggtagaacggtcgctagcagag 2641ggtgggaaggtggtatgtgtgggggagaggagaaagagaggttgattaatgggtacaaac 2701agacagttagatggaaggagtgagatctgttgttcgacagtagagtagggtgactacagt 2761taacaacaatatttgcatatttcaaaatagctagaagacaggacttggaatgttcccaac 2821acatagaaaggtgatgaactcaaggtgctgaacaccccaaataccctgacttgatcatta 2881tgcaataacaaaatatcacatgtaccctgtaaatatgtacaaatactacatatcaattta 2941aaaattttcacacaagaatgagatgtgctgatgcatgtggaggccctagctccagactgg 3001gtgtaaacttcaagccactgaagatcttatttccaaggtttttctactttgaaattccaa 3061acttatttttctagcagatttataagggacacgggacaacataaacttgttaaagtgaca 3121agagaaagtaaatatgcccttaaatttataccaaatcttctgacaagtcttgactgataa 3181ttgtttccttcaaatttgtgaaaaacatgagagaaaacgtgtttgtat~ctcatttttaag .

3241tgtggacacttggcattgctcacggcttccaacggaataaaatagggcttagttgttttc 3301cattagctttttcctttgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgttgtgtgt 3361acatattggctctaagcatttattagcccaataatttttagtgaaactctccacttctca 3421atatcttttgccgtattagatttttgtaacatgtgctaaaggttaaaacaccttttcccc , 3481ttcatgaagcctgagagaagtcggttttctgggttttctcaagacaacccagaggttttg 3541tatacgtctgtctaaaaagtctcagatttttcttgctaattgtgcaccttcataatcaag 3601cagacaaatcagaatattattttggtgaggccatcatctaaactaacagtctttatgtac 3661agaagcagcactgaccgggttcatactcctcagttagcaagtcaacatcttcctcctgcc 3721agcaacccatcccagaatatctgtggcttattaatacttatgaaaacaacagtcttcatt 3781atttactaattaggagatgatcagatgtatctattgatagcaacaggctatttaaaagtg 3841aaataatctatcaaacagattttttatcaactcaaagtttccagttagatatttttcatt 3901aaattgattgctagattgcagccacaatcaaacttaagtattataagaagtttggttggt 3961cttttaaaatcatgcaaaaattcaaggggtgctattaaatatagaattccaaatgtataa 4021agtcttgtcctaaaatggtcaataaaatgaaccagtccactggttcatttatagggggcc 4081agtccactacattaatttggatgttcttcgtctgcattttcatgttttcacacacctgca 4141gtcattgtgtacaattctggactcttgattttcatttagcattctgcgttaatattctga 4201catgttgctgccaggtcttcatggccaccacttttaatggccagaaaatatttcatgtag 4261tgaacatttcataaattacttaaccatgtcccaattattggttatttaaggaatttaaaa 4321ctaaaacaccactcttgtgacaaagttctgatgtatccagatgtactcatgccaagtcgt 4381ccatcaatagttctgctaaaccctgtcagagcccttttctgaagggaaccaggaaacatc 4441tcacaacaagaagcttaaggcctctacaaaatgacttcagggttaggatttcaatttcac 4501tctgaggcacatacaggaaccactaggttatttggcttagaatggagggaagtgtcattt 4561tgtttctgttcggcctgcaggaagctccttcccaggccctgcattgccaattgaacaatt 4621gaacaattctcattgttcaattcccacctatgagtgagaacatgcattgtttggtttcct 4681gtccttgcgatagtttactgagaatgatggtttccagcttcatccatgtccctacgaagg 4741acatgaactcatcattttttatggctgcatagtattccatggtgtatatgtgccacattt 4801tcttaatccagtctatcactgatggacatttgggttggttccaagtctttgctattgtga 4861atagtaccgcaataaacatacgtgtgcatgtgtctttatagtgcctagaacataatagga 4921gctccagaaatactgttgaaaaaatgaataaattgagcacactaagtgtctgaataaaat 4981accctgaccatacccctaaataaacaacataaataagcaaatttcaatttctcggaaaag 5041ttatattttagtgtccaatgctcttgttatgcagtaatggcatctttgattattcatatt 5101cgttagagcttccagaaaggagtattgcaaatcacacgggcctctgactctcatgaccaa 5161atccccctgtcactgtccttgttctctgatccttcctctgggccctcggaaatgctggtc 5221tccatcaaattgctgtaaacagttttcagaaaaagttctctttgggaagtttcaagagaa 5281aaccacaaatttcctggaaatgcttcatgcttcatgacatttaaggctttcagagccttg 5341aacttcaggagcaagatagctggtaggtcttctggaggtcttgcctaacctgagaaggtc 5401ccagagaatttgtgcatagaacctcccaggaagcagtaagacaggctggtgcagtcccac 5461aggatgagaaaggtaagagcttaccaatgtctccagttttgtaaatgaatgttcttagca ?.14.

5521 tttttggtgaggagaaaaaaatatcaaacccatcacagacagatcagcagtctcttgacc 5581 taggtcactcaaggggttctcaacaatcaattctaaaatgcaagtgaaaaatgtcaatat 5641 aaggctagacacaggggctcatgcctgtaattccaacactttggaaggccaaggcagacc 5701 tagaactttgtaaatctgagattttgctccatgactttgtggatactttctactaatacc 5761 acctacacaaaatcttcaaccaagaatcttaattgcatttatcaacttgtgtccttagat 5821 cataacatttagattcatttgaaagaaatttattgaagtaaaagaaataagaagaacttg 5881 atagcacaaaacaaagaaaacccagaaagagagagagagagagaagcagaaaaactaaac 5941 actgaaacccagagagagagagagaagtagaaaaactaaacactgagtcttaatctgttc 6001 tgccactagtcagcagcctgcacagagcactttaatgtattctctgtccattagtttcct 6061 tgtttatgaaagtatatagctccaaaaaaattctgtgttctgatttttgtctctccaaac 6121 cacaaccagtcccctgctcccttctctcctcctcctcctccttcttcttctttctctctc 6181 tctccctgtctetctctctctctctctctctccccctttccctctcccccacccacccac 6241 ctcccaacccctgcatacacctaggacacctccagcataggttactaccaattttgcaca 6301 cctccagcaYaggttactaccaattttgctgggtttatctccttctgtcctttccgcttt 6361 gatctgaggaatagctgagatttaggacagcaacaaggtgtacctccttccaggttataa 6421 aacaggattaatgattaggctcaaggccccttcctagtcactcagtaaagtctgtgcact 6481 ggaaaactgtggtagcagttttctgagcattagaaaactgtggttctcacagaggctgga 6541 tgagtcaacactgccatctggcggcctcttggagggtgatgtggagcctggctttcattg 6601 aagaatgaaggtcccttgatttcctgaccctcagccaactctccagcagcttctcactgc 6661 agaagaggtcaggccattggtcagcttgaggacaaagtgggaggatcacactttcgatca 6721 cctatactttctaacaatcagccctgtggacatctgctcacgccccatgctgtttttaaa 6781 atattttcccattatagaaatatttttcaaagatgattcacaagctccaggagccattca 6841 gacaagggagagcaaattggcagctaaactcattcaagagtggagcagatgcacatgaag 6901 ctctgtctggcggaggaggcacaagacaccgagcctggctgggagggtgctcatgacaag 6961 agtggggccacaggcctctcctttcattggacatagtggccatacaaagtggctgccttg 7021 aaatgcacccacatacactatcggtcctcccggtctagggagaaaactagcacagtatgt 7081 caacagataaatcagcgcaatcctgtgggtgaagcagtgcacccatactcttcattctgc 7141 tgagcggaactcaagggtgagacacttgtattcctaactccacttgccttcaggctcctc 7201 caacattccaaattgcccatggacagagctactacccctccatagaagtgacaacttgaa 7261 ataaaagatttgaagctccttcccacgtttagacccaggcctgctgctaggaactccaga 7321 ggagggatggaaagaagtttgcactgctcacagatttaatgtttctctcacaaccagaag 7381 taggcagcaggatggattttcaatcaacactaacaaacggatcactcctgggtcctttaa 7441 acaagttccatgtctctttataggttttaggtgcctcctatgtgttcagacttCgtataa 7501 tggatatataagaaaagtaaatgggaggggcaatatttaagaaataacagcaaacaattg 7561 cattcatatttaatataaactacaagtatcaagttaatagacgctcagaagaaattcata 7621 aaatctagaaaagttgggaaaatctcaatagagaaaataaaacttgatctggactttaag 7681 agtatgatttataaagttcaaggggacagtacacaaagtcagacaatgttagctgaatca 7741 ctgaagaatgagaatatcacacccacttaacaaagcagcccagctagttaaagaagtatg 7801 ttgaagaggtagggagttgggtgggggaggcgaggatggcgtggagggatctgaaaacta 7861 tcaaccttaaataatgagatttagaaaatatgattaagtagagggttaattcgagtgcag 7921 agcttgagaatggccacctggaaacactgactctaaaccagtaaggttaatgtttcaaag 7981 tggagaagttaaggtttcacttagaaattttagcaggatcacattttccatacaagacca 8041 gtgcattcgccacagcaatttgattggttatagattgctgctcattccaagattacttta 8101 ttactctgtgcggaggagtagtgatttgaggggtcttatgtctggtgcctttttgtcttg 8161 tttacaggggaaaaggcagaagttgcgcctgcatgccgcataactcaggctctgcatagc 8221 cacatgtctttcaaggctcagaataatttgaagttccaacagctttaagtttgaattaat 8281 ttcacaaagcggagaaagacttggacttcgtgcagtaatgaagaccaccgatgggtactg 8341 aacagctctggtgggtttgcactcagagaaaggagcctaagatgcagaaggtgcagtgag 8401 gcagcagccatctgctcttgtgctgctgagcagagcatgatgggctgtcaccgctcacgc 8461 gtgttctttacctgctgactcacctggcggcatgggctgcatatggggtcccagctcctt 8521 aagctcctgtcaggcccttctgcaacttctcccaagctcttgggccaggtgcatgtctag 8581 ccatgaaaaaggaggccagtacctgatcactaagtgaaagttctaaggtagtgggactgc 8641 cacaggtgtcccccatggtcccaggtcacaatccagtctgttgaccctcctccttttgca 8701 ccatcgcccctttgacagcctgtgctatgggttttaggctcctagcaccaaacagaaaca 8761 ggcttatatagatcatctaatcagctcttcttatgtgaggccgaactctgtaataaatct 8821 ttttatgtctcctagggcttctctgattgaacctgtctgatgaggagttaaagaagttct 8881 caaattgtgtatgcataagaatcacctgggatttctagctcagagactgggacaataggt 8941 ctattgaacctaggagttcattttgaacaagtgctctacgtaattctgatacagggaatc 9001 ttccagttacagtttgaaattcacaaatacaaggaatgagagacctagaatcagaaagca 9061 tgttaatacacttttgggccattaagtgctcacccaggtaacaggtacagaaaggcagaa 9121 aaaggaaacctatcagggtaataattatgcctttttttttttttttttttgagacagggt 9181 cttgctctatcacccaggctggagtgcagtggcacaaccacagctcactgcagccttgac 9241 ctcctgggctcaagtgattcttccagttcagcctcttgagtaactacgactacaggcatg 9301 tgccaccatccctggctcattttttgtagagagggggtttggccatgctgcacaggctgg 9361 tctcaaattcctgggctcatgtgatttccccacctcagcctcctaaagtattaggattac 9421 aggcgtaagccactgtgcttggccaagacattttggtaagaaatattattttcctactaa 9481 attgtctacattccccttgggtaggcttgcaaagtcactgtgactacagcaggagctatt 9541 gctgcatgggaaatatggagacacgagtggtacctggcagtcacgggctcagtttgtttc 9601 taacctcccaagtcagcacagccccactgagcagactgccggaaagtatttatgccatct 9661 gtcggataattaagacaaatccaaacatctacgtgcattctgtgtgtataaatggagtca 9721 tggccaacctctcaagcagttttccatcaatcacttgtaatattaccagatacttccaat ?.1 S

66061 tgacagtatc ctaacctctc tactatcatg gcgcccgcct ggcaacacct gagcttgcat 66121 caactcaaca gtcagtctct cctttccaag ctgtgggcca gatgaggtct ctccttcaca 66181 gacgtcccat ctgatggtga cccatctctc ctacaccttc aacctctcca tcctccccat 66241 ctacactgca acttgtttct ctttcccatc tcagaaacag caacaaatct cccttcacta 66301 agaggtcctt caccagcctc ctctcccggc attatcccat ctacccctcc acattcaagt 66361 ttttggaaag attctacact cccagtctct acttcctcac ttcttccttg ctgcccacgc 66421 cataaactag ctgctgcctc cagcattgcc ctgacaccta gtggctggtg tcaccaagac 66481 gctagaccca atggttattt atttatttat ttacttattt tgagacggag tctcactctg 66541 tcgcccaggc tggagtgcag cggtgccatc tcggctcact gcaacttccg cctccagggt 66601 tcaagtggtt ctcgtgcctc agcctcccaa gtagtttgga ctacaggtgc ctgccaccat 66661 gtctggctaa tttttgtatt tttagtagag acagggtttc accatgttgg ccaggcttgt 66721 cttaaactcc tgacctcaag tgatccaccc acctcggcct cccaaaatgc taggattata 66781 ggcgtgagcc accgcacccg gccaatggtt gtttttcagg tcttctcttg cttgacttcc 66841 cagagggatc ccttactgtt gcacctaccc ttctgggaac tctcttcctc tggcgtctgt 66901 gatatttccc tctcctgctg gctcctccct ctccagatgc tgtttctcac atctactctc 66961 ttctagagag tgtggtagac agaataatgg tcaccaaaga tgtccctgca tgaatccctg 67021 gaacttgtga atatgatagg ttaaatggcc aaaagggaat taaggttgca gatggaatta 67081 agctgaccaa tctcctgatt ttattttatt ttattttgtt tttgaggtgg agtttcgctc 67141 ttgttgccca actggagtgc aatggtgtga tctcggctca ctgcaacctc cgcctgccag 67201 gttcgagaga ttctcctgcc tcagcctccc gagtagctgg gattacaggc acccgccatc 67261 atgcctggct aattttttaa atttttagta gagacagggt ttcgctatat tggccaggct 67321 ggtcttgaac tcctgacctc aggtgatccg cccacctcgg cctcccaaag tgctgggatt 67381 acaggcgtga gccaccgtgc ccagcctatc tatctattta tttatttatt tttgagatgg 67441 agttttgctc ttgttgccca ggctagaatg caatggtgct atctcgactc accgcaacct 67501 ccacctcccc ggttaaagcg attctcctgc ctcaggctcc tgagtagctg ggattatagg 67561 catgtgccac cacgcctggc taattttttg tatttttagt agagatgggg tttctccatg 67621 ttggtcaggc tggtctcaaa ctcctgacct cagatgatcc acccacctgg gcctcccaaa 67681 gtgctgggat tataggcgtg agccatcata ccaggctcta ttgatttatt tttattttta 67741 tttttgagac ggagtctcgc tctgttgcct aggctggagt gcagtggcac aatcttggct 67801 cattataact tccgcccccc cccaggttca agccattctc ctgcctcagc ctcccgagca 67861 gttgggacta caggcgcgtg caaccatgcc tggctaattt ttgtattttt agtagagacg 67921 gggtttcact gtgttggcca ggctggtctc gaactcctga ctttgtgatc tgcctgcctc 67981 agcctcccaa agtgctggga ttacaagtgt aagccaccac gcccagccta ttttgtttat 68041 tttttcaaag acccttgaca cccaggctgg agtgtagtgg cactgtcata actcactgca 68101 acctccgtct cccaggttca agcgattctt gcacctcagc ctccctagta gctaggagta 68161 caagtacgtc ccaccacacc tggctaattt atttttattt ttgtagagat ggggtctcac 68221 tttgtttccc aggctggtct aaacttctgg tttcaagcaa cctteccacc tcaaagtgct 68281 gggagtacag gcatgagcca ccaccacacc tggcctaatt tgctgatttt tatttatttt 68341 ttattattta tcttaatttt tattttgaga cagagtcttg ctctgtcatc caggctggag 68401 tacggtggtg caatctcagc tcactgcaac ctccccctct cgggttcaag cMattcttgt 68461 gcctcaacct cccaagtagc tgggattata ggtgctggcc accacgcctg actaattatt 68521 gtaatttttt ttttttttag tagagacggg atttcaccat gttggccagg ctggtcttga 68581 actcctgacc tcaagtgatc cacctgcctc agcctctcaa agtatgggga ttacgggtgt 68641 gagccgccgt gcctggccca atttttgtat tttcagtgga gatggggttt tgccatgttg 68701 gccaggctgg tctggaactc ctgacctcag gtgacccgcc tgcctccgcc tctcaaagtg 68761 ctgggattac aggcataagc caccatgcct ggcccacagg ggtccttaaa aaatgaagga 68821 ggatggcaga agaaagtcag agggagatgt gagtaaagaa aaaagacaca gagagctgca 68881 atgtttctgg tttgaagatg gaggaagggg attgtgagct aataaatacg ggtggcctct 68941 aaaggcaaga aagggtaaag aactggattc tcactctaga gtcaccggga aggaactatc 69001 aacatcttga tttcagccca gtgagactct gtcagacttc taagctacag aactgtaaga 69061 taaatttgtg ttgttttaca tcattaaatg tgcagtaact tgttacagca gcaattagaa 69121 atgaatacag aggactgggc attaggcctg tatctcagct ttctctgatc tcctggtgtg 69181 ttcctgttat ttattgttgg tttcccccag aatgagtgat ctaagaggaa gcaaaataga 69241 agccgcaatc tctttatgac ttagcctcag aagacacaca ctggggccag gtgcagtggc 69301 ttatgcctat aatcccagca ctttgggagg ctgaggcagg aggaccactt gagcccagga 69361 gtttgagaca ccctggacaa cacagggaga ccctcactct ataaaaaata aacaaaatta 69421 gccaggtgtg gtggtgcaca cctgtagtcc cagaactttg ggaggctgag acaagacaat 69481 gacttgagcc caggagtttg agacaggtct ggacaacgtg gtaagactct gtctttataa 69541 acatttttaa aattaggcgg ggcatggtgg ctcatgcctg taatcccagc aatttgggag 69601 gctgaggtgg gtggatcacc tgaggtcagg agtttaagac aagcttggcc aacatggcga 69661 aaccYcgtct ctactaaaaa Yacaaaaatt agccgggcat ggtggtgggt gcctgtaatc 69721 ccagctactc aggaggctga ggcaggagaa tcatttgaac ccgggaggtg gaagttgtag 69781 tgagccgaga ttgccttcct cactccaaga gttataaaag attttgacca tattttcttc 69841 tagcatttaa tcaattaatt aattaatgtg agacagtccc actctgctgc ccaggctgaa 69901 atgcagtggt gcaatctcgg ctcactgcaa cctctgcctc ccggattcaa gtgattctcc 69961 tgccttagcc tcctgagtag ctgtgattac aggcaccagc cactatgcgt ggctgatttt 70021 tgtgttttta gtagagacgg ggtttcacca tattggccag gctggtctca aactcctgac 70081 ctcatgatcc Rccctccttg gcttcctaaa gtgctgggat tacaggcgtg agccactgtg 70141 cctggccttt ttctttcttt tttttttttt ttcattagag atgagttgtt gttatgttgc 70201 ctctaactcc tgggctcaag cagttctccc accctggctt cccaaagtgc tgctgggatt 70261 acaggagtga gccactgccc ccagcctctg acagtttttg tgcactagga atttgggaag 1R~

70321 acaattttac ctggctattt ctggctcata caattgcagt cagatggtgg ctaaagctgg 70381 aacaataagc agctaaaaca gctgaaagat aacctagcat tctctctccc tttctctgag 70441 tagtctccga acctatctat gttgtcctct gcatgggcta gcttgggctt cctcacagca 70501 tggcagcctt aaggctttaa tagtcagctt ccaaaatggt cctcagtgat tcctgcttcc 70561 tggtattgat accattgtga agtctcttct cacattgaaa ggggctgaac tggcccattg 70621 ggataatgca gaaatgacag tgtgtgactt tagaggctaa atcatgaaga tattgtggct 70681 tccatcttgc tcctttgtag atcactcatt ctagacaaag ccagctacca tgatatgaaa 70741 gcactcaagt aaccctaggg agagaggtct ccttagtgag gaactgaggc cctgtaagaa 70801 acgtgggtgt gctgcagtca agtgggcata ggccaaagta aacatccaga gtgactcagt 70861 gagtttagag tgcaggcata tagctccact tgttatcaca gccgtgtagc cataacatgg 70921 gaaggctcat cacttggctc tgagccactg ttgtctgtaa aaggtataat tgccctgctg 70981 acactgtgca cagggctcgg cccaacatgg cttgacatgg gacatggctc ttgtgcaggt 71041 gcttgtaccc agagaaagag agaaagccag agctgtccat ctcggggaag ccaagacaca 71101 gctcagctag ctcatgccca gagggagaaa gagtaaggct gtggggtgtg gtggctcatg 71161 cccataatcc cagcactttg ggaggccaag gcaggtggat cacaaggtta ggagtttgag 71221 accagcctgg tcaacatggt gaaacccctt ctcaactaaa aatacaaaaa ttagctggcc 71281 atggtggtgc atgcctgtaa tcccagctac tcaggaggct gaggcaggag aattgcttga 71341 acccaggagg cagaggttgc agtgagccga gatcacacca ctgcactcca gcctgggcaa 71401 cagcgcgaga ctccatctca ggaaaaaaag aaaaaagaaa agaaaagaaa gagtgaagct 71461 gctgaccctg aagggagagc tggccacaca gctgtgtgtg tgtgggagct gccggagtaa 71521 gcagctgaga cagagcagac agtgcgagag taagatgttg atgatgagag agctgctgaa 71581 taaagccatg tctcatttac ctgctgtctc tcgagtgttc ttctagctcc ctgcctcacg 71641 tccactgctt cctctcacac ctcagctggg gctggacccc aaccctgagc atgacgggcc 71701 ttctgtcaac aaccagcagt aacctgctgg gcatgtgagg gagctacctt ggaatcagat 71761 tctgtaaaac agtcacgcct tcagatgacg gtagcattgg ccaacatttt gactgcactt 71821 catgagagac cctgagccag aaccccctag attectaacc caaggaaact gtgtgtgata 71881 agtgtttatt gttttttttt tttttttttt tttttgagaa agagtctcgc tctattgccc 71941 aggctggagc acagtggcac aatcttggct cactgcaagc tccgcctctc aggttcacac 72001 cattctcctg aatcagcctc ctgagtagct gggactacag gcacccacca ccacgcctag 72061 ttaatttttt tgtattttca gtagagacag ggtttcaccg tgttagccag gatggtctca 72121 atctcctgac ctcgtgatcc gCCCgCCtCC gcctcccaaa atgctgggat tacaggcgtg 72181 agtcaccaca cccggccagt gtttattgtt ttaagatatt ggctaggcgc agtggttcac 72241 acctgtaatc ccagcacttt ggaaggccga agtgggagga tcacttgagc tcaggagttc 72301 aagttcaaga acagcctggg caacatagtg agaccttgtc tctatttaaa aaaatgtttt 72361 taagatgtta tgtttgagct gggtatggtg tggctcacgc ctgtaatccc agcactttgg 72421 gaggctgagg tgggtggatc acctgtggtc aggagatgga gaccagcctg gccaacatag 72481 tgaaaccccg tctctactaa aaatacaaaa aattagctgg gcatggtggt gggcgcctgt 72541 aatcccagct actagggagg ctgaggcagg agaatcgctt gaacccggga ggcagaggtt 72601 gcagtgagcc aagatcgtgc cattgcactc cagcatggtg ctatgttttg gaggtaattt 72661 gttacacagc aataaataat tcgtacaggg caccagcctg gccaacatgg agaaaccctt 72721 ctctagtaaa aattatccgg gtatggtggt gcatgcctgt aatcccagct acttgggagg 72781 ctgaagcagg agaatccctt gaacctggga ggtggaggct gcagtgagcc aagatcgcac 72841 cactgcactc cagcctgggt cacagagcaa gactctgtct caatttaaaa ataaaataat 72901 aataatatag ggcagtcaga ctgcccacct ggcagctcag gactagcaca tgtgctccag 72961 aaagccaggt ggaagctaca tattttatga tctaaactca gaagtcatat agcatctgtt 73021 ccactgtaat cacaagcctt cccagttcca aggggaggga acatagactc cctcacctct 73081 tgatacaaga agtgtcaaag ttatatggta agaagttggc caggccctgc ttgtctctgt 73141 tgttcatgcc tgtaatccca gcactttggg aagacgaggc agatggatca cctgaggtca 73201 ggagtttgaa gccagcctgg ccaacatggt gaaaccctat ctctacaaaa atacaaaaat 73261 tagctgggca tggtggtatg cacctgtaat cccagctact tgggaggcca aggcacgaga 73321 attgcttgaa gctgggaggc agaagttgca gtgagccgag attgtgccac tacactctgg 73381 cctgggttac agtgcaagac tctgtctcaa aaaaaaaaaa aaaaaaaaag agagaagttg 73441 gttgggccca gtggctcacg cctgtaatcc caacactttg ggaagctgag atgggaggat 73501 cgcttcaggc cagaagatcc atcgttacca gcctgagcaa cacaaggaga tcccgtcctt 73561 acaaaatttt tttaaaaatc agctgggtgt ggtggcaggc acctgtggtc acagctactc 73621 gggatgctga ggtaggagga tcgcttgagt cagggaggtt gtggctgccg taagccatga 73681 acatgccatt gcattctagc ctgggtaaca gagtgagaca ctgtttcaga aaaaataata 73741 aaataaaata aataatgttg taggacaggc gtggggctca cgcttggaat ttcagtgctt 73801 tgggagactg aggcaggagg attgcttgag aacaggagtt cgaggctgca gtgagctgtg 73861 atcgcaccac tgcactccag ccttggtgac atgagcgata tcttgtctca ataaataaat 73921 acatacagtt ctcttttaca tcgagtatat gtaaattttt aaaaatacat tgaaagcgct 73981 tagaaagccg cctgactctc cctctccctc tccctctccc tctccctctc cgtctccgtc 74041 tccgtctccg tctccgtctc cgtctccgtc tccctccacg gtctccttcc acggtctccc 74101 tctgatgccg agccaaggct ggacggtgct gctgccatct cggctcactg cagcctccct 74161 gcctgattct cctgcctcag cctgctgagt gcctgcgatt gcaggcgcac gccgccacgc 74221 ctcactggtt ttcgtttttt tttttggtgg agacggggtt ttgctgtgtt ggccgggctg 74281 gtctccagct cctagccgcg agtgatccgc cagcctcggc ctcccggggt gccgggattg 74341 cggacggagt ctcgttcact cagtgctctg tggtgcccag gctggagtgc agtggcgtga 74401 tctcggctcg ctacagcctc cacctcccag ccgcctgcct tggcccccca aagtgccgag 74461 attgcagcct ctgcccagcc gccaccccgt ctgggaagtg aggagcgtct ctgcttggcc 74521 acccatcgtc tgggatatga ggagcctctc tgcctggctg cccagtctgg aaagtgagga 74581 gcgtctctgc ccggccgcca tcccatctag gaagcgagga gcgcctcttc cccgccRcct 74641 tcccatctag gaagtgagga gcgtctctgc ccggccgccc atcgtctgag atgtggggag 74701 cacctctgcc ccgccgccct gtctgggatg tgaggagcgc ctctgctggc cgcaaccctR
74761 tctgggaggt gaggagcgtc tctgcccggc cgccccgtct gagaagtgag gaaaccctct 74821 gcctggcaac cgccccgtct gagaagtgag gagcccctcc gtccggcagc caccccgtct 74881 gggaagtgag gagcgtctcc gcccggcagc caccccgtcc gggagggagg tggggggggt 74941 cagccccccg cccggccagc cgccccatcc gggaggtgag gggctcctct gcccggccgc 75001 ccctactggg aagtgaggag cccctctgcc tggccagtcg ccccgtccag gagggaggtg 75061 ggggggtcag ccccccgccc ggccagccgc ccagtccggg aggtgagggg cgcctctgcc 75121 cggccgcccc tactgggaag tgaggagccc ctctgcccgg ccagccgccc cgtccgggag 75181 gggggagggg gggtcagccc cctgcccggc cagccgcccc gtccgggagg gaggtggtgg 75241 gggtcagccc cccgcccggc cagccgcccc gtccgggagg tgaggggtgc ctctgcccgg 75301 ccgcccctac tgggaagtga ggagcccctc tgcccggcca gccgccccgt ccgggaggga 75361 ggtggggggg tcagcccccc gcccggccgg ccgccccgtc cgggaggtga ggggcgcctc 75421 tgccccgccg cccctactgg gaagtgagga cccctctgcc cagccagccg ccccgtccgg 75481 gagggaggtg ggggggtcag ccccccgccc ggccagccgc ccagtccggg agggaggtgg 75541 ggggatcagc cccccgcccg gccagccgcc cagtccggga gggaggtggg gggatcagcc 75601 ccccgcctgg ccagccgccc cgtccgggag gtgaggggcg cctctgcccg gccgccccta 75661 ctgggaagtg aggagcccct ctgcccggcc agccgccccg tccgggaggg aggtgggggg 75721 gtcagccccc cgcccggcca gccgccccgt ccgggaggga agtggggggg gtcagccccc 75781 cgcccgacca gccgccccgt ccgggaggga ggtgggggga tcagcccccc gcctggccag 75841 ccgccccgtc cgggaggtga ggggcgcctc tgcccggccg cccctactgg gaagtgagga 75901 gcccctctgc cctgcttgaa ggcagcatgc tcgttaagag tcatcaccac tccctaatct 75961 taagtaccca gggacacaaa cactgcggaa ggccgcaggg tcctctgcct aggaaaacca 76021 gagacctttg ttcacttgtt tatctgctga ccttccctcc actattgtcc tatgaccctg 76081 ccaaatcccc ctctgcgaga aacacccaag aatgatcaat aaaaaataaa aataaaaaaa 76141 aaaaaataaa aaaataaaaa aaaaaaaaaa gaaagccgcc tgacctgtat acagtattct 76201 gaaaaggggg tcgcgaggtg catgtccaac ctccgccgcc gggggcagca gcgagtccag 76261 gccgagccgg ggcctagcga gcggggtcaa atggggtgag gcctgtgcca gacctctcca 76321 cctcggtggc agccgcagcc tcctccgcct gcggctcctg tccacgccgc ggccacgtga 76381 gcgccagatt ctggcgcaca gaccactgcc agtcctttgc tgctttgcgc agcctgtcct 76441 ccccgccagg agcacccttc ccgctccctt ttaccacggg ctccagccgt ggctgccttg 76501 gggctgccgc cgcctggctg taYtccagga cgttgggaaa gaacgggtgg gaatggtgtg 76561 ggtgggggtc aaagaggaaa cccagagatg cagggcgccc ctttcccgtg gtctgccccc 76621 aattgctcag gcaggccagt cacggtgagg cgtcctccct ccaagtttat atttattatt 76681 atttattatt tatttttttc accttcaagt ttattattta ttatttattt atttattttt 76741 gagacggagc ctctctctgt cgcccaggct ggagtgcatt ggcacgatct tggctcactg 76801 caacctccgc ctcccgggtt caagcgattc ttctgcctca gcctcccgag tagcagggat 76861 tacaggtgca tgccaccaca tccggctaat ttttgtattt ttagtaaaga cagagtttca 76921 ccatattggc caggctggtc tcgaactcct gacctcaggt catctgcccg ccttggcctc 76981 ccaaagtgct gggattacaa gcatgagcca ctgcacctgg ctaacctcca agtttaaaga 77041 cagccgccag gcccagtggc tcactcctgt aaccccaaca actcaggagg ctgaggccag 77101 gaatttgaga ccagcctggg caacatagcg agaccccggc tctaagaaaa ataggccagg 77161 cacggtgggt tacgtctgta atcccagcac tttgggaggc tgtggcaaaa ggattgcctg 77221 agggggaaaa aatcaccctg ggggtagtgg tgcacactta cagtctcggc tacttgagag 77281 gctgaggtgg gaggatcatt taagtcggag gctgcagtga gctactatgg agcgactgta 77341 ttacagcttg agcaacagag cgagacccca tctccaaata aataaataaa gatagcctcc 77401 aaagatgtca cttgcttcac ttagcacttt ttattgaaca tatttaggaa atatataacc 77461 atggtaaaga aaattgcaat tagtacaaat acacactaca cacatatgca cgtgcacaca 77521 ctgaaacgtg tcccttccag cgcctcctgc ctggataatt tttttttttt ttgcaacgga 77581 gttttgctct tgttgcccag gatggagagc agtggcggga tatcggctca ctgcaacctc 77641 ctcctcccgg gttcgagcga ttctcctgcc tcagcctcgc gagtagctgg gattacaggc 77701 gccagccaca acacccggct gatttttgta tttttagtag agacggggtt ttgccaagtt 77761 ggccaggctg gtctggaact cctgagatcc gcccacctcg tcctctcaaa gtgctgggat 77821 tacaggcctg agccactgcg cctggcctaa agtaattgtc ttcttattgg tttctctgcc 77881 tttggtctca ccaaacgccc cactctaaat cactgcagac aaggggttct gtctaaggag 77941 gagagcccac cagttaaaac ccttcagtag ttcctaacta ccctaggaca aatgcagact 78001 tatccttcgc tctctgctgc cgcccctctc cttcccagat cccatatggc tccagccata 78061 tcctcagacc atctgggctg ttgtctgtcc tgccacacac ccttcccacc ccgctccctt 78121 gcaagtccta ctcaggctgc acctacacag ctgtctcagt ttctatctga ggctcccgca 78181 gcctcctctg aaagtcctca tcacagccaa tgatactgaa actgttttct tatgcagggc 78241 acggaaagat ctattcaact cactgcccaa tctcctctcc tggtgcagaa aagacaccca 78301 gtcagcgact tgcattatct gcaggcatga gtgaataata ataatgccta acccttatat 78361 agtgctaatt ccacgcctgg cactgttcta ggcactcata taaattcatg taatccacac 78421 aaccccaaaa ctgatgatat ctcttcatct taccaagcac tgagcagtta aataacttgc 78481 tccagatatt aaggggtcga gctggggttt gaagcctggt tacccataaa tgaaccaaga 78541 actggaagga ggacaagaSc tccgagaagg agtcaggtag ggcgtgatct gtgcgcttta 78601 catctaagat cttccagctc ccagggagcc cgtttcatag agcaggagat agaggctggg 78661 agggacacgg agagcctcga gagccgtgtg gaggaagcgg tgctgtttgg ggtccgggag 78721 caagggcgtg gcctggatgc gcgggcgccc gggacggcac gtcctcagac caaactacaa 78781 ctcccaggac ccagcgggcg ctgccgccca cgcgacgtca cggcggcgga gggcgcaggc 78841 ggctgggcgc ctggcgagtg gactgttcga gcccttccgc tgggacccgg gccctggctc 78901 cggccccgcg gtaagtgggg cgaccccagc ctactcagtc cgcggaggcc ccgcggcgca 78961 cgtccgcagc ctccatcaca gcgcgggcgc gcagacgggg ctggcatcta ccatatgggg 79021 ggcatccggg ccgaaccaag tgacccgcgt ggggggtccc gctggggact ccgtgccgca 79081 ccctcccaag ccggccccag gggcccaggg ctggtgtcgc acgttcgctg gccgcgctcc 79141 cagggcccgg gtttgaaggc gctgggcagg caggggcagc cccgccccct gagaagggta 79201 cccgggaccc cggggcgctg gggcgaggtt ttcgggctgg aagggtctga ggggctcctc 79261 ccccgacagc cctcccaccg ccagtagagc ctcgggttgg ggaatagaag cccccgggag 79321 gctaggtcct ttgggcgcgg cctgtgtgca tctggggaga cggtgggagt ggtggggaga 79381 ggtcgcccgg gtctggggag accgatgcac aggtggagag atggtgcggg ttctgtggat 79441 tcggatcctt acaacttcct cttccccgcc ccggtagatg ggagctgctc tccgcgggct 79501 gagcctgtca gcatcctcga cgcaccctgg tccctgaagt cggagaagMg cccctaccca 79561 cccacacccc cttgccccat tttgggtcgc ctgggtcctc agtcctagcg gatcctcagt 79621 cctagcggcc accgggtctg aaaggagcaa gacgatgatc ctggcgtcgg tgctgaggag 79681 cggtcccggg ggcgggcttc cgctccggcc cctcctggga cccgcactcg cgctccgggc 79741 ccgctcgacg tcggccaccg acacacacca cgtggagatg gctcgggagc gctccaagac 79801 cgtcacctcc ttttacaacc agtcggccat cgacgcggca gcggagaagg tgcgcaaggg 79861 ggcagccagc ccagggtccg gRatgtaggc gggagggaga gtgttggggg ttctctgctc 79921 aaggcctctc tccctctcta gccctcagtc cgcctaacgc ccaccatgat gctctacgct 79981 ggccgctctc aggacggcag ccaccttctg gtaagattca cgccctctat tttcctcgtg 80041 gatcctggag ctctcccaga cactcaggct ccagccccgc cttcccttct cattttctcc 80101 cagaaaagtg ctcggtacct gcagcaagaa cttccagtga ggattgctca ccgcatcaag 80161 ggcttccgct gccttccttt catcattggc tgcaacccca ccatactgca cgtggtaagg 80221 tagagaggac cttaggtcag cgggccaccc tgccccgggg gcaagtgggg agtctggggc 80281 ccagagtggc agacgattgc ttgcctaaag gtgtcagggc cacacaggat tcaaccccag 80341 gccttcagaa gccaaaggtg tgtattcacg gagcctggaa gggtcgaagt gggggtttga 80401 tcacgtggtc gaccagctgg gtggtgatcc ccatgggtag gtgggggtgg ctgttctctg 80461 ctcagtgccc atgcggcttt gtgaattccc acacctcttc cttgcagcat gagctatata 80521 tccgtgcctt ccagaagctg acagacttcc ctccggtgag tgctgggcca gagcagggtg 80581 aggggctgag aggttgggct tggaccaccc ttcctcatga ctctgtgacc tgcagatcaa 80641 ggaccaggcg gacgaggccc agtactgcca gctggtgcga cagctgctgg atgaccacaa 80701 ggatgtggtg accctcttgg cagagggcct acgtgagagc cggaagcaca tagaggttgg 80761 ggcagcaaag gagaggccgg gcctgctggg ggtgggaagg gcacgggatt ctgagacctc 80821 actctttaca ggatgaaaag ctcgtccgct acttcttgga caagacgctg acttcgaggc 80881 ttggaatccg catgttggcc acgcatcacc tggcgctgca tgaggacaag gtggggctct 80941 gggacctgag acccacctgg gaacattaag tgagacagag gagactgggc tggggatccg 81001 ggtcaagggc ctgggggctg aggctgtggg gctggtgctt tggggcagtt ccgaagttgc 81061 cagcatcttg gggtggggct aggggcgtgg gtagtcctga cctcctttct ccggccagcc 81121 tgactttgtc ggcatcatct gtactcgtct ctcaccaaag aagattattg agaagtgggt 81181 ggactttgcc aggtgaggca agaatggctc agggggtggg cagacatctg gggcagggaa 81241 ggcttgggtc tgagcccttg cccggggcat gatctgcggg gagcagggtt tctcaaccat 81301 ggcactattg acatttccag ccagataatt ctttgtcaYa ggggctgccc cgtgcacgtt 81361 aggaagttca gcagcatccc tggcgccagc agtactgcct agttgtgaca aacaaaaatg 81421 tctctgcaca ttgccatatg ttacttaggg gggcagaatt gtttccagtt gcaaaccact 81481 ggtggagggg cccctgactg aaccctcgct cctatccgca gacgcctgtg tgagcacaag 81541 tatggcaatg cgccccgtgt ccgcatcaat ggccatgtgg ctgcccggtt ccccttcatc 81601 cctatgccac tggactacat cctgccggag ctgctcaaga atgccatgag gtggggtggc 81661 ttgatgtgct ggcttggggg Yggacaggaa ccgggNtgct tgtacctact ggtctttccc 81721 ctctgcatag agccacaatg gagagtcacc tagacactcc ctacaatgtc ccagatgtgg 81781 tcatcaccat cgccaacaat gatgtcgatc tgatcatcag gtttgccctg agtgggagtt 81841 gagctgaggt ggatgggatg ggggtctagg cactgtttct gacttgattt aggaccttga 81901 gccccttcct gccccattct gggacttggt ccctgaccag acaaactatt ctctgaatcc 81961 tgagatggcc atgagctgct tattaatgga tctggggcca gctgcaggcc taggtatcct 82021 gcctctgtca gcagctgagg agcttgaaat tgagaaatag tcaggagtcg gtctaggatg 82081 ctgggccgag gataaatgtc acatcctgtg agaaggtata agcagtcagt ggccctggca 82141 ggggtgagga tgatataaac aaggcccaag ggtctaggtg gaccacattc cagctctggg 82201 tggaaggaac aggaaggcag actttgcact gtctgcttgg ggggtggtga gtaccccatc 82261 aaagctgagc caagcccatt gttgttgcca tcttgctagg atctcagacc gtggtggagg 82321 aatcgctcac aaagatctgg accgggtcat ggactaccac ttcactactg ctgaggccag 82381 cacacaggac ccccggatca gccccctctt tggccatctg gacatgcata gtggcgccca 82441 gtcaggaccc atgcacgggt gagaccctgc caggccagga tggaggggtg ggggacccca 82501 ggagactcaa gCCtCtgaag CCtCCtgtCC tgtCCCCCtg CCCaCCCCCa gCtttggCtt 82561 cgggttgccc acgtcacggg cctacgcgga gtacctcggt gggtctctgc agctgcagtc 82621 cctgcagggc attggcacgg acgtctacct gcggctccgc cacatcgatg gccgggagga 82681 aagcttccgg atctgacccc acagcctttg gcctgctcac ccgaccagcc tgggccgcat 82741 tccctgcagg acctcccggg tcaggcaggg cggccccctg ctccacacac tgctgcatct 82801 tgggtctcag ggacccagac agatggactt acatggagct gggcactgcc ctgcctcaac 82861 agggtccatt gcctcctcgc ctccagaact tggagcaggg aagtgggcac cctgaggcct 82921 ccagcaccag ttccgtcatt ctcgttcctg gggaaccccc actctgacct gttattaaag 82981 ttcacatttt gaatgccctc tcgggccccg tgtgtgggga gggcaggtga acttttgttt 83041 ctgcccccat tcaggttcac tgagcccttg ggttgaactg gttcgtgtcc cagtctctta 1 St H

83101 cctgccctga gagcctggca ggccaggagt agaatgggtc ccaagtctgt tgcatgtttg 83161 atttggtggg agtgggatga ctgcagcacc ttatacaaag agctttcatt catcttgttg 83221 aacaaatgtt tccgggtccc agataatatt gaaggcccag actgacccag cttcgggcat 83281 cagttttgac tcttcctttc ctggcagtca cagtttctag aggtgaaggt caccagactg 83341 ggcaaactcc tgagccaact gcttcccaag cctgagtagg ttaaaaatac tgtgtctgct 83401 gctgccaagg aaaagaacat acaaggttgt gccttggcag gccctagcag ggactgggtg 83461 ccccactgca aggaaaggtg gggccctgat agaaaggacc aaggatttgg gcaaagRtat 83521 caggtaggct caaggttaga cctgaatcag aactccagat gacatcttag gtaggaacac 83581 cctacccacc ttgccaggga agaaaggcct aagggcggcc tggtggggct gggaggagaa 83641 ctggaaagtt ctcttgcctt cacatgtgag ctcccacagc aaacttcctg aggctggctc 83701 taggcctgta ccatctccta cccttcacgg ggatggaggg gaagttgtat gtggaagcca 83761 aatggcaggg gctaggaaac cacagtgact tgctagactg aaaaatcccg ccagctgcaa 83821 ggcagggtgc tgaggctgga gaggcaggca gcagtcagag gccagggccc tgaaacatgg 83881 gatttatctt gagccatagg gatccatggg tgagttttta tttatttaga aatggggtct 83941 tgctctgttg cccaggctgg aatatggtgg ctgcagagtt cactgcagcc ttgaactcct 84001 gggatcaaga gattctccca cctcagcctt ctgagtagct tggaccatca tgccaggcta 84061 aattttaaaa ttttttgtag aaacagggtt tctacaaagc cctatgttgc cccgggctgg 84121 acttgaactt ctgggctcaa atgatccttc caccccagcc tcccaaagtg gtggggttac 84181 aggcatgagc cactgcagct ggcccatgag tgggttttga gctgggaagg gatgtttctg 84241 gttggagtcc ctgagaggat tcatgtccac gtgatttctt aagaaagtgc tcccagaaca 84301 gagtagggga agtaggaagg ggaaggggag gaagccaagc aaggatgtga cctcaggcaa 84361 aagcccagaa ccagtcaatt atgcctcagg gttgaaggta agagagctaa acctcagagt 84421 tactgattaa tttctccact tggcagtcac tggttaaagt cagttgggaa agtgaacagc 84481 tctattaacc taaggatggt tttttaagaa gagcctcagg tgctggtgtg ggtctttgaa 84541 agcacatcaa aggtaatctg ggcacacaga aacagcaaga actcccagag gatctgggtg 84601 gagcacctac attgtttttt tgtttgtttt gtttcgtttt gtttttttaa acggagtctc 84661 aatctgttgc tcaggctgga gtgcagtggc tggatcttcg ctcactgcaa cctccgcccc 84721 accccccccc aaccccaggt tcaagcgatt ctcctgcctc agcctcccga gtagctggga 84781 ttacaggcgc gtgccaccac acccagctaa tttttctatt tttagtagag atggggtttc 84841 accacgttgg ccaggctggt ctcgaactcc caacctcgtg atccatccac ctcagcctcc 84901 caaagtgcca ggattacagg catgagccac catgcctgtc ggatgtttct tgatttgtaa 84961 cctctgagag acccatccgc aggccctgag cattccactc ctctcagaat tgtttccaag 85021 cccaataacc acattataaa tcaaacaaga ttcagagaat agccaaaggg aatgtttact 85081 gagtacctac ccggtctggc actttgcaat acacttgtat attgctaaga cggatagttc 85141 aaccgttaca tagttatatg attgatagtt atacatgctt aactgctggg gattggttcc 85201 aggaccgcct gtgaataccg aaatctgcag gcgctcaagt cctacagttg gccctgccaa 85261 acagcagata tgaagtcagc tcttcagatc tgtgggttct gcatccttac aatatttcct 85321 ttcctttcct tttcttttcc tcccttcctc cctctttttt ctttttcttt tttgagatgg 85381 agtcttgttg tgtcggccag gttggagtgc agtggcgcga tctcggctca Mtgcaacctc 85441 cacctcctgg gttcaagcag ttctcctgcc tcagcctccc aagtagctgg gattacaggc 85501 acacgccacc acccctgact gttttgtatt ttcagtagag acggggtttc acaatgtggg 85561 ccaagctggt tttgaactcc tgacctcaag taatccacct gcttcggcct cccaaagtgc 85621 tgggattaca ggtgtgagcc accgcgccca gtcttttttt tttttttttt gaggcagagt 85681 ttcactcttg ttgcccaggc tggagtgcaa tggcacaatc tcagctcacc acaacctctg 85741 cctcccaggt tcaagcggtt ctcctgcctc agcctcccga gtagctggga ttacaggcat 85801 gcggccacca cgcctggcta attttgtatt tttagtagag atggggtttc tccatgttgg 85861 tcaggctggt ctcgaactcc cgacctcagg tgatctgcct gcctcggcct cccaaagtgg 85921 tgggattaca ggagtgagcc actgcgccca gcctcctttt ctttcccccc tttttttttg 85981 agacagggtc tctgtcaccc aagctggagt gcagtggagg gattatagct cactcagcct 86041 cgacctcctg ggtttaagcg atccctctgc ctcagcctcc tgagtaggtg ggactacagg 86101 tgcgggcccc gaggcccagc taattttttt tttcccccaa atttttagta gaaaggaggt 86161 ctctatgctg cccaggctgg tcttgaactc ctggcctgaa gcgatcctcc tgcttggatt 86221 cctgaagtgc gagattacag gtgtgagcca ccatacctca acactgtatt ttcaacccgc 86281 tcttcgttca atctccaaag gtgggacatg cggatatgga gggccgattg tRtatggttg 86341 gaccatacac atataaatgg ctttaacctt tactgactct cacagaaccc tcagtgcagt 86401 ggcgtgatct cagctcactg caagctccac ctcccgggtt cacaccattc tcctgcctca 86461 gcctcccgag tagctgggac tacaggggcc cgccaccacg cccggctaat tgttttgtat 86521 ttttttttag tagagacgga gtttcatcgt gttagccaga atagtctcga tcttctgacc 86581 tcgtgatcca cccgcctagg cctcccaaag tgctgggatt acaggcgtga accaccgcac 86641 ccggcctttt tatttttttt gagatggagt ctggctcttg gtccccaggc tggagtgcaa 86701 tggcgggatc tcggctcact gcaacctccg cctcccgggt tcaagcgatt ctcctgcctc 86761 agcctcccga gtagctggga ctacaggtgc gtgccaccac gcccggctaa attttgtatt 86821 tttagtagag acggagtttc acggtgttag ccaggatggt ctcgatctcc gcccgcctcg 86881 gcctctcaaa gtgctgagat tacaggcgtg agccaccacg ccccgcccaa ctcgtccttt 86941 ctttagactt tatcctgtga gggtgaatta tggcctgtcc ctggacacac ccgttctgct 87001 ttccccgcac caactgtatc ccaaataggg gaagtagtct cttcaacctt caaaaatggg 87061 gcactggctg ggcacggtgg ctcacgcctg taaccctagc actttgggag gccgaggcgg 87121 gcggatcacc tgaggtcagg agttcgagac cagcctggcc aacagggtga agccctctct 87181 ctactaaaaa tacaaaaaat agccgggcgt ggtggcgcgc gattgtaatc ccagctattc 87241 aggaggctga ggcaggagaa tcgcttgaac ccgggaggcg gaggctgcag tgagccgaga 87301 tcgcgtcact gcactccagc ctgggcgaca gagcgagact ccatctcaaa aaaaaaaRag DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (60)

1. A method for identifying a subject at risk of osteoarthritis, which comprises detecting the presence or absence of one or more polymorphic variations associated with osteoarthritis in a nucleic acid sample from a subject, wherein the one or more polymorphic variations are detected in a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A, or a substantially identical sequence thereof, or a fragment of the foregoing;
whereby the presence of the polymorphic variation is indicative of the subject being at risk of osteoarthritis.

2. The method of claim 1, which further comprises obtaining the nucleic acid sample from the subject.

3. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 31118000 to 31129000 of chromosome 16 in human genomic DNA.

4. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 1 selected from the group consisting of 247, 1535, 2386, 6440, 9133, 9143, 9471, 13150, 13717, 14466, 15769, 16870, 18545, 18749, 19123, 20736, 21038, 21046, 21050, 21056, 21706, 23170, 25028, 27871, 28070, 31717, 32019, 32318, 33080, 33101, 34236, 34285, 34818, 35168, 37981, 38113, 38117, 38481, 38615, 38944, 39288, 41385, 42136, 42185, 42353, 42434, 44580, 44675, 45739, 46439, 47457, 47735, 50319, 50708, 51185, 53002, 53064, 53637, 55274, 55825, 55986, 56684, 57653, 57659, 57692, 57775, 61313, 61431, 61699, 62906, 63619, 64664, 68452, 69665, 69681, 70091, 74637, 74760, 76523, 78559, 79549, 79882, 81339, 81681, 81696, 83517, 85431, 86332, 87358, 87725, 89052, 90020, 90231, 90284, 90447, 90601, 90724, 92559, 95176, 95195 and 96822.

5. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 1 selected from the group consisting of 13150, 21046, 23170, 25028, 44580, 62906, 64664 and 83517.

6. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 36914000 to 36931000 of chromosome 4 in human genomic DNA.

7. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 2 selected from the group consisting of 211, 7217, 7895, 13308, 14279, 17026, 18271, 20417, 21843, 22069, 22145, 22519, 22539, 23236, 23256, 23402, 23499, 23620, 23871, 24136, 25427, 25866, 26541, 26576, 26689, 26720, 27113, 27164, 27186, 28341, 29160, 29844, 30665, 30830, 31061, 31523, 32326, 32346, 32358, 34909, 34975, 35066, 35096, 35375, 36304, 36712, 36770, 37342, 37412, 37884, 38077, 38300, 38301, 41189, 44408, 44493, 44571, 44670, 45219, 45258, 47261, 48473, 48771, 55292, 56479, 56747, 60620, 60688, 61058, 61129, 61577, 61961, 63351, 63926, 65798, 66043, 66044, 66246, 66318, 66547, 71238, 71283, 71492, 72274, 73762, 74209, 75284, 77347, 77589, 78096, 78606, 78862, 79135, 79146, 79456, 79609, 80086, 80119, 80766, 81110, 81269, 81668, 82433, 82559, 83298, 83821, 84121, 84147, 84543, 84554, 84691, 84727, 85678, 86699, 86700, 86792, 86832, 87045, 87140, 87365, 88342, 88498, 88589, 95502, 96968, 97448, 97568 and 98724.

8. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 2 selected from the group consisting of 23236, 32358, 47261, 48771, 55292, 60688, 72274, 74209, 77589, 79135, 79456, 79609, 80119, 80766, 81110, 82433, 84121, 84147, 85678, 86699, 86832, 87140 and 88589.

9. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 170719500 to 170766500 of chromosome 6 in human genomic DNA.

10. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 3 selected from the group consisting of 229, 6310, 11840, 11870, 12064, 13392, 16354, 16559, 16935, 17616, 17737, 18321, 18453, 18811, 20020, 21662, 23197, 23446, 24339, 25504, 27174, 28008, 29294, 29759, 30832, 44512, 44850, 45884, 46345, 48589, 53371, 53911, 53990, 55152, 55667, 58952, 59315, 60029, 61477, 62988, 63090, 64021, 65685, 70220, 70323, 70959, 73436, 82945, 82958, 82961, 82964, 82965, 83006, 83025, 83034, 83074 ,83132, 83155, 83172, 83174, 83206, 83216, 83234, 83252, 83260, 83263, 83296, 83319, 83322, 83324, 83357, 83375, 83381, 83389, 83443, 83499, 83545, 83566, 83591, 83619, 83698, 83780, 83784, 83826, 83832, 83852, 86297, 86315, 86420, 86460, 86714, 86718, 86736, 86753, 86766, 88162, 88218, 88246, 88255, 88309, 88310, 88471, 88619, 88904, 89044, 90531, 90534, 90613 and 46252.

11. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 3 selected from the group consisting of 229, 6310, 16559, 18453, 25504, 27174, 30832, 44850, 45884, 48589, 61477, 82961 and 46252.

12. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 27963000 to 27983000 of chromosome 8 in human genomic DNA.

13. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 4 selected from the group consisting of 211, 473, 1536, 5639, 17186, 17335, 25029, 25111, 28811, 28863, 30809, 40985, 45147, 45282, 46168, 46328, 49077, 51925, 52141, 52168, 60852, 62468, 65572, 79089, 79541, 79790, 90843, 90978, 91052, 91131, 91132, 94439 and 94621.

14. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 4 selected from the group consisting of 40985, 46168, 51925 and 52168.

15. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 44962000 to 45013000 of chromosome 13 in human genomic DNA.

16. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 5 selected from the group consisting of 243, 10208, 15049, 15111, 15272, 15287, 15326, 15327, 17038, 19391, 21702, 22431, 22881, 27744, 32564, 32698, 33104, 33181, 33256, 33543, 35567, 40085, 40482, 45641, 46059, 48504, 48919, 49693, 49874, 50020, 50616, 50719, 55511, 65533, 70529, 75591, 77266, 80368, 82475, 92462, 92480, 95819 and 96275.

17. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 5 selected from the group consisting of 15111, 45641, 46059, 49693, 49874, 50020, 50719, 70529, 82475, 92462, 92480 and 96275.

18. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 76196500 to 76221500 of chromosome 14 in human genomic DNA.

19. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 6 selected from the group consisting of 218, 1440, 1442, 2611, 4317, 4724, 4788, 5202, 5780, 5974, 6644, 7430, 7938, 8095, 8183, 8312, 8352, 9348, 9378, 9617, 9727, 9834, 9899, 10211, 10377, 10695, 10729, 10730, 11433, 11951, 12697, 12982, 14419, 14501, 14983, 15280, 15475, 15888, 15976, 16307, 16442, 17255, 18948, 19435, 19753, 20021, 20022, 20503, 20590, 21804, 21919, 21990, 22412, 22536, 23432, 23468, 23772, 24325, 24773, 26274, 27440, 28561, 30071, 31764, 33008, 35310, 35460, 37112, 37285, 37747, 38057, 38859, 38860, 39525, 40216, 40281, 41453, 42091, 42513, 42935, 42985, 43003, 43281, 43716, 43866, 44234, 44596, 44871, 45005, 45282, 47178, 47816, 47887, 48134, 48135, 48276, 48400, 48798, 48803, 49146, 49969, 51059, 51064, 53285, 54560, 54748, 54785, 55102, 55644, 55705, 55841, 56623, 56825, 56827, 56892, 59150, 59958, 60231, 60524, 61871, 62226, 63230, 63468, 63787, 65732, 65989, 68832, 69904, 70365, 70886, 73088, 73103, 75934, 75966, 76273, 77943, 78466, 78861, 78872, 79836, 80908, 81509, 83576, 83662, 83782, 84282, 84444, 85129, 85151, 85296, 85809, 86387, 86494, 89786, 89894, 90122, 92067, 92187, 92312, 92824, 93733, 96553 and 96941.

20. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 6 selected from the group consisting of 4788, 8312, 9378, 9727, 9899, 10211, 27440, 40216, 40281, 42091, 43866, 48803, 51059, 55644, 56623, 73103, 78872, 79836, 85129, 92824 and 96941.

21. The method of claim 1, wherein the one or more polymorphic variations are detected within a region spanning chromosome positions 38830000 to 38844000 of chromosome 21 in human genomic DNA.

22. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 7 selected from the group consisting of 231, 882, 960, 1194, 1530, 1673, 2096, 2285, 5873, 7256, 7988, 8222, 8381, 8814, 8915, 9642, 9902, 10619, 10927, 11032, 14377, 15608, 15928, 16296, 17598, 19272, 20084, 20577, 28051, 29466, 29530, 29987, 30012, 30322, 32216, 32516, 32544, 32746, 33137, 33538, 33798, 33802, 33964, 34132, 34210, 34317, 34499, 34753, 34845, 35335, 36423, 36450, 36481, 38447, 38784, 39387, 39458, 39822, 40305, 40869, 40926, 41010, 41134, 41984, 42172, 42753, 43011, 43176, 43320, 43381, 44142, 44383, 44726, 45087, 45141, 45359, 45421, 45456, 45467, 45486, 45709, 45716, 47626, 49413, 49796, 49962, 50075, 50093, 50571, 50615, 50780, 50851, 51459, 53193, 53702, 53736, 53795, 54109, 54126, 54230, 54894, 55455, 55499, 56522, 56662, 56954, 57267, 58282, 58916, 59544, 59666, 59913, 66846, 67245, 67652, 67955, 67966, 68420, 70226, 70810, 72246, 73330, 73457, 74389, 74638, 74640, 75358, 75952, 76098, 77836, 78449, 78507, 80031, 81695, 82775, 82795, 84611, 84657, 84693, 85020, 85048, 85100, 85325, 85452, 85868, 85936, 85990, 86139, 86497, 87236, 87248, 87533, 87912, 88108, 88494, 89598, 90235, 91287, 91359, 92384, 92410, 92900, 94495, 94512, 97777 and 98333.

23. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in SEQ ID NO: 7 selected from the group consisting of 1673, 20577, 33137, 39822, 45716, 49962, 51459, 54894, 55455, 55499, 58282, 68420 and 80031.

24. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in Table A.

25. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in linkage disequilibrium with one or more positions in claim 4, 7, 10, 13, 16, 19, 22 or 24.

26. The method of claim 1, wherein detecting the presence or absence of the one or more polymorphic variations comprises:

hybridizing an oligonucleotide to the nucleic acid sample, wherein the oligonucleotide is complementary to a nucleotide sequence in the nucleic acid and hybridizes to a region adjacent to the polymorphic variation;
extending the oligonucleotide in the presence of one or more nucleotides, yielding extension products; and detecting the presence or absence of a polymorphic variation in the extension products.

27. The method of claim l, wherein the subject is a human.

28. The method of claim 27, wherein the subject is a human female.

29. The method of claim 27, wherein the subject is a human male.

30. A method for identifying a polymorphic variation associated with osteoarthritis proximal to an incident polymorphic variation associated with osteoarthritis, which comprises:
identifying a polymorphic variation proximal to the incident polymorphic variation associated with osteoarthritis, wherein the polymorphic variation is detected in a nucleotide sequence selected from the group consisting of (a) a nucleotide sequence in SEQ )D NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising a polymorphic variation;
determining the presence or absence of an association of the proximal polymorphic variant with osteoarthritis.

31. The method of claim 30, wherein the incident polymorphic variation is at one or more positions in claim 4, 7, 10, 13, 16, 19 or 24.

32. The method of claim 30, wherein the proximal polymorphic variation is within a region between about 5 kb 5' of the incident polymorphic variation and about 5 kb 3' of the incident polymorphic variation.

33. The method of claim 30, which further comprises determining whether the proximal polymorphic variation is in linkage disequilibrium with the incident polymorphic variation.

34. The method of claim 30, which further comprises identifying a second polymorphic variation proximal to the identified proximal polymorphic variation associated with osteoarthritis and determining if the second proximal polymorphic variation is associated with osteoarthritis.

35. The method of claim 34, wherein the second proximal polymorphic variant is within a region between about 5 kb 5' of the incident polymorphic variation and about 5 kb 3' of the proximal polymorphic variation associated with osteoarthritis.

36. An isolated nucleic acid comprising a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising a polymorphic variation; and (e) a nucleotide sequence complementary to the nucleotide sequences of (a), (b), (c), or (d);
wherein the nucleotide sequence comprises a polymorphic variation associated with osteoarthritis selected from the group consisting of in SEQ ID NO: 1 a guanine at position 13150, a thymine at position 21046, an adenine at position 23170, an adenine at position 25028, a guanine at position 44580, a guanine at position 62906, a cytosine at position 64664 and a cytosine at position 83517; in SEQ ID NO: 2 an adenine at position 23236, a cytosine at position 32358, a guanine at position 47261, a guanine at position 48771, a cytosine at position 55292, an adenine at position 60688, a guanine at position 72274, a guanine at position 74209, a cytosine at position 77589, an adenine at position 79135, a thymine at position 79456, an adenine at position 79609, an adenine at position 80119, a cytosine at position 80766, an adenine at position 81110, a cytosine at position 82433, a cytosine at position 84121, a thymine at position 84147, a cytosine at position 85678, a thymine at position 86699, an adenine at position 86832, a guanine at position 87140 and an adenine at position 88589; in SEQ ID NO: 3 a thymine at position 229, a guanine at position 6310, a thymine at position 16559, an adenine at position 18453, an adenine at position 25504, an adenine at position 27174, an adenine at position 30832, a guanine at position 44850, an adenine at position 45884, an adenine at position 48589, a cytosine at position 61477, a cytosine at position 82961 and a thymine at position 46252; in SEQ ID NO: 4 a cytosine at position 40985, a guanine at position 46168, a thymine at position 51925 and a cytosine at position 52168; in SEQ ID NO: 5 a guanine at position 15111, a thymine at position 45641, an adenine at position 46059, a cytosine at position 49693, an adenine at position 49874, an adenine at position 50020, a guanine at position 50719, an adenine at position 70529, an adenine at position 82475, a thymine at position 92462, a thymine at position 92480 and a cytosine at position 96275; in SEQ ID NO: 6 a guanine at position 4788, a thymine at position 8312, a deletion at position 9378, a cytosine at position 9727, a guanine at position 9899, a cytosine at position 10211, a guanine at position 27440, a guanine at position 40216, a cytosine at position 40281, an adenine at position 42091, a guanine at position 43866, an adenine at position 48803, an adenine at position 51059, an adenine at position 55644, a cytosine at position 56623, a cytosine at position 73103, an adenine at position 78872, a guanine at position 79836, a cytosine at position 85129, a guanine at position 92824 and an adenine at position 96941; in SEQ ID NO: 7 a guanine at position 1673, a thymine at position 20577, a guanine at position 33137, a guanine at position 39822, an adenine at position 45716, a guanine at position 49962, an adenine at position 51459, a cytosine at position 54894, an adenine at position 55455, an adenine at position 55499, a guanine at position 58282, an adenine at position 68420 and a thymine at position 80031; and an allele associated with osteoporosis in Table A for positions rs552, rs12904, rs2282146, rs734784, rs1042164, rs749670, rs955592, rs1143016, rs755248, rs1055055, rs835409, rs927663, rs8162, rs831038, rs33079, rs1710880, rs1078153, rs799570, rs1282730, rs1518875, rs1568694, rs905042, rs1957723, rs794018, rs707723, rs893861, rs1914903, rs2062232, rs26609, rs1370987, rs1012414, rs435903, rs1248, rs703508, rs226465, rs241448, rs763155, rs1040461, rs462832, rs804194, rs1022646, rs756519, rs1042327, rs8770, rs1569112, rs1563055, rs805623, rs1019850, rs1599931, AA, rs912428, rs279941, rs1062230, rs1859911, rs1477261, rs1191119, rs657780, rs1393890, rs1478714, rs868213, rs690115, rs1465501, rs899173, rs10477, rs926393, rs465271, rs1888475, rs13847 and rs738658.

37. An oligonucleotide comprising a nucleotide sequence complementary to a portion of the nucleotide sequence of (a), (b), (c), or (d) in claim 36, wherein the 3' end of the oligonucleotide is adjacent to a polymorphic variation associated with osteoarthritis.

38. A microarray comprising an isolated nucleic acid of claim 36 linked to a solid support.

39. An isolated polypeptide encoded by the isolated nucleic acid sequence of claim 36.

40. A method for identifying a candidate therapeutic for treating osteoarthritis, which comprises:
(a) introducing a test molecule to a system which comprises a nucleic acid comprising a nucleotide sequence selected from the group consisting of:
(i) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(ii) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(iii) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(iv) a fragment of a nucleotide sequence of (a), (b), or (c); or introducing a test molecule to a system which comprises a protein encoded by a nucleotide sequence of (i), (ii), (iii), or (iv); and (b) determining the presence or absence of an interaction between the test molecule and the nucleic acid or protein, whereby the presence of an interaction between the test molecule and the nucleic acid or protein identifies the test molecule as a candidate therapeutic for treating osteoarthritis.

41. The method of claim 40, wherein the system is an animal.

42. The method of claim 40, wherein the system is a cell.

43. The method of claim 40, wherein the nucleotide sequence comprises one or more polymorphic variations associated with osteoarthritis.

44. The method of claim 43, wherein the one or more polymorphic variations associated with osteoarthritis are at one or more positions in claim 4, 7, 10, 13, 16, 19 or 24.

45. A method for treating osteoarthritis in a subject, which comprises contacting one or more cells of a subject in need thereof with a nucleic acid, wherein the nucleic acid comprises a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c); and (e) a nucleotide sequence complementary to the nucleotide sequences of (a), (b), (c), or (d);
whereby contacting the one or more cells of the subject with the nucleic acid treats the osteoarthritis in the subject.

46. The method of claim 45, wherein the nucleic acid is RNA or PNA.

47. The method of claim 46, wherein the nucleic acid is duplex RNA.

48. A method for treating osteoarthritis in a subject, which comprises contacting one or more cells of a subject in need thereof with a protein, wherein the protein is encoded by a nucleotide sequence which comprises a polynucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;

(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c);
whereby contacting the one or more cells of the subject with the protein treats the osteoarthritis in the subject.

49. A method for treating osteoarthritis in a subject, which comprises:
detecting the presence or absence of one or more polymorphic variations associated with osteoarthritis in a nucleic acid sample from a subject, wherein the one or more polymorphic variation are detected in a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising a polymorphic variation; and administering an osteoarthritis treatment to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

50. The method of claim 49, wherein the one or more polymorphic variations are detected at one or more positions in claim 4, 7, 10, 13, 16, 19 or 24.

51. The method of claim 49, wherein the treatment is selected from the group consisting of administering a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase-2 (COX-2) inhibitor, an antibody, a glucocorticoid, hyaluronic acid, chondrotin sulfate, glucosamine or acetaminophen; prescribing a heat/cold regimen or a joint protection regimen;
performing joint surgery;
prescribing a weight control regimen; and combinations of the foregoing.

52. A method for detecting or preventing osteoarthritis in a subject, which comprises:
detecting the presence or absence of one or more polymorphic variations associated with osteoarthritis in a nucleic acid sample from a subject, wherein the polymorphic variation is detected in a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;

(d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising a polymorphic variation; and administering an osteoarthritis prevention or detection procedure to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

53. The method of claim 52, wherein the one or more polymorphic variations are detected at one or more positions in claim 4, 7, 10, 13, 16, 19 or 24.

54. The method of claim 52, wherein the osteoarthritis prevention is selected from the group consisting of administering a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase-2 (COX-2) inhibitor, an antibody, a glucocorticoid, hyaluronic acid, chondrotin sulfate, glucosamine or acetaminophen; prescribing a heat/cold regimen or a joint protection regimen; performing joint surgery; prescribing a weight control regimen; and combinations of the foregoing.

55. A method of targeting information for preventing or treating osteoarthritis to a subject in need thereof, which comprises:
detecting the presence or absence of one or more polymorphic variations associated with osteoarthritis in a nucleic acid sample from a subject, wherein the polymorphic variation is detected in a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(b) a nucleotide sequence which encodes a polypeptide encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to the amino acid sequence encoded by a nucleotide sequence in SEQ ID NO: 1-7 or referenced in Table A;
(d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising a polymorphic variation; and directing information for preventing or treating osteoarthritis to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

56. The method of claim 55, wherein the one or more polymorphic variations are detected at one or more positions in claim 4, 7, 10, 13, 16, 19 or 24.

57. A composition comprising a cell from a subject having osteoarthritis or at risk of osteoarthritis and an antibody that specifically binds to a protein, polypeptide or peptide encoded by a nucleotide sequence identical to or 90% or more identical to a nucleotide sequence in SEQ m NO: 1-7 or referenced in Table A.

58. The composition of claim 57, wherein the antibody specifically binds to an epitope comprising an amino acid encoded by rs734784, rs1042164, rs749670, rs955592, rs241448 and rs 1040461.

59. A composition comprising a cell from a subject having osteoarthritis or at risk of osteoarthritis and a RNA, DNA, PNA or ribozyme molecule comprising a nucleotide sequence identical to or 90% or more identical to a portion of a nucleotide sequence in SEQ ID
NO: 1-7 or referenced in Table A.

60. The composition of claim 59, wherein the RNA molecule is a short inhibitory RNA
molecule.