CA2548375A1 - Assessment of risk for colorectal cancer - Google Patents

Abstract

Disclosed is a method for identifying an individual who has an altered risk for developing colorectal cancer comprising detecting a single nucleotide polymorphism (SNP).

Description

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ASSESSMENT OF RISK FOR COLORECTAL CANCER
FIELD OF THE INVENTION

This invention relates to prediction of the susceptibility of an individual to colorectal cancer. Basis for the prediction lies in relating an individual's genetic makeup, as through molecular analysis, to the genetic makeup of a population of individuals.
BACKGROUND

During the course of evolution, spontaneous mutations arise in the genomes of organisms. Variations in genomic DNA sequences are created continuously at a rate of about 100 new base changes per individual (Kondrashov, 1995; Crow, 1995). These germ-line changes may produce an evolutionary advantage and be retained in the population, or they may be deleterious and ultimately eliminated. In many cases, equilibrium between multiple germline forms of a sequence is established within a population if reproductive ability of individuals containing either polymorphism is not affected. Over time, significant numbers of mutations have accumulated within the human population that may be observed to varying extents in geographically separated groups based upon the presence of common ancestors.

Colorectal cancer is the third most common cancer and the third most common cause of death from cancer for both men and women. Colorectal cancer is responsible for more deaths that are not due primarily to tobacco use than any other type of cancer and inflicts a huge financial burden. Early detection of some human tumors such as uterine cervical cancer has dramatically reduced mortality from this condition (Herzog, 2003). Early detection of colorectal cancer can reasonably be expected to prevent death from this condition by identifying patients at risk for the disease, or those with the disease in an early stage and allow life saving intervention. A validated genetic test for colon cancer predisposition will have clinical utility, allowing prevention of cancer mortality through targeted screening programs. There are good reasons to expect that at least some of the genetic risks of common disease is due to common variants - for example, based on evolutionary arguments, and the fact that most human genetic variation is common. Although approximately 20%
of colorectal cancers have a familial component with relatives exhibiting a doubling of risk (Carstensen et al., 1996), less than 5% of colorectal cancer is explained by rare, highly penetrant genetic syndromes such as APC
and HNPCC (de Leon et al., 1999). Familial colon cancer occurring in patterns inconsistent with classical inherited syndromes suggests that variation in genome sequence plays a major role in determining individual risk to colon cancer. These genetic causes appear complex due to a variety of reasons such as genetic heterogeneity, incomplete penetrance, phenocopies and variation in exposures to environmental co-factors etc. There is little insight into the genetic or environmental determinants of almost 90% of cases of human colorectal carcinoma (Lynch and de La, 2003).

Although common human genetic variation is limited compared to other species, it remains impractical to discover and test every one of the estimated 10,000,000 common genotype variants (Sachidanandam et al., 2001) as predictors of disease risk. Genotypic complexity is reduced through linkage disequilibrium that exists across long segments of the human genome with restriction in the diversity of haplotypes observed (Daly et al., 2001; Rioux et al., 2001; Liu et al., 2004). That is, single nucleotide polymorphisms found at specific locations within the human genome are inherited in conjunction with nucleotides that can be polymorphic that are physically located near by. In European genomes, allelic association between pairs of markers typically extends over 10-50k, although there is tremendous variability in the magnitude of association observed at any given distance (Clark et al., 1998; Kikuchi et al., 2003; Dunning et al., 2000; Abecasis et al., 2001).
Genome-wide data (Gabriel et al., 2002; Reich et al., 2001; Dawson et al., 2002) supports the generality of this description as well as its application across populations. This confirms that measurement of single nucleotide polymorphisms at sites in tight linkage disequilibrium with adjacent genomic regions can provide information about the presence of diversity not just at sites actually measured, but also about large areas of the adjacent genome.

Numerous types of polymorphisms exist and are created when DNA sequences are either inserted or deleted from the genome. Another source of sequence variation results from the presence of repeated sequences in the genome variously termed short tandem repeats (STR), variable number of tandem repeats (VNTR), short sequence repeats (SSR) or microsatellites. These repeats commonly are comprised of 1 to 5 base pairs. Polymorphism occurs due to variation in the number of repeated sequences found at a particular locus.

The most common form of genomic variability are single nucleotide polymorphisms or SNPs. SNPs account for as much as 90% of human DNA polymorphism (Collins et al., 1998).
SNPs are single base pair positions in genomic DNA at which different sequence alternatives (genotypes) exist in a population. By common definition, the least frequent allele occurs at least 1%
of the time. These nucleotide substitutions may be a transition, which is the substitution of one purine by another purine or the substitution of one pyrimidine by another, or they may be transversions in which a purine is replaced by a pyrimidine or vice versa.

Typically SNPs are observed in about 1 in 1000 base pairs (Wang et al., 1998;
Taillon-Miller et al., 1999). The frequency of SNPs varies with the type and location of the change.
Specifically, two-thirds of the substitutions involve the C t-> T (G H A) type, which may occur due to 5-methylcytosine deamination reactions that occur commonly. SNPs occur at a much higher frequency in non-coding regions than they do in coding regions.

SUMMARY OF THE INVENTION

It has been discovered that polymorphic variations in a number of loci in human genomic DNA are associated with susceptibility to colorectal cancer. This invention thus includes methods for identifying a subject at risk of colorectal and/or determining risk of colorectal cancer in a subject, which comprise detecting the presence or absence of one or more polymorphic variations associated with colorectal cancer in a nucleic acid sample from the subject. In a specific embodiment, this invention relates to identifying an individual who is at altered risk for developing colorectal cancer based on the presence of specific genotypes defined by 51 single nucleotide polymorphism (SNPs), observed alone or in combination.

Through large scale genotyping studies on 2373 blood samples from patients with colon cancer and 2296 control samples from unaffected individuals we have identified 51 polymorphic markers found in 25 genes which are found more frequently in patients with colorectal cancer than in those without this disease. These markers, or those in close linkage disequilibrium, may change the composition, function or abundance of the elements of cellular constituents resulting in a predisposition to colorectal cancer. Measuring these markers in individuals who do not ostensibly have colon cancer will identify those at heightened risk for the subsequent development of colorectal cancer, providing benefit for, but not limited to, individuals, insurers, care givers and employers. Genes containing colorectal cancer-associated polymorphic markers that we have identified and genes found in linkage disequilibrium with these that we have identified are valuable targets for the development of therapeutics that inhibit or augment the activity of the gene products of these genes for therapeutic use in, but not restricted to, colon cancer. Information obtained from the detection of SNPs associated with colorectal cancer is of great value in the treatment and prevention of this condition.

Accordingly, one aspect of the present invention provides a method for diagnosing a genetic predisposition to colon cancer in a subject, comprising obtaining a sample containing at least one polynucleotide from the subject and analyzing the polynucleotide to detect the genetic polymorphism wherein the presence or absence of the polymorphism is associated with an altered susceptibility to developing colorectal cancer. In one embodiment, one or more of the 51 polymorphisms found distributed among 25 genes that we have identified may be used.

Another aspect of the present invention provides an isolated nucleic acid sequence comprising at least 16 contiguous nucleotides or their complements found in the genomic sequences of the 25 genes adjacent to and including the 51 polymorphic sites the inventors have identified to be associated with colorectal cancer.

Yet another aspect of the invention provides a method for treating colon cancer comprising obtaining a sample of biological material containing at least one polynucleotide from the subject, analyzing the polynucleotides to detect the presence of at least one polymorphism associated with colon cancer and treating the subject in such a way as to counteract the effect of any such polymorphism detected.
Still another aspect of the invention provides a method for the prophylactic treatment of a subject identified with a genetic predisposition to colon cancer identified through the measurement of all or some of the 51 polymorphic SNP markers described in Tables 1 to 51.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. It should be understood however, that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modification within the spirit and scope of the invention will become apparent to those skilled in the art from the following detailed description.

Tables 1 to 51 report the result of a genotyping analysis of 4669 samples by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2475 subjects (1234 cases with colorectal cancer and 1241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2194 subjects (1139 cases with colorectal cancer and 1055 age matched individuals undiseased at the time of testing).

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that polymorphic variants in a number of sequences, SEQ
ID NOs: 1 to 1119 are associated with an altered risk of developing colorectal cancer in subjects. The present invention thus provides SNPs associated with colorectal cancer, nucleic acid molecules containing SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The colorectal cancer-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to colorectal cancer and related pathologies in humans.
Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.

A large number of colorectal cancer-associated SNPs have been identified by genotyping DNA from 4669 individuals, 2373 of these individuals having been previously diagnosed with colorectal cancer and 2296 being "control" or individuals thought to be free of colorectal cancer.

The present invention thus provides individual SNPs associated with colorectal cancer, genomic sequences (SEQ ID NOs: 1120 to 1144) containing SNPs, and transcript sequences amino acid sequences. The invention includes methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing colorectal cancer, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as colorectal cancer, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment strategy, methods of treating a disorder associated with a variant gene/protein (i.e., therapeutic methods), and methods of using the SNPs of the present invention for human identification.

When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome correlates with an increased probability of that individual contracting colorectal cancer vis-a-vis a population not having that base at that location in the genome, that individual is said to be at "increased risk" of contracting colorectal cancer, i.e., to have an increased susceptibility. In certain cases, this effect can be a "dominant" effect in which case such increased probability exists when the base is present in one or the other or both alleles of the individual. In certain cases, the effect can be said to be "recessive", in which case such increased probability exists only when the base is present in both alleles of the individual.

When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome decreases the probability of that individual contracting colorectal cancer vis-6-vis a population not having that base at that location in the genome, that individual is said to be at "decreased risk" of contracting colorectal cancer, i.e., to have a decreased susceptibility. Such an allele is sometimes referred to in the art as being "protective". As with increased risk, it is also possible for a decreased risk to be characterized as dominant or recessive.

An "altered risk" means either an increased or a decreased risk.

The genetic analysis detailed below linked colorectal cancer with SNPs in the human genome. A SNP
is a particular type of polymorphic site, a polymorphic site being a region in a nucleic acid sequence at which two or more alternative nucleotides are observed in a significant number of individuals from a population. 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. Each of the specific polymorphic sites found in SEQ ID NOs:1120 to 1144 is a "single nucleotide polymorphism" or a "SNP."

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 majority of samples from a population is sometimes referred to as a "prevalent allele" and the polymorphic variant that is less prevalently represented is sometimes referred to as an "uncommon allele."
An individual who possesses two prevalent alleles or two uncommon alleles is "homozygous" with respect to the polymorphism, and an individual who possesses one prevalent allele and one uncommon allele is "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.

A genotype or polymorphic variant may also be expressed in terms of a "haplotype," which refers to the identiy of two or more polymorphic variants occurring within genomic DNA
on the same strand of DNA. For example, two SNPs may exist within a gene where each SNP position may include a cytosine variation or an adenine variation. Certain individuals in a population may carry an 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.

A "phenotype" is a trait which can be compared between individuals, such as presence or absence of a condition, for example, occurrence of colorectal cancer.

Polymorphic variants are often reported without any determination of whether the variant is represented in a significant fraction of a population. Some reported variants 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.

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.

In our genetic analysis associating colorectal cancer with the polymorphic variants set forth in the tables, samples from individuals having been diagnosed with colorectal cancer and individuals not having cancer were allelotyped and genotyped. The allele frequency for each polymorphic variant among cases and controls was determined. These allele frequencies were compared in cases and controls, or combinations. Particular SNPs were thus found to be associated with colorectal cancer when genotype and haplotype frequency differences calculated between case and control pools were established to be statistically significant.

As mentioned above, polymorphic variants can travel together. Such variants are said to be in "linkage disequilibrium" so that heritable elements e.g., alleles that have a tendency to be inherited together instead of being inherited independently by random assortment are in linkage disequilibrium. Alleles are randomly assorted or inherited independently of each other if the frequency of the two alleles together is the product of the frequencies of the two alleles individually.
For example, if two alleles at different polymorphic sites are present in 50% of the chromosomes in a population, then they would be said to assort randomly if the two alleles are present together on 25% of the chromosomes in the population. A higher percentage would mean that the two alleles are linked.
For example, a first polymorphic site P1 having two alleles, e.g. A and C--each appearing in 50% of the individuals in a given population, is said to be in linkage disequilibrium with a second polymorphic site P2 having two alleles e.g. G and T--each appearing in 50% of the individuals in a given population, if particular combinations of alleles are observed in individuals at a frequency greater than 25% (if the polymorphic sites are not linked, then one would expect a 50% chance of an individual having A at P 1 and a 50% chance of having G at P2 thus leading to a 25% chance of having the combination of A at P1 and G at P2 together). Heritable elements that are in linkage disequilibrium are said to be "linked"
or "genetically linked" to each other.

One can see that in the case of a group of SNPs that are in linkage disequilibrium with each other, knowledge of the existence of all such SNPs in a particular individual generally provides redundant information. Thus, when identifying an individual who has an altered risk for developing colorectal cancer according to this invention, it is necessary to detect only one SNP of such a group of SNPs associated with an altered risk of developing colorectal cancer.

It has been shown that each SNP in the genomic sequences identified as SEQ ID
NOs: 1120 to 1144 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which includes detecting the presence or absence of one or }
more of the SNPs described herein in a human nucleic acid sample.

Three different analyses were performed for each marker and significant results reported below are derived from one or more of the following tests: (a) a test of trend across the 3 genotypes (Sasieni et al. 1997); (b) a dominant model where the homozygous genotype for allele "B"
is combined with the prevalent heterozygote genotype; and (c) a recessive model where the homozygous genotype for allele "A" is combined with the heterozygous genotype. Asymptotic significance and empirical significance based on permutation tests were estimated for each test; when both were significant, only the empirical significance level is reported. Odds ratios measuring the strength of the association are also reported for each analysis, and are calculated in a model-specific manner as described in the next paragraph.

Pertinent results for each SNP are summarized in the tables: Chromosomal number and position-using the International Human Genome Sequencing Consortium build 35 (http://www.ncbi.nlm.nih.gov/genome/seq/) as made available by the National Center for Biotechnology Information (NCBI), National Library of Medicine, Building 38A, Bethesda, Maryland 20894 U.S.A., gene marker name-using the nomenclature of the NCBI dbSNP
(http://www.ncbi.nlm.nih.gov/SNP/) and gene name-using the unigene naming convention. Under the "Case Flag" the number 1 designates Cases and the number 0 designates Controls. The identity of the base designated "A" in the analysis is indicated where 1= A (adenine), 2 = C
(cytosine), 3 = G
(guanine) and 4 = T (thymidine). "B" indicates the polymorphic allele. AA, AB, BB are the counts of the number of individuals with the given genotype, by cases/controls. For dominant models, an odds ratio measuring the increase in risk associated with one or two copies of allele B is calculated. For recessive models, an odds ratio associated with exactly two copies of allele B
is calculated. For the trend models, the Mantel-Haenszel odds ratio showing the increase in risk with each additional copy of allele B is calculated. A superscript "e" on the p-value means that it was empirically estimated by permutation analysis, whereas the superscript "a" means that the p-value was estimated asymptotically, comparing the relevant test statistic to a chi-squared distribution with one degree of freedom.

It has been discovered that each polymorphic variation in the genomic sequences identified as SEQ ID
NOs:1120 to 1144 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which comprises detecting the presence or absence of one or more of the polymorphic variations described herein in a human nucleic acid sample. The polymorphic variation, SNP, are detailed in the tables.

Methods for determining whether a subject is susceptible to, i.e., at risk of colorectal cancer are provided herein. These methods include detecting the presence or absence of one or more polymorphic variations, i.e., SNPs, associated with colorectal cancer in a sample from a subject.
SNPs can be associated with a disease state in humans or in animals. The association can be direct, as in conditions where the substitution of a base results in alteration of the protein coding sequence of a gene which contributes directly to the pathophysiology of the condition.
Common examples of this include diseases such as sickle cell anemia and cystic fibrosis. The association can be indirect when the SNP plays no role in the disease, but is located close to the defective gene such that there is a strong association between the presence of the SNP and the disease state.
Because of the high frequency of SNPs within the genome, there is a greater probability that a SNP
will be linked to a genetic locus of interest than other types of genetic markers.

Disease-associated SNPs can occur in coding and non-coding regions of the genome. When located in the coding region altered function of the ensuing protein sequence may occur.
If it occurs in the regulatory region of a gene it may affect expression of the protein. If the protein is involved in protecting the body against pathological conditions this can result in disease susceptibility.
Numerous methods exist for the measurement of specific SNP genotypes.
Individuals carrying mutations in one or more SNPs of the present invention may be detected at the DNA level by a variety of techniques. Nucleic acids for diagnosis may be obtained from a patient's cells, such as from blood, urine, saliva, tissue biopsy and autopsy material.

The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR prior to analysis (Saiki et al., 1986). RNA or cDNA may also be used in the same ways. As an example, PCR primers complementary to the nucleic acid of one or more SNPs of the present invention can be used to identify and analyze the presence or absence of the SNP. For example, deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to radiolabeled SNP RNA of the present invention or alternatively, radiolabeled SNP antisense DNA sequences of the present invention. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase A digestion or by differences in melting temperatures.

Sequence differences between a reference gene and genes having mutations also may be revealed by direct DNA sequencing. In addition, cloned DNA segments may be employed as probes to detect specific DNA segments. The sensitivity of such methods can be greatly enhanced by appropriate use of PCR or another amplification method. For example, a sequencing primer is used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabeled nucleotide or by automatic sequencing procedures with fluorescent-tags.

Genetic testing based on DNA sequence differences may be achieved by detection of alteration in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents. Small sequence deletions and insertions can be visualized by high resolution gel electrophoresis. DNA fragments of different sequences may be distinguished on denaturing formamide gradient gels in which the mobilities of different DNA fragments are retarded in the gel at different positions according to their specific melting or partial melting temperatures (Myers et al., 1985).

Sequence changes at specific locations also may be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method (Cotton et al., 1988).

Thus, the detection of a specific DNA sequence may be achieved by methods which include, but are not limited to, hybridization, RNase protection, chemical cleavage, direct DNA
sequencing or the use of restriction enzymes, (e.g., restriction fragment length polymorphisms ("RFLP") and Southern blotting of genomic DNA).

In addition to more conventional gel-electrophoresis and DNA sequencing, mutations also can be detected by in situ analysis.

Genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotides probes (Cronin et al., 1996; Kozal et al., 1996). For example, genetic mutations can be identified in two-dimensional arrays containing light-generated DNA probes as described in Cronin et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations.
This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected.
Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. Specific mutations can also be determined through direct sequencing of one or both strands of DNA using dideoxy nucleotide chain termination chemistry, electrophoresis through a semi-solid matrix and fluorescent or radioactive chain length detection techniques. Further mutation detection techniques may involve differential susceptibility of the polymorphic double strand to restriction endonuclease digestion, or altered electrophoretic gel mobility of single or double stranded gene fragments containing one polymorphic form. Other techniques to detect specific DNA polymorphisms or mutation may involve evaluation of the structural characteristics at the site of polymorphism using nuclear magnetic resonance or x-ray diffraction techniques.

These genetic tests are useful for prognosing and/or diagnosing colorectal cancer and often are useful for determining whether an individual is at an increased or decreased risk of developing or having colorectal cancer.

Thus, the invention includes a method for identifying a subject at risk of colorectal cancer, which includes detecting in a nucleic acid sample from the subject the presence or absence of a SNP
associated with colorectal cancer at a polymorphic site in a nucleotide sequence identified as SEQ ID
NOs:l to 1144.

Results from prognostic tests may be combined with other test results to diagnose colorectal cancer.
For example, prognostic results may be gathered, a patient sample may be ordered based on a determined predisposition to colorectal cancer, the patient sample analyzed, and the results of the analysis may be utilized to diagnose colorectal cancer. Also colorectal cancer diagnostic methods can be developed from studies used to generate prognostic/diagnostic methods in which populations are stratified into subpopulations having different progressions of colorectal cancer. In another embodiment, prognostic results may be gathered; a patient's risk factors for developing colorectal cancer analyzed (e.g., age, family history); and a patient sample may be ordered based on a determined predisposition to colorectal cancer. In an alternative embodiment, the results from predisposition analyses may be combined with other test results indicative of colorectal cancer, which were previously, concurrently, or subsequently gathered with respect to the predisposition testing. In these embodiments, the combination of the prognostic test results with other test results can be probative of colorectal cancer, and the combination can be utilized as a colorectal cancer diagnostic.
Risk of colorectal cancer sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. The risk is based upon the presence or absence of one or more of the SNP 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 (Agresti, 2001). 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. Risk determinations for colorectal cancer are useful in a variety of applications. In one embodiment, colorectal cancer risk determinations are used by clinicians to direct appropriate detection, preventative and treatment procedures to subjects who most require these. In another embodiment, colorectal cancer risk determinations are used by health insurers for preparing actuarial tables and for calculating insurance premiums.

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.
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.

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 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., TAQMANTM PCR System (Applied Biosystems)), and nucleotide sequencing methods may be used.

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
01/27327; 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 GENEAMPTM, systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon the nucleotide sequences set forth in SEQ ID NOs: 1 to 1144.

Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. An adjacent fragmen 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 0 1/20039. 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. Multiple extension oligonucleotides may be utilized in one reaction, which is referred to as multiplexing.

A microarray can be utilized for determining whether a SNP 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 SNP set forth in the tables.

A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit can include one or more pairs of oligonucleotide primers useful for amplifying a fragment of a nucleotide sequence of interest, 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 the nucleotide sequence in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it can also include 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. The kit can include one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides.
Kits optionally include buffers, vials, microtiter plates, and instructions for use.

An individual identified as being susceptible to colorectal cancer may be heterozygous or homozygous with respect to the allele associated with an increased risk of colorectal cancer, as indicated in the tables. A subject homozygous for an allele associated with an increased risk of colorectal cancer is at a comparatively high risk of colorectal cancer as far as that SNP is concerned whether or not the allelic effect has been determined to be dominant or recessive. A subject who is heterozygous for an allele associated with an increased risk of colorectal cancer, in which the allelic effect is recessive would likely be at a comparatively reduced risk of colorectal cancer predicted by that SNP.

Individuals carrying mutations in one or more SNP of the present invention may be detected at the protein level by a variety of techniques. Cells suitable for diagnosis may be obtained from a patient's blood, urine, saliva, tissue biopsy and autopsy material.

Also featured are methods for determining risk of colorectal cancer and/or identifying a subject at risk of colorectal cancer by contacting a polypeptide or protein encoded by a nucleotide sequence from a subject with an antibody that specifically binds to an epitope associated with an altered, usually increased risk of colorectal cancer in the polypeptide.
Isolated Nucleic Acids Oligonucleotides can be linked to a second moiety, which can be another nucleic acid molecule to provide, for example, a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), etc. Alternatively, the moiety might be one that facilitates linkage to a solid support or a detectable label, e.g., a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, etc.

Nucleic acid sequences shown in the tables can be used for diagnostic purposes for detection and control of polypeptide expression. Also, oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide are part of this invention.

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

DNA encoding a polypeptide can also be used in the diagnosis of colorectal cancer, resulting from aberrant expression of a target gene. For example, the nucleic acid sequence can 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).

Expression of a polypeptide during embryonic development can also be determined using nucleic acid encoding the polypeptide, particularly production of a functionally impaired polypeptide that is the cause of colorectal cancer. In situ hybridizations using a polypeptide as a probe can be employed to predict problems related to colorectal cancer. Administration of human active polypeptide, recombinantly produced can 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 a dysfunctional polypeptide.

Included as part of this invention are nucleic acid vectors, often expression vectors, which contain a nucleotide sequence set forth in the tables. A vector is 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.

A vector can include a nucleotide sequence from the tables in a form suitable for expression of an encoded protein or nucleic acid in a host cell. The recombinant expression vector generally includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. A
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, etc. Expression vectors can be introduced into host cells to produce the desired polypeptides, including fusion polypeptides.

Recombinant expression vectors can be designed for expression of polypeptides in prokaryotic or eukaryotic cells. For example, the 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 by Goeddel (Goeddel, 1990).A recombinant expression vector can also be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.
Expression of polypeptides in prokaryotes can be 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.
Such fusion vectors typically serve to increase expression of recombinant polypeptide, to increase the solubility of the recombinant polypeptide and/or to aid in the purification of the recombinant polypeptide by acting as a ligand during 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 after 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, 1988)), pMAL
(New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.

Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector can be 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.
Expressing a polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide can be used to maximize recombinant polypeptide expression (Gottesman, 1990). The nucleotide sequence of the nucleic acid to be inserted into an expression vector can be changed so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., 1992).

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 can be 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). Examples of suitable tissue-specific promoters include an albumin promoter (Pinkert et al., 1987), lymphoid-specific promoters (Calame and Eaton, 1988) (Winoto and Baltimore, 1989), promoters of immunoglobulins (Banerji et al., 1983; Queen and Baltimore, 1983), neuron-specific promoters (Byrne and Ruddle, 1989), pancreas-specific promoters (Edlund et al., 1985), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat.
No. 4,873,316 and European Application Publication No. 264,166).
Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (Kessel and Gruss, 1990) and the .alpha.-fetopolypeptide promoter (Camper and Tilghman, 1989).

A nucleic acid from one of the tables might be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a nucleic acid 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.

The invention includes host cells having a nucleotide sequence from the tables within a recombinant expression vector or a fragment of such a sequence which facilitate homologous recombination into a specific site of the host cell genome. Terms such as host cell and recombinant host cell refer not only to the particular subject cell but also to the progeny of 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. A host cell can be any prokaryotic or eukaryotic cell. For example, a 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).

Vectors can be introduced into host cells via conventional transformation or transfection techniques.
The terms transformation and transfection refer to a variety of techniques known for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transduction/infection, DEAE-dextran-mediated transfection, lipofection, or electroporation.

A host cell can be used to produce a polypeptide. Accordingly, methods for producing a polypeptide using the host cells are included as part of this invention. Sucha a method can include culturing host cells into which a recombinant expression vector encoding a polypeptide has been introduced in a suitable medium such that the polypeptide is produced. The method can further include isolating the polypeptide from the medium or the host cell.

The invention also includes cells or purified preparations of cells which include a transgene from the tables, or which otherwise misexpress a 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. The transgene can be misexpressed, e.g., overexpressed or underexpressed. In other embodiments, the cell or cells include a gene which misexpress an endogenous 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., hematopoietic stem cells) transformed with a nucleic acid from the tables.

The invention includes cells or a purified preparation thereof (e.g., human cells) in which an endogenous nucleic acid from the tables is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene corresponding to the sequence. 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, U.S. Pat. No. 5,272,071; WO 91/06667, published on May 16, 1991.

Non-human transgenic animals that express a heterologous polypeptide (e.g., expressed from a nucleic acid from the tables) can be generated. Such animals are useful for studying the function and/or activity of a polypeptide and for identifying and/or evaluating modulators of the activity of the nucleic acids and encoded polypeptides. 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 melanogaster), 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.
Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a nucleic acid from the tables 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.

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 nucleotide sequence from the tables to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of the nucleotide sequence 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 nucleotide sequence can further be bred to other transgenic animals carrying other transgenes.

Polypeptides can be expressed in transgenic animals or plants by introducing a nucleic acid encoding the polypeptide into the genome of an animal. In certain 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.

Isolated polypeptides encoded by a nucleotide sequence from the tables can be synthesized. Isolated polypeptides include both the full-length polypeptide and the mature polypeptide (i.e., the polypeptide minus the signal sequence or propeptide domain). 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 is substantially free from chemical precursors or other chemicals when chemically synthesized. Substantially free means a preparation of a polypeptide having less than about 5% (by dry weight) of contaminating protein, or of chemical precursors or non-target chemicals.
When the desired polypeptide is recombinantly produced, it is typically substantially free of culture medium, specifically, where culture medium represents less than about 10% of the polypeptide preparation.

Also, 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 different polypeptide. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire polypeptide as it exists in nature or a fragment thereof. The other polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.

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 from the tables, 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).

Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these polypeptides can be used to affect the bioavailability of a substrate of the polypeptide and may effectively increase 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 polypeptide; (ii) mis-regulation of the gene encoding the polypeptide; and (iii) aberrant post-translational modification of a polypeptide.
Also, target polypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify the polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a polypeptide with a substrate.

Polypeptides can be 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 known modification including specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction;
metabolic synthesis in the presence of tunicamycin; etc. may be used. Additional post-translational modifications include, for example, N-linked or 0-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 0-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.

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) are also part of this invention. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene 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.
The polymer may be of any molecular weight, and may be branched or unbranched.
For polyethylene glycol, the molecular weight often is between about 1 kDa and about 100 kDa 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).

The polymers can 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. (Malik et al., 1992) 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 attachment sometimes is at an amino group, such as attachment at the N-terminus or lysine group.

Proteins can be chemically modified at the N-terminus. Using polyethylene glycol, for example, 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 achievable.

Applications of Prognostic and Diagnostic Results to Pharmacogenomic Methods Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype. For example, based upon the outcome of a prognostic test, 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). As therapeutic approaches for colorectal cancer continue to evolve and improve, the goal of treatments for colorectal cancer related disorders is to intervene even before clinical signs manifest themselves. Thus, genetic markers associated with susceptibility to colorectal cancer prove useful for early diagnosis, prevention and treatment of colorectal cancer.

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 beneficial interaction with a prevalent allele and a comparatively weak interaction with an uncommon 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 uncommon allele, and sometimes not administered to a subject genotyped as being heterozygous for the uncommon allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a prevalent allele but is comparatively toxic when administered to subjects heterozygous or homozygous for an uncommon allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the uncommon allele.

Methods of the invention are applicable to pharmacogenomic methods for detecting, preventing, alleviating and/or treating colorectal cancer. For example, a nucleic acid sample fi=om an individual may be subjected to a genetic test. Where one or more SNPs associated with increased risk of colorectal cancer are identified in a subject, information for detecting, preventing or treating colorectal cancer and/or one or more colorectal cancer detection, prevention and/or treatment regimens then may be directed to and/or prescribed to that subject.

In certain embodiments, a detection, preventative and/or treatment regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing colorectal cancer assessed by the methods described herein. Methods are thus provided for identifying a subject at risk of colorectal cancer and then prescribing a detection, therapeutic or preventative regimen to individuals identified as being at increased risk of colorectal cancer. Thus, certain embodiments are directed to methods for treating colorectal cancer in a subject, reducing risk of colorectal cancer in a subject, or early detection of colorectal cancer in a subject, which comprise:
detecting the presence or absence of a SNP associated with colorectal cancer in a nucleotide sequence set forth in SEQ ID NOs: l to 1144, and prescribing or administering a colorectal cancer treatment regimen, preventative regimen and/or detection regimen to a subject from whom the sample originated where the presence of one or more SNPs associated with colorectal cancer are detected in the nucleotide sequence. In these methods, genetic results may be utilized in combination with other test results to diagnose colorectal cancer as described above.

The use of certain colorectal cancer treatments are known in the art, and include surgery, chemotherapy and/or radiation therapy. Any of the treatments may be used in conibination to treat or prevent colorectal cancer (e.g., surgery followed by radiation therapy or chemotherapy).

Pharmacogenomics methods also may be used to analyze and predict a response to a colorectal cancer treatment or a drug. For example, if pharmacogenomics analysis indicates a likelihood that an individual will respond positively to a colorectal cancer 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 regiment (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.

The methods described herein also are applicable to clinical drug trials. One or more SNPs indicative of response to an agent for treating colorectal cancer or to side effects to an agent for treating colorectal cancer may be identified. 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.

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 variant, e.g., SNP which is associated with a positive response to the treatment or the drug, or at least one SNP 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 the SNP associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said SNP associated with a negative response to the treatment or the drug. The SNP may be in a sequence selected individually or in any combination from those disclosed in the tables. Step (c) can also include administering the drug or the treatment to the individual if the nucleic acid sample contains the SNP associated with a positive response to the treatment or the drug and the nucleic acid sample lacks the SNP associated with a negative response to the treatment or the drug.

Compositions Comprising Colorectal Cancer-Directed Molecules The invention includes a composition made up of a colorectal cancer cell and one or more molecules specifically directed and targeted to a nucleic acid comprising a nucleotide sequence shown in the tables, or a polypeptide encoded thereby. Such directed molecules include, but are not limited to, a compound that binds to a nucleic acid or a polypeptide; a RNAi or siRNA
molecule having a strand complementary to a nucleotide sequence; an antisense nucleic acid complementary to an RNA
encoded by a DNA sequence; a ribozyme that hybridizes to a nucleotide sequence; a nucleic acid aptamer that specifically binds a polypeptide; and an antibody that specifically binds to a polypeptide or binds to a nucleic acid. In specific embodiments, the colorectal cancer directed molecule interacts with a nucleic acid or polypeptide variant associated with colorectal cancer.
Compounds Compounds can be obtained using any of 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 (Zuckermann et al., 1994).
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, 1997). Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al. (DeWitt et al., 1993), Erb et al. (Erb et al., 1994), Zuckermann et al. (Zuckermann et al., 1994), Cho et al. (Cho et al., 1993) and Gallop et al. (Gallop et al., 1994).

Libraries of compounds may be presented in solution (Houghten et al., 1992), or on beads (Lam et al., 1991), chips (Fodor et al., 1993), bacteria or spores (Ladner, U.S. Pat.
No. 5,223,409), plasmids (Cull et al., 1992) or on phage (Scott and Smith, 1990; Devlin et al., 1990;
Cwirla et al., 1990; Felici et al., 1991).

A compound sometimes alters expression and sometimes alters activity of a target polypeptide and may be a small molecule. Small molecules include peptides, peptidoniimetics (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.

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 in a nucleic acid molecule having a sequence of one of SEQ ID NOs: 1120 to 1144, or to a portion 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.

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 of interest, 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 (SNP) 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 below, can be designed to target a nucleotide sequence in any of SEQ ID NOs:1120 to 1144. Uncommon alleles and prevalent alleles can be targeted, and those associated with an increased risk of colon cancer are often designed, tested, and administered to subjects.

An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid molecule 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.

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 vectors.
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.

Antisense nucleic acid molecules sometimes are anomeric nucleic acid molecules (Gautier et al., 1987). Antisense nucleic acid molecules can also comprise a 2'-o-methylribonucleotide (Inoue et al., 1987a) or a chimeric RNA-DNA analogue (Inoue et al., 1987b). Antisense nucleic acids sometimes are composed of DNA or peptide nucleic acid (PNA).

In another embodiment, an antisense nucleic acid is a ribozyme. A ribozyme having specificity for a target nucleotide sequence 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 (Haseloff and Gerlach, 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 n1RNA (see e.g., Cech et al., U.S. Pat. No. 4,987,071; and Cech et al., U.S. Pat. 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 (Bartel and Szostak, 1993).

Colorectal cancer directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a target nucleotide sequence, 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 target nucleotide sequence (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells (Helene, 1991; Helene et al., 1992; Maher, III, 1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a switchback nucleic acid molecule. Switchback molecules are synthesized in an alternating 5'-3',3'-5' 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.

Colorectal cancer 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., U.S. Pat. No.
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 J M, Labouesse (Bosher and Labouesse, 2000). 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 (Caplen et al., 2001a) (Elbashir et al., 2002). 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. (Caplen et al., 2001b), Abderrahman et al. (Abderrahmani et al., 2001).

An siRNA or RNAi is 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 is 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 is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA.

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.
(Elbashir et al., 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 motif NA
(N2 1). 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 motif NAR (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 po1 III promoters can be more efficient when the first transcribed nucleotide is a purine.
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 to 50 nucleotides in length, and the double stranded siRNA is about to 50 base pairs in length, sometimes about 20 to 30 nucleotides in length or about 20 to 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 known in the art, and specific siRNA molecules may be purchased from a number of companies including Dharmacon 10 Research, Inc.

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 15 nucleic acids (see Hyrup et al., Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)). A 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. (Hyrup and Nielsen, 1996), and Perry-O'Keefe et al. (Abderrahmani et al., 2001).

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 SNPs 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 and Nielsen, 1996) or as probes or primers for DNA sequencing or hybridization (Hyrup and Nielsen, 1996; Perry-O'Keefe et al., 1996).

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. (Letsinger et al., 1989); Lemaitre et al. (Lemaitre et al., 1987) and 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 (van der Krol et al., 1988) or intercalating agents (Zon, 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).

Also included as part of this invention are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a target nucleotide sequence, 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. Pat. No. 5,854,033;
Nazarenko et al., U.S. Pat. No.
5,866,336, and Livak et al., U.S. Pat. No. 5,876,930.

Antibodies An immunogen typically is used to prepare antibodies by immunizing a suitable subject, (e.g., rabbit, goat, mouse or other mammal). An appropriate immunogenic preparation can contain, for example, recombinantly expressed chemically synthesized polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent.
Amino acid polymorphisms can be detected using antibodies specific for the altered epitope by western analysis after the electrophoresis of denatured proteins. Protein polymorphism can also be detected using fluorescently identified antibodies which bind to specific polymorphic epitopes and detected in whole cells using fluorescence activated cell sorting techniques (FACS). Polymorphic protein sequence may also be determined by NMR spectroscopy or by x-ray diffraction studies.
Further, determination of polymorphic sites in proteins may be accomplished by observing differential cleavage by specific or non specific proteases.

An antibody is an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody can be polyclonal, monoclonal, or 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.
A full-length polypeptide or antigenic peptide fragment encoded by a target nucleotide sequence 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 of one of SEQ ID NOs:1120 to 1144, 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.

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 for use in the invention.

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, for example using methods described in Robinson et al., Intemational Application No. PCT/US86/02269; 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. Pat. No.
4,816,567; Cabilly et al., European Patent Application 125,023; (Better et al., 1988; Liu et al., 1987a; Liu et al., 1987b; Sun et al., 1987; Nishimura et al., 1987) (Wood et al., 1985; Shaw et al., 1988;
Morrison, 1985) and Winter U.S. Pat. No. 5,225,539, (Verhoeyen et al., 1988; Beidler et al., 1988).

Completely human antibodies can be 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 (Lonberg and Huszar, 1995) and U.S. Pat.
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, Calif.) and Medarex, Inc. (Princeton, N.J.), can be engaged to provide human antibodies directed against a selected antigen. Completely human antibodies that recognize a selected epitope also can be generated using 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.
(Jespers et al., 1994).

An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al. (Colcher et al., 1999) and Reiter (Reiter and Pastan, 1996). Single chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.

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).

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, I
dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include 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).

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, -y-interferon, ac-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. Pat. No.
4,676,980, for example.
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 supematant) 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 ofa given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. 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, alkaline phosphatase, B-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 include1251 131I, 35S or 3H. Also, an antibody can be utilized as a test molecule for determining whether it can treat colorectal cancer, and as a therapeutic for administration to a subject for treating colorectal cancer.

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

Included as part of this invention 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 colorectal cancer.
Screening Assays The invention includes methods for identifying a candidate therapeutic for treating colorectal cancer.
The methods include contacting a test molecule with a target molecule in a system. A target molecule is a nucleic acid molecule having a sequence of any of SEQ ID NOs: l to 1144, or a fragment thereof, or an encoded polypeptide of SEQ ID NOs:1120 to 1144. The method also includes 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 colorectal cancer therapeutic. The interaction between the test molecule and the target molecule may be quantified.

Test molecules and candidate therapeutics include compounds, antisense nucleic acids, siRNA
molecules, ribozymes, polypeptides or proteins encoded by target nucleic acids, 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 colorectal cancer).

According to an aspect of this invention a system, i.e., a cell free in vitro environment and a cell-based environment such as a collection of cells, a tissue, an organ, or an organism, 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. An 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.

There are known 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.

Test molecule/target molecule interactions can be detected and/or quantified using known assays. 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 125I1' 3' I, 35S 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 et al., 1992).

In cell-based systems, cells typically include a nucleic acid from SEQ ID NOs:
1 to 1144 or an encoded polypeptide from SEQ ID NOs: 1120 to 1144, 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, TritonTMX-100, TritonTM X-114, etc.

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. Pat. No.
5,631,169;
Stavrianopoulos et al., U.S. Pat. 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 inolecule 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).

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 (Sjolander and Urbaniczky, 1991; Szabo et al., 1995). Surface plasmon resonance (SPR) or biomolecular interaction analysis (BIA) can be utilized to detect biospecific interactions in real time, without labeling any of the interactants (e.g., BlAcore). 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, resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

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 one 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.

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. Pat. 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 (Lam et al., 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 attachments to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are known (see, e.g., U.S. Pat. Nos. 6,261,776;
5,900,481; 6,133,436; and 6,022,688; and WIPO publication WO 01/18234).

In one embodiment, a target molecule may be immobilized to surfaces via biotin and streptavidin. For example, a biotinylated polypeptide can be prepared from biotin-NHS (N-hydroxysuccinimide, e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), 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/-polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized 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.

In one 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.

In another embodiment, an assay is performed utilizing antibodies that specifically bind a target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule.
Such antibodies can be linked 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.

Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by known techniques, including:
differential centrifugation (Rivas and Minton, 1993); electrophoresis (1999) and immunoprecipitation (1999). Media and chromatographic techniques are known (Heegaard, 1998; Hage and Tweed, 1997).
Further, fluorescence energy transfer may also be conveniently utilized to detect binding without further purification of the complex from solution.

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 polypeptide is evaluated relative to the level of expression of target mRNA or polypeptide in the absence of the candidate compound. When expression of target mRNA or 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 polypeptide expression. Alternatively, when expression of target mRNA or 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 polypeptide expression. The level of target mRNA or polypeptide expression can be determined by methods described herein.

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 or 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 colorectal cancer.

Binding partners of target molecules can be identified by known methods. 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 (Zervos et al., 1993; Madura et al., 1993; Bartel et al., 1993; Iwabuchi et al., 1993): see also, e.g., U.S.
Pat. No. 5,283,317 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 nucleic acid from one of SEQ ID
NOs: 1120 to 1144, 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 target nucleic acid 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.

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.

The assays can be conducted in a heterogeneous or homogeneous format. In heterogeneous assays, a 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.

In a heterogeneous assay, 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 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.

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.

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 label(s) is quenched upon complex formation (e.g., U.S. Pat. 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.

Identification of Candidate Therapeutics Candidate therapeutics for treating colorectal cancer 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 ranking modulators are selected.
Also, pharmacogenomic information 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 15%, 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 Formulations and pharmaceutical compositions typically include in combination Nvith 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. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner. Also, formulations may include a polypeptide combination with a pharmaceutically acceptable carrier.

A pharmaceutically acceptable carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. See for example, Remington's Pharmaceutical Sciences (2005).
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.

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 administrations 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 sodiuin bisulfite; 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.

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; 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.

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, N.J.) or phosphate buffered saline (PBS).
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.

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 methods of preparation often utilized 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.

Systemic administration might 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.

hi 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. Pat. No.
4,522,811.

It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Each unit containing a predetermined quantity of active compound is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

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 LD50 (the dose lethal to 50% of the population) and the ED₅₀ (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 LD50/ED50. Molecules which exhibit high therapeutic indices often are utilized.
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.

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 typically lies within a range of circulating concentrations that include the ED50 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 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 IC₅₀ (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.

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, can include a series of treatments.

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 dosage 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. (Cruikshank et al., 1997).

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. Pat. No.
4,676,980.

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.

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. Pat. No.
5,328,470) or by stereotactic injection (Chen et al., 1994). 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 A therapeutic formulation described above can be administered to a subject in need of a therapeutic for treating colorectal cancer. 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.

A treatment is 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 colorectal cancer, symptoms of colorectal cancer or a predisposition towards colorectal cancer. A therapeutic formulation includes small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides.
Administration of a therapeutic formulation can occur prior to the manifestation of symptoms characteristic of colorectal cancer, such that the cancer is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.
As discussed, successful treatment of colorectal cancer 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')2 and FAb expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.

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.

Another method by which nucleic acid molecules may be utilized in treating or preventing colorectal cancer 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 (Osborne et al., 1997;
Patel, 1997).

Yet another method of utilizing nucleic acid molecules for colorectal cancer treatment is gene therapy, which can also be referred to as allele therapy. The invention thus includes a gene therapy method for treating colorectal cancer in a subject, which includes contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence.
Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer.
The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer SNPs associated with colorectal cancer 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 SNPs associated with colorectal cancer.

Another allele therapy 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.
Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer. The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence includes fewer SNPs associated with colorectal cancer than the second nucleotide sequence. The first nucleotide sequence may include a gene sequence that encodes a full-length polypeptide or a fragment thereof.
The subject is usually a human.

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 colorectal cancer.

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 (Herlyn and Birebent, 1999; Bhattacharya-Chatterjee and Foon, 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 colorectal cancer also may be generated in this fashion.

In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies often are utilized. Lipofectin or liposomes can be used to deliver the aritibody 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 often is utilized. 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 (Marasco et al., 1993).
Modulators can be administered to a patient at therapeutically effective doses to treat colorectal cancer. A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of colorectal cancer. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (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 LD50/EDSO. Modulators that exhibit large therapeutic indices often are utilized. 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.
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 typically lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. 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 IC50 (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.

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. (Ansell et al., 1996).
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. (Vlatakis et al., 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 IC50. 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 ICs0=

The examples set forth below are intended to illustrate but not limit the invention.

Genomic DNA samples from patients aged 25-74 and patients with both familial and sporadic CRC
with family and unrelated ethnically matched controls were studied. We identified CRC-associated alleles by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2475 subjects (1234 cases with colorectal cancer and 1241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2194 subjects (1139 cases with colorectal cancer and 1055 age matched individuals undiseased at the time of testing). Patients with clinically documented well characterized inherited colorectal cancer syndromes such as Familial Adenomatous Polyposis (FAP) or Hereditary Non Polyposis Colorectal Cancer were excluded from our analysis. Single nucleotide polymorphisms were selected to maximize measurement of genomic variability by choosing these markers that were in the greatest degree of linkage disequilibrium with neighboring SNPs. This was determined by calculating correlation coefficients (r2) with successive neighboring SNPs at each site of polymorphism until an arbitrary cut off of 0.8 was observed. Marker SNPs selected for measurement were in linkage disequilibrium with a maximal number of adjacent SNPs, thus providing an economical method for measuring diversity over a large portion of the genome.

Single Nucleotide Polymorphisms selected for study were derived from the International Haplotype Mapping Project (http://www.hapmap.org) August 2004 release, information about which is available from the National Institutes of Health, National Institutes of Health (NIH;
http://www.nih.gov/), 9000 Rockville Pike, Bethesda, Maryland 20892. The SNPs were analyzed on DNA from our control and study population using either the Illumina Bead Array system (http://www.illumina.com; Illumina, Inc., 9885 Towne Centre Drive, San Diego, CA 92121-1975), the MIP platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, CA 95051), or the Affymetrix platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, CA 95051). The SNPs for the Illumina Bead Array system were selected on the basis of being associated with genes involved in DNA repair, chromosomal stability or signal transduction and expressed in human colon epithelium. The SNPs for the MIP platform were selected to include most SNPs that would alter the coding sequence of a protein product. The SNPs for the Affymetrix platform were selected as to cover the entire genome, but the SNPs were preferentially selected in genic regions present on Xbal or HindIII restriction fragments varying in length from about 20 base pairs to about 1000 base pairs. Data was stored and organized using the Nanuq informatics environment of the McGill University and Genome Quebec Innovation Centre (http://www.genomequebec.mcgill.ca/; McGill University and Genome Quebec Innovation Centre, 740, Docteur Penfield Avenue, Montreal, Qu6bec H3A 1A4). Allele frequencies found within DNA
from patients with colorectal cancer and those without this disease were compared using the univariate Mantel-Haenszel Chi-Square statistic.

The inventors of the present invention have discovered single base pair polymorphisms that are present in a highly significant percentage of the genetic DNA of individuals affected with colorectal cancer while only present in a smaller percentage of individuals who are not known to be affected by the disease.

Example 1 For individuals with colon cancer, the distribution of polymorphic alleles at position 97159204 of chromosome 1, found within the PTBP2 gene, was different from those without colon cancer (Table 1). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0008 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.503 (Table 1). These data further suggest that this marker, located within the PTBP2 gene, is associated with colon cancer risk and that the C allele at position 97159204 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 1 rs no. 10493889 Chromosome; Position 1; 97159204 Gene Name PTBP2 SEQ ID NO; Position 1120;
Genotype; Pheno e n=C; increased risk Hard -Weinber 0.799522 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 842 123 5 Trend 0.0008e 1.503 Table IA indicates SNPs found to be in strong linkage disequilibrium with rs10493889. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 1A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs17525524 0.667 96911594 1 rs17115733 0.647 96961817 2 rs12024594 0.73 97005044 3 rs11165746 1.0 97141267 4 rs10493889 - 97159204 5 Example 2 For individuals with colon cancer, the distribution of polymorphic alleles at position 97657313 of chromosome 1, found within the DPYD gene, was different from those without colon cancer (Table 2). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0845 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.100 (Table 2). These data further suggest that this marker, located within the DPYD gene, is associated with colon cancer risk and that the A allele at position 97657313 of chromosome I is associated with an increased risk of developing colon cancer.

Table 2 rs no. 945881 Chromosome; Position 1; 97657313 Gene Name DPYD
SEQ ID NO; Position 1121; 441288 Genotype; Phenotype n=A; increased risk Hardy-Weinberg 0.188 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 246 585 407 Trend 0.0845e 1.100 Table 2A indicates SNPs found to be in strong linkage disequilibrium with rs945881. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 2A Linked SNPs SNP r 2 Position on chrl SEQ ID NO
rs11165879 0.699 97653506 6 rs945881 - 97657313 7 rs11165881 1.0 97659904 8 Example 3 For individuals with colon cancer, the distribution of polymorphic alleles at position 115166656 of chromosome 1, found within the SYCP1 gene, was different from those without colon cancer (Table 3). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.0087 based on permutation analysis, and the corresponding recessive odds ratio is 1.323 (Table 3). These data further suggest that this marker, located within the SYCP1 gene, is associated with colon cancer risk and that the A allele at position 115166656 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 3 rs no. 360659 Chromosome; Position 1; 115166656 Gene Name SYCP 1 SEQ ID NO; Position 1122; 57160 Genotype; Phenotype n=A; increased risk rg 0.428 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 424 565 208 Recessive 0.0087e 1.323 Table 3A indicates SNPs found to be in strong linkage disequilibrium with rs360659. To generate this list, correlation coefficients (rz) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 3A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs2010899 0.518 114947052 9 rs969273 0.522 114968711 10 rs2007231 0.522 114978348 11 rs2144428 0.569 114981253 12 rs6663115 0.522 114984296 13 rs4140445 0.522 115004020 14 rs3121503 0.966 115071842 15 rs3121506 0.599 115075249 16 rs3121507 0.964 115077252 17 rs6689326 0.583 115081154 18 rs3126216 0.966 115084567 19 rs1286560 0.583 115087972 20 rs869990 0.583 115091656 21 rs360599 0.815 115100040 22 rs360606 0.583 115103811 23 rs360607 0.599 115104443 24 rs360614 1.0 115111982 25 rs360617 0.603 115116141 26 rs360622 1.0 115119103 27 rs360627 1.0 115125087 28 rs360634 0.965 115132157 29 rs360635 0.564 115132560 30 rs360636 1.0 115132947 31 rs360643 1.0 115139005 32 rs360647 1.0 115141772 33 rs360655 0.564 115159909 34 rs360659 - 115166656 35 rs360661 0.62 115167322 36 rs360576 0.546 115171216 37 rs360586 0.564 115179531 38 rs360588 1.0 115180386 39 rs360590 0.504 115182953 40 rs360591 0.809 115183282 41 rs360596 0.815 115185601 42 rs506934 0.51 115200356 43 rs360675 0.583 115202960 44 rs360682 0.815 115209101 45 rs12135023 0.815 115217819 46 rs1591899 0.815 115226640 47 rs12125190 0.815 115234779 48 rs12026343 0.815 115236258 49 rs7416955 0.812 115242333 50 rs4839017 0.815 115242502 51 rs11102859 0.806 115242740 52 rs6698174 0.815 115244057 53 rs7536888 0.815 115261728 54 rs4839399 0.815 115268188 55 rs11102872 0.815 115277042 56 rs7515454 0.815 115278233 57 rs7517739 0.815 115278345 58 rs7541251 0.815 115278448 59 rs6537849 0.815 115278686 60 rs1575070 0.674 115279927 61 rs1575069 0.689 115280070 62 rs12136420 0.689 115281663 63 rs7530810 0.689 115282510 64 rs1321108 0.689 115284407 65 rs11102874 0.749 115285912 66 rs3754363 0.686 115287160 67 rs1321107 0.583 115287345 68 rs7514765 0.612 115289952 69 rs1998008 0.703 115292582 70 rs461 1011 0.633 115298443 71 rs7413646 0.638 115298798 72 rs11102878 0.565 115303040 73 Example 4 For individuals with colon cancer, the distribution of polymorphic alleles at position 143040559 of chromosome 1, found within the FLJ25124 gene, was different from those without colon cancer (Table 4). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.0011 based on permutation analysis, and the corresponding recessive odds ratio is 1.585 (Table 4).
These data further suggest that this marker, located within the FLJ25124 gene, is associated with colon cancer risk and that the G allele at position 143040559 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 4 rs no. 10494240 Chromosome; Position 1; 143040559 Gene Name FLJ25124 SEQ ID NO; Position 1123; 2272 Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.144192 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 438 449 92 Recessive 0.001le 1.585 Table 4A indicates SNPs found to be in strong linkage disequilibrium with rs10494240. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 4A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs4636400 0.611 142933600 74 rs6688400 0.71 142994415 75 rs872786 0.71 142996870 76 rs2274617 0.898 143024965 77 rs12410298 0.501 143037007 78 rs720899 1.0 143039966 79 rs10494240 - 143040559 80 Example 5 For individuals with colon cancer, the distribution of polymorphic alleles at position 20254115 of chromosome 2 was different from those without colon cancer (Table 5). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0028 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.226 (Table 5). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 20254115 of chromosome 2 is associated with an increased risk of developing colon cancer.

Table 5 rs no. 973128 Chromosome; Position 2; 20254115 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hard -Weinber 0.14711 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 198 485 243 Trend 0.0028e 1.226 Table 5A indicates SNPs found to be in strong linkage disequilibrium with rs973 128. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 5A Linked SNPs SNP r 2 Position on chr2 SEQ ID NO
rs 17697743 0.755 20250764 81 rs6753830 1.0 20250981 82 rs975951 1.0 20252966 83 rs973128 - 20254115 84 rs875411 1.0 20254650 85 rs875412 1.0 20255588 86 rs6744463 1.0 20256013 87 rs2881879 0.534 20257476 88 rs4666362 0.527 20258973 89 rs6531212 0.522 20259648 90 rs4666364 0.513 20260227 91 Example 6 For individuals with colon cancer, the distribution of polymorphic alleles at position 186869364 of chromosome 2 was different from those without colon cancer (Table 6). The recessive test for risk associated with carrying the C allele had an asymptotic p-value of 0.00049577, and the corresponding recessive odds ratio is 6.624 (Table 6). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 186869364 of chromosome 2 is associated with an increased risk of developing colon cancer.

Table 6 rs no. 10497667 Chromosome; Position 2; 186869364 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hard -Weinber 0.00834769 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 783 194 3 Recessive 0.00049577a 6.624 Table 6A indicates SNPs found to be in strong linkage disequilibrium with rs10497667. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An rz cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 6A Linked SNPs SNP r 2 Position on chr2 SEQ ID NO
rs7582258 0.611 186729521 92 rs12615770 0.611 186748482 93 rs12998383 0.635 186752544 94 rs16827480 0.63 186753368 95 rs12614513 0.726 186759677 96 rs991084 0.63 186774634 97 rs13005466 0.63 186783677 98 rs6750636 0.61 186788675 99 rs13003934 0.612 186795981 100 rs12999989 0.629 186797056 101 rs13028175 0.59 186797101 102 rs12999474 0.627 186804008 103 rs12373738 0.63 186822924 104 rs6725283 0.891 186849447 105 rs13419562 0.611 186854278 106 rs13394207 0.63 186854406 107 rs13421172 0.63 186856196 108 rs4284795 1.0 186866149 109 rs2887816 0.63 186869233 110 rs10497667 - 186869364 111 rs13388196 0.629 186870116 112 rs2370681 0.63 186873391 113 rs12233005 0.63 186873805 114 rs8179713 1.0 186874321 115 rs13416578 0.63 186876760 116 rs12614595 1.0 186877596 117 rs2370677 1.0 186878043 118 rs4500906 0.908 186883056 119 rs16827554 1.0 186887466 120 rs7584724 1.0 186895423 121 rs16827602 1.0 186898014 122 rs6434164 1.0 186899824 123 rs2370670 1.0 186903194 124 rs16827614 1.0 186905158 125 rs3107174 0.915 186910195 126 rs2887818 0.915 186918660 127 rs3112312 0.901 186933341 128 rs1878754 0.915 186935034 129 rs3112315 0.915 186937617 130 rs2370659 0.915 186938372 131 rs3112316 0.915 186938761 132 rs3107410 0.915 186940537 133 rs3112317 0.915 186942136 134 rs10195099 0.591 186944471 135 rs2370662 0.915 186945120 136 rs10931232 0.915 186950816 137 rs2029085 0.915 187032899 138 rs10497669 0.643 187050892 139 Example 7 For individuals with colon cancer, the distribution of polymorphic alleles at position 218776751 of chromosome 2, found within the FLJ46536 gene, was different from those without colon cancer (Table 7). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0238 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.147 (Table 7). The recessive test for risk associated with carrying the C
allele had an asymptotic p-value of 0.0021509, and the corresponding recessive odds ratio is 1.395 (Table 7). These data further suggest that this marker, located within the FLJ46536 gene, is associated with colon cancer risk and that the C allele at position 218776751 of chromosome 2 is associated with an increased risk of developing colon cancer.

Table 7 rs no. 4133195 Chromosome; Position 2; 218776751 Gene Name FLJ46536 SEQ ID NO; Position 1124; 51535 Genotype; Phenotype n=C; increased risk Hardy-Weinberg 0.94839 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 284 479 204 Trend 0.0238e 1.147 1 2 252 402 244 Recessive 0.0021509a 1.395 Table 7A indicates SNPs found to be in strong linkage disequilibrium with rs4133195. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 7A Linked SNPs SNP r2 Position on chr2 SEQ ID NO
rs4672870 0.647 218767422 140 rs12694425 0.647 218767819 141 rs12694426 0.637 218767857 142 rs10932745 0.669 218768482 143 rs11687200 0.665 218770121 144 rs11676275 0.669 218770314 145 rs12694427 0.669 218770551 146 rs6737563 0.934 218771180 147 rs13013361 0.933 218773021 148 rs4133195 - 218776751 149 rs6726126 1.0 218777739 150 rs10804264 0.819 218781315 151 rs12694428 0.63 218784326 152 rs13035513 0.935 218786186 153 rs13007992 0.792 218789557 154 rs7426289 0.935 218791821 155 rs4674257 0.935 218814280 156 rs4674259 0.935 218816511 157 rs6723449 0.934 218823086 158 rs1126579 0.967 218826240 159 rs4674261 0.625 218830515 160 rs11677534 0.935 218832566 161 rs13009946 0.935 218833258 162 rs7594532 0.918 218833506 163 rs7607437 0.935 218833898 164 rs11676348 0.782 218835652 165 rs1008563 0.625 218852394 166 rs1008562 0.935 218852478 167 rs4674267 0.625 218871943 168 rs13397673 0.641 218873288 169 Example 8 For individuals with colon cancer, the distribution of polymorphic alleles at position 230825727 of chromosome 2 was different from those without colon cancer (Table 8). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0021 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.222 (Table 8). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 230825727 of chromosome 2 is associated with an increased risk of developing colon cancer.

Table 8 rs no. 10498243 Chromosome; Position 2; 230825727 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hard -Weinber 0.0296796 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 472 410 61 Trend 0.0021 e 1.222 Table 8A indicates SNPs found to be in strong linkage disequilibrium with rs10498243. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 8A Linked SNPs SNP r2 Position on chr2 SEQ ID NO
rs12694839 0.52 230822818 170 rs12694840 0.517 230822908 171 rs6706782 1.0 230823742 172 rs6707129 1.0 230824051 173 rs1529377 1.0 230825316 174 rs12694841 1.0 230825613 175 rs10498243 - 230825727 176 rs6715536 1.0 230825877 177 rs1549567 1.0 230827852 178 rs6721137 1.0 230828862 179 rs1365775 1.0 230829298 180 rs10933326 1.0 230830081 181 rs2396713 0.961 230830316 182 rs13004807 1.0 230830886 183 rs10048686 1.0 230832540 184 rs11677105 0.507 230842525 185 Example 9 For individuals with colon cancer, the distribution of polymorphic alleles at position 25062781 of chromosome 3 was different from those without colon cancer (Table 9). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0086 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.302 (Table 9). These data further suggest that this marker is associated with colon cancer risk and that the A allele at position 25062781 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 9 rs no. 4484159 Chromosome; Position 3; 25062781 Gene Name SEQ ID NO; Position Genotype; Phenotype n=A; increased risk Hard -Weinber 0.411896 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 22 273 677 Trend 0.0086e 1.302 Table 9A indicates SNPs found to be in strong linkage disequilibrium with rs4484159. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 9A Linked SNPs SNP r2 Position on chr3 SEQ ID NO
rs13067187 0.583 25052936 186 rs6777624 0.854 25054402 187 rs9866836 0.877 25056885 188 rs17015670 1.0 25061156 189 rs4484159 - 25062781 190 rs1604007 0.817 25068060 191 rs988268 0.808 25076452 192 rs6550943 0.778 25084253 193 rs6777955 0.932 25084806 194 rs6766372 0.757 25086476 195 rs994267 0.825 25090198 196 rs1574901 0.825 25090417 197 rs1587430 0.825 25100369 198 rs4858700 0.517 25102693 199 rs11294076 0.788 25105990 200 rs4858703 0.825 25108277 201 rs2036270 0.825 25112900 202 rs972016 0.825 25114656 203 rs1603987 0.825 25115540 204 rs6807196 0.696 25117575 205 rs4858704 0.517 25118394 206 rs1580817 0.825 25121605 207 Example 10 For individuals with colon cancer, the distribution of polymorphic alleles at position 62952892 of chromosome 3 was different from those without colon cancer (Table 10). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.0012 based on permutation analysis, and the corresponding recessive odds ratio is 2.148 (Table 10).
These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 62952892 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 10 rs no. 4404442 Chromosome; Position 3; 62952892 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hardy-Weinber 0.910304 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 627 271 28 Recessive 0.0012e 2.148 Table 10A indicates SNPs found to be in strong linkage disequilibrium with rs4404442. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 10A Linked SNPs SNP r 2 Position on chr3 SEQ ID NO
rs9828340 0.51 62937809 208 rs12631618 1.0 62941462 209 rs6807315 1.0 62943033 210 rs4312654 1.0 62943151 211 rs4583651 1.0 62943547 212 rs13072243 1.0 62945427 213 rs4613448 0.948 62949979 214 rs4404442 - 62952892 215 rs13091015 1.0 62955440 216 rs9814898 1.0 62957942 217 rs17067503 1.0 62958060 218 rs10510890 0.948 62959133 219 rs9821058 1.0 62959399 220 rs10510891 1.0 62960430 221 rs4147406 0.95 62962215 222 rs2367590 1.0 62964393 223 rs17067527 0.898 62965607 224 rs12488885 0.948 62966446 225 rs17361212 0.752 62966549 226 rs11130909 0.947 62968123 227 rs13099709 0.948 62968779 228 rs13079904 0.948 62968976 229 rs2367591 0.898 62969677 230 rs9850740 0.947 62970029 231 rs10510892 0.948 62970190 232 rs2367592 0.852 62970589 233 rs11130910 0.887 62971291 234 rs7372226 0.947 62972138 235 rs13061838 0.898 62975188 236 rs6770985 0.528 62981633 237 rs1447443 0.528 62982901 238 rs12637433 0.528 62983787 239 rs4688357 0.555 62985367 240 Example 11 For individuals with colon cancer, the distribution of polymorphic alleles at position 120037273 of chromosome 3 was different from those without colon cancer (Table 11). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0016 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.489 (Table 11). These data further suggest that this marker is associated with colon cancer risk and that the A allele at position 120037273 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 11 rs no. 1402582 Chromosome; Position 3; 120037273 Gene Name SEQ ID NO; Position Genotype; Phenotype n=A; increased risk Hardy-Weinber 0.0111588 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 777 132 0 Trend 0.0016e 1.489 Table 11A indicates SNPs found to be in strong linkage disequilibrium with rs1402582. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 11A Linked SNPs SNP r 2 Position on chr3 SEQ ID NO
rs1081903 0.549 120036240 243 rs1402582 - 120037273 244 rs812824 0.608 120037336 245 rs2936727 0.608 120037804 246 rs1521289 0.608 120039183 247 rs2684320 0.608 120039851 248 rs2649882 0.608 120044441 249 Example 12 For individuals with colon cancer, the distribution of polymorphic alleles at position 120037336 of chromosome 3 was different from those without colon cancer (Table 12). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.057 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.122 (Table 12). These data further suggest that this marker is associated with colon cancer risk and that the G
allele at position 120037336 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 12 rs no. 812824 Chromosome; Position 3; 120037336 Gene Name SEQ ID NO; Position Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.0190876 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 586 359 34 Trend 0.057e 1.122 Table 12A indicates SNPs found to be in strong linkage disequilibrium with rs812824. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 12A Linked SNPs SNP r2 Position on chr3 SEQ ID NO
rs881603 0.705 120013362 241 rs881604 0.711 120013382 242 rs1081903 0.953 120036240 243 rs1402582 0.608 120037273 244 rs812824 - 120037336 245 rs2936727 1.0 120037804 246 rs1521289 1.0 120039183 247 rs2684320 1.0 120039851 248 rs2649882 1.0 120044441 249 Example 13 For individuals with colon cancer, the distribution of polymorphic alleles at position 186033203 of chromosome 3, found within the KIAA0804 gene, was different from those without colon cancer (Table 13). The recessive test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0045, and the corresponding recessive odds ratio is 1.266 (Table 13). These data further suggest that this marker, located within the KIAA0804 gene, is associated with colon cancer risk and that the A allele at position 186033203 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 13 rs no. 9830734 Chromosome; Position 3; 186033203 Gene Name KIAA0804 SEQ ID NO; Position 1125; 8081 Genotype; Phenotype n=A; increased risk Hard rg 0.0561279 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 100 526 528 Recessive 0.0045e 1.266 Table 13A indicates SNPs found to be in strong linkage disequilibrium with rs9830734. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 13A Linked SNPs SNP r2 Position on chr3 SEQ ID NO
rs4686769 0.765 186008653 250 rs2377115 0.71 186008673 251 rs725656 0.636 186008910 252 rs7640976 1.0 186012692 253 rs13079793 0.619 186027445 254 rs10513799 0.636 186032241 255 rs9830734 - 186033203 256 rs4432622 0.617 186038166 257 rs11710551 0.643 186041770 258 rs16859344 0.636 186043671 259 rs2305240 0.636 186049741 260 rs11720538 0.623 186052729 261 rs6443999 0.6 186056257 262 rs724273 0.647 186058533 263 rs6809079 0.597 186059022 264 rs7340698 0.636 186060619 265 rs3733165 0.553 186063619 266 rs2377107 0.593 186070576 267 rs7619460 0.597 186070838 268 rs9757458 0.615 186072802 269 rs7628188 0.553 186073295 270 rs7638317 0.557 186076934 271 rs11717139 0.593 186079782 272 rs11714752 0.588 186081364 273 rs9881074 0.593 186083378 274 rs1000270 0.593 186090182 275 rs6762984 0.529 186099834 276 rs4324453 0.593 186104572 277 rs7618180 0.532 186112996 278 rs4686879 0.556 186115949 279 rs7611263 0.597 186117351 280 rs9825856 0.604 186119962 281 rs9290804 0.557 186126928 282 rs10446349 0.597 186131728 283 rs13066369 0.518 186142625 284 rs9870352 0.576 186146360 285 rs4422281 0.518 186148006 286 rs9820111 0.518 186149057 287 rs6784179 0.518 186152026 288 rs7623170 0.512 186156901 289 rs6765821 0.524 186244971 290 rs6783157 0.521 186252104 291 rs12636670 0.526 186267820 292 Example 14 For individuals with colon cancer, the distribution of polymorphic alleles at position 187873329 of chromosome 3, found within the HRG gene, was different from those without colon cancer (Table 14). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0504 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.109 (Table 14). These data further suggest that this marker, located within the HRG gene, is associated with colon cancer risk and that the C allele at position 187873329 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 14 rs no. 9898 Chromosome; Position 3; 187873329 Gene Name HRG
SEQ ID NO; Position 1126; 6830 Genotype; Phenotype n=C; increased risk Hard -Weinber 0.0124873 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 168 491 494 Trend 0.0504e 1.109 Table 14A indicates SNPs found to be in strong linkage disequilibrium with rs9898. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 14A Linked SNPs SNP r 2 Position on chr3 SEQ ID NO
rs3733159 0.8 187843111 293 rs1868154 0.574 187857373 294 rs9898 - 187873329 295 rs1042464 0.547 187878274 296 Example 15 For individuals with colon cancer, the distribution of polymorphic alleles at position 4862109 of chromosome 4 was different from those without colon cancer (Table 15). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0017 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.430 (Table 15). The dominant test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.001, and the corresponding dominant odds ratio is 1.457 (Table 15). These data further suggest that this marker is associated with colon cancer risk and that the A allele at position 4862109 of chromosome 4 is associated with an increased risk of developing colon cancer.

Table 15 rs no. 10516168 Chromosome; Position 4; 4862109 Gene Name SEQ ID NO; Position Geno e; Phenotype n=A; increased risk Hard -Weinber 1 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 821 156 7 Trend 0.0017e 1.430 1 1 705 196 8 Dominant 0.OOle 1.457 Table 15A indicates SNPs found to be in strong linkage disequilibrium with rs10516168. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 15A Linked SNPs SNP r 2 Position on chr4 SEQ ID NO
rs2089781 1.0 4857130 297 rs13149006 0.848 4857759 298 rs10516168 - 4862109 299 rs767564 0.79 4867970 300 Example 16 For individuals with colon cancer, the distribution of polymorphic alleles at position 73418955 of chromosome 4, found within the GPR74 gene, was different from those without colon cancer (Table 16). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0583 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.112 (Table 16). These data further suggest that this marker, located within the GPR74 gene, is associated with colon cancer risk and that the G allele at position 73418955 of chromosome 4 is associated with an increased risk of developing colon cancer.

Table 16 rs no. 10518098 Chromosome; Position 4; 73418955 Gene Name GPR74 SEQ ID NO; Position 1127;
Genotype; Phenotype n=G; increased risk Hard -Weinber 0.0585416 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 411 369 110 Trend 0.0583e 1.112 Table 16A indicates SNPs found to be in strong linkage disequilibrium with rs10518098. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 16A Linked SNPs SNP r 2 Position on chr4 SEQ ID NO
rs11726886 0.533 73187634 301 rs10518093 0.621 73200067 302 rs4129733 0.749 73328055 303 rs4337703 0.749 73346262 304 rs11733404 0.73 73346848 305 rs11737827 0.749 73348223 306 rs12651098 0.738 73357454 307 rs11734943 0.675 73363372 308 rs9790741 0.676 73365920 309 rs11940196 0.925 73368604 310 rs10755169 0.963 73376981 311 rs11729989 0.884 73386336 312 rs4333153 0.963 73387894 313 rs17775363 0.888 73401936 314 rs17718934 0.889 73402263 315 rs885521 0.889 73403367 316 rs2137735 0.889 73409745 317 rs7675397 1.0 73418036 318 rs10518098 - 73418955 319 rs1554016 1.0 73419931 320 rs10938007 0.91 73420592 321 rs4444797 1.0 73420874 322 rs4502651 1.0 73420904 323 rs4301078 1.0 73420954 324 rs7700096 1.0 73421198 325 rs7654146 1.0 73421361 326 rs2056022 1.0 73421626 327 rs2056023 1.0 73421636 328 rs2365795 1.0 73424191 329 rs6840004 0.926 73426574 330 rs1121770 1.0 73428206 331 rs11940139 1.0 73428609 332 rs868028 1.0 73429022 333 rs868026 1.0 73429166 334 rs7673208 1.0 73429961 335 rs4694467 1.0 73430864 336 rs4694468 0.924 73432371 337 rs1398982 1.0 73432662 338 rs10938009 0.926 73433172 339 rs996154 1.0 73435810 340 rs996153 1.0 73435851 341 rs1018283 1.0 73437882 342 rs10805048 0.926 73438096 343 rs957047 1.0 73440758 344 rs957046 1.0 73441001 345 rs957045 1.0 73441029 346 rs10008822 1.0 73442206 347 rs4547769 1.0 73445194 348 rs7674709 0.835 73446950 349 rs10938010 0.888 73448534 350 rs7662481 1.0 73453617 351 rs884511 0.89 73454336 352 rs10029245 0.924 73456969 353 rs970649 1.0 73461203 354 rs10938012 0.925 73461427 355 rs4694120 0.926 73468266 356 rs10518099 0.926 73468802 357 rs10518100 0.89 73469693 358 rs9985540 0.889 73472897 359 rs985302 0.921 73473510 360 rs2117380 0.855 73474331 361 rs1865383 0.816 73475459 362 rs984406 0.842 73476824 363 rs2175830 0.603 73481968 364 rs1554017 0.603 73482388 365 rs10006866 0.603 73484550 366 rs1513894 0.661 73489468 367 rs11729217 0.593 73491229 368 rs6857543 0.662 73491598 369 rs1398980 0.574 73492707 370 rs7681169 0.574 73493192 371 rs10433664 0.574 73493907 372 rs10050160 0.574 73496343 373 rs6446823 0.662 73496916 374 rs7679388 0.574 73501955 375 Example 17 For individuals with colon cancer, the distribution of polymorphic alleles at position 114720973 of chromosome 5 was different from those without colon cancer (Table 17). The recessive test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0059, and the corresponding recessive odds ratio is 1.325 (Table 17). These data further suggest that this marker is associated with colon cancer risk and that the A allele at position 114720973 of chromosome 5 is associated with an increased risk of developing colon cancer.

Table 17 rs no. 2963765 Chromosome; Position 5; 114720973 Gene Name SEQ ID NO; Position Genotype; Phenotype n=A; increased risk Hardy-Weinber 0.798586 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 251 487 245 Recessive 0.0059e 1.325 Table 17A indicates SNPs found to be in strong linkage disequilibrium with rs2963765. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 17A Linked SNPs SNP r 2 Position on chr5 SEQ ID NO
rs269511 0.677 114716570 376 rs12654556 0.74 114718052 377 rs10519405 0.525 114719100 378 rs10519406 0.525 114719186 379 rs2963765 - 114720973 380 rs2964560 1.0 114721020 381 rs269503 0.525 114724952 382 rs10463669 0.544 114727927 383 rs12657417 0.525 114728598 384 rs2925172 0.935 114729688 385 rs17383755 0.559 114730035 386 rs11241322 0.9 114730402 387 rs11241323 0.501 114731087 388 rs2963749 0.934 114734391 389 rs17383865 0.932 114735264 390 rs2963747 0.934 114735588 391 rs17137667 0.902 114735981 392 rs2925170 0.934 114736503 393 rs7715232 0.505 114739954 394 rs2198712 0.935 114741070 395 rs10477531 0.841 114742706 396 rs7703997 0.615 114743558 397 rs17137708 0.9 114743576 398 rs13162208 0.933 114744950 399 rs751485 0.934 114747047 400 rs897478 0.933 114747337 401 rs2016888 0.964 114747490 402 Example 18 For individuals with colon cancer, the distribution of polymorphic alleles at position 121110284 of chromosome 5 was different from those without colon cancer (Table 18). The recessive test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.0055, and the corresponding recessive odds ratio is 1.451 (Table 18). These data further suggest that this marker is associated with colon cancer risk and that the T allele at position 121110284 of chromosome 5 is associated with an increased risk of developing colon cancer.

Table 18 rs no. 1988515 Chromosome; Position 5; 121110284 Gene Name SEQ ID NO; Position Genotype; Pheno e n=T; increased risk Hard -Weinber 0.3509 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 11 152 703 Recessive 0.0055e 1.451 Table 18A indicates SNPs found to be in strong linkage disequilibrium with rs 1988515. To generate this list, correlation coefficients (rl) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 18A Linked SNPs SNP r2 Position on chr5 SEQ ID NO
rs11958025 0.693 121091463 403 rs2567820 0.553 121091499 404 rs17148244 0.732 121091674 405 rs7710646 0.553 121092163 406 rs7710680 0.693 121092323 407 rs2174984 0.843 121093100 408 rs17148266 0.744 121093738 409 rs10213700 0.744 121093873 410 rs17148275 0.744 121095213 411 rs1431964 0.948 121096396 412 rs1508809 0.948 121097405 413 rs1828180 0.895 121099073 414 rs1560552 0.948 121099678 415 rs1560551 0.948 121099771 416 rs983441 0.895 121100720 417 rs983440 0.895 121100858 418 rs983439 1.0 121101095 419 rs2567817 0.895 121102610 420 rs2662291 0.71 121102897 421 rs2567816 0.681 121103646 422 rs2136184 1.0 121103950 423 rs2136183 1.0 121104009 424 rs1431963 1.0 121104729 425 rs1431962 0.948 121104747 426 rs1588260 0.897 121105473 427 rs2567803 1.0 121107768 428 rs1156684 1.0 121110035 429 rs1988515 - 121110284 430 rs2662296 1.0 121110706 431 rs1367938 0.948 121114213 432 rs1560553 0.711 121115356 433 rs769365 0.778 121115515 434 rs919651 0.947 121116167 435 rs930180 0.948 121116191 436 rs2406704 0.843 121116332 437 rs2406705 0.855 121116360 438 rs982148 0.744 121119962 439 rs6595320 0.711 121128383 440 rs1431947 0.691 121137238 441 rs2897529 0.711 121153311 442 Example 19 For individuals with colon cancer, the distribution of polymorphic alleles at position 128145987 of chromosome 5, found within the SLC27A6 gene, was different from those without colon cancer (Table 19). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0144 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.172 (Table 19). These data further suggest that this marker, located within the SLC27A6 gene, is associated with colon cancer risk and that the A allele at position 128145987 of chromosome 5 is associated with an increased risk of developing colon cancer.

Table 19 rs no. 10491268 Chromosome; Position 5; 128145987 Gene Name SLC27A6 SEQ ID NO; Position 1128;
Genotype; Phenotype n=A; increased risk Hard -Weinber 0.928532 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 529 337 55 Trend 0.0144e 1.172 Table 19A indicates SNPs found to be in strong linkage disequilibrium with rs10491268. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 19A Linked SNPs SNP r2 Position on chr5 SEQ ID NO
rs247184 0.545 128103463 443 rs247195 0.545 128108152 444 rs247210 0.583 128113997 445 rs247094 0.583 128120050 446 rs10074635 0.503 128134369 447 rs10061806 1.0 128135572 448 rs7449021 1.0 128139763 449 rs17163935 0.56 128141175 450 rs10491268 - 128145987 451 rs17790915 0.512 128146786 452 rs1496344 0.576 128156553 453 rs1019137 0.545 128157693 454 rs7735162 0.961 128160641 455 rs7707454 0.926 128164258 456 rs10066082 0.816 128197696 457 rs10058629 0.778 128206257 458 rs17678073 0.778 128220969 459 rs2214369 0.816 128223084 460 rs6860974 0.778 128227979 461 rs10050439 0.778 128228401 462 rs7723679 0.767 128232311 463 rs7723683 0.777 128232320 464 rs10079808 0.772 128233576 465 rs1363170 0.769 128233727 466 rs13360809 0.778 128234493 467 rs13356389 0.778 128234617 468 rs17678190 0.778 128234806 469 rs17616306 0.778 128235438 470 rs7712212 0.778 128235745 471 rs7712497 0.778 128235767 472 rs7716412 0.778 128236078 473 rs13362019 0.778 128236528 474 rs9327496 0.523 128238639 475 rs13358000 0.778 128240119 476 rs4469239 0.776 128241301 477 rs13360401 0.583 128258653 478 rs6595867 0.578 128260778 479 rs6873372 0.552 128260800 480 rs6880855 0.558 128263313 481 rs1421889 0.61 128265259 482 rs9285913 0.558 128269933 483 rs10478827 0.544 128271956 484 rs9327500 0.591 128273703 485 rs13436689 0.549 128279649 486 rs13156417 0.558 128280539 487 rs10477690 0.555 128287628 488 rs6867677 0.554 128289750 489 rs10042256 0.567 128327389 490 rs11740497 0.556 128340511 491 rs10038006 0.54 128341528 492 rs17617241 0.507 128345166 493 rs10065480 0.516 128346380 494 rs11743701 0.525 128348967 495 rs3886286 0.525 128351543 496 rs7735034 0.524 128352581 497 rs7730969 0.525 128352924 498 rs11749027 0.558 128353107 499 rs17679250 0.525 128355391 500 rs17617329 0.525 128355483 501 rs3851463 0.525 128356081 502 rs6859805 0.642 128358774 503 Example 20 For individuals with colon cancer, the distribution of polymorphic alleles at position 1032946 of chromosome 6, found within the LOC285768 gene, was different from those without colon cancer (Table 20). The dominant test for risk associated with carrying the A allele had an asymptotic p-value of 0.074953, and the corresponding dominant odds ratio is 1.453 (Table 20).
These data further suggest that this marker, located within the LOC285768 gene, is associated with colon cancer risk and that the A allele at position 1032946 of chromosome 6 is associated with an increased risk of developing colon cancer.

Table 20 rs no. 9328033 Chromosome; Position 6; 1032946 Gene Name LOC285768 SEQ ID NO; Position 1129; 13622 Genotype; Phenotype n=A; increased risk Hard erg 0.932075 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 60 370 553 Dominant 0.074953a 1.453 Table 20A indicates SNPs found to be in strong linkage disequilibrium with rs9328033. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 20A Linked SNPs SNP r 2 Position on chr6 SEQ ID NO
rs9405439 0.795 1026731 504 rs9391899 0.837 1032864 505 rs9328033 - 1032946 506 rs7756730 0.756 1033885 507 rs7770094 0.756 1033964 508 rs10900904 0.75 1034131 509 rs10458112 0.756 1034217 510 rs6596783 0.744 1035056 511 rs6914197 0.72 1035451 512 rs9405441 0.753 1037138 513 rs6911992 0.685 1037761 514 Example 21 For individuals with colon cancer, the distribution of polymorphic alleles at position 69521107 of chromosome 6, found within the BAI3 gene, was different from those without colon cancer (Table 21). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0056 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.194 (Table 21). The recessive test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.0983, and the corresponding recessive odds ratio is 1.180 (Table 21). These data further suggest that this marker, located within the BAI3 gene, is associated with colon cancer risk and that the T allele at position 69521107 of chromosome 6 is associated with an increased risk of developing colon cancer.

Table 21 rs no. 10484791 Chromosome; Position 6; 69521107 Gene Name BAI3 SEQ ID NO; Position 1130; 116950 Genotype; Phenotype n=T; increased risk Hard erg 0.0463995 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 239 453 277 Trend 0.0056e 1.194 1 4 170 442 289 Recessive 0.0983e 1.180 Table 21A indicates SNPs found to be in strong linkage disequilibrium with rs10484791. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 21A Linked SNPs SNP r 2 Position on chr6 SEQ ID NO
rs2585614 0.595 69379328 515 rs2246104 0.656 69411039 516 rs2585627 0.656 69414352 517 rs2585626 0.656 69414862 518 rs2802694 0.807 69416925 519 rs2802691 0.739 69420759 520 rs2253759 0.868 69428738 521 rs2253866 0.746 69429357 522 rs2802689 0.865 69429728 523 rs2585622 0.709 69435338 524 rs2585621 0.716 69435377 525 rs2254654 0.837 69435704 526 rs3121775 0.69 69436412 527 rs6931872 0.743 69437088 528 rs2585592 0.656 69437132 529 rs7754835 0.69 69437929 530 rs2746125 0.746 69439747 531 rs2746127 0.746 69440936 532 rs2585597 0.715 69445347 533 rs2746141 0.837 69447873 534 rs2585598 0.69 69449271 535 rs2802684 0.742 69454318 536 rs2802683 0.868 69455343 537 rs2585599 0.733 69461590 538 rs2802680 0.776 69462851 539 rs2585600 0.718 69463179 540 rs2585604 0.776 69469800 541 rs2746132 0.718 69471343 542 rs715294 0.744 69483117 543 rs2802676 0.901 69483590 544 rs12206222 0.717 69486083 545 rs12210045 0.776 69490498 546 rs10945138 0.901 69496298 547 rs7768591 0.901 69497479 548 rs11752837 0.776 69504298 549 rs11752398 0.718 69504487 550 rs10945139 0.775 69511710 551 rs12154008 0.775 69513299 552 rs7745837 0.813 69517615 553 rs12201488 0.813 69518419 554 rs10484791 - 69521107 555 Example 22 For individuals with colon cancer, the distribution of polymorphic alleles at position 83094274 of chromosome 6, found within the TPBG gene, was different from those without colon cancer (Table 22). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.0999 based on permutation analysis, and the corresponding recessive odds ratio is 1.291 (Table 22). These data further suggest that this marker, located within the TPBG gene, is associated with colon cancer risk and that the T allele at position 83094274 of chromosome 6 is associated with an increased risk of developing colon cancer.

Table 22 rs no. 723142 Chromosome; Position 6; 83094274 Gene Name TPBG
SEQ ID NO; Position 1131;
Genotype; Phenotype n=T; increased risk Hardy-Weinber 0.0954124 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 496 367 88 Recessive 0.0999e 1.291 Table 22A indicates SNPs found to be in strong linkage disequilibrium with rs723142. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 22A Linked SNPs SNP r 2 Position on chr6 SEQ ID NO
rs2323642 0.621 82950808 556 rs540814 0.553 83037702 557 rs2753211 0.682 83052756 558 rs2753212 0.696 83052893 559 rs9344267 0.797 83059529 560 rs62953 0.768 83059811 561 rs529833 0.754 83063355 562 rs544734 0.959 83065585 563 rs554594 0.959 83065715 564 rs511002 1.0 83066965 565 rs507500 0.921 83067321 566 rs532219 1.0 83079412 567 rs577767 0.959 83086171 568 rs526833 0.958 83086772 569 rs7756828 1.0 83087733 570 rs508106 1.0 83088471 571 rs555844 0.921 83089659 572 rs1923137 1.0 83092525 573 rs1923138 0.958 83092537 574 rs723142 - 83094274 575 rs2180742 1.0 83094499 576 rs1547614 0.959 83094576 577 rs2145368 1.0 83095347 578 rs2180743 1.0 83095565 579 rs7762072 0.956 83095939 580 rs13191698 0.921 83096974 581 rs13207433 0.959 83097004 582 rs1321622 0.879 83097222 583 rs9353066 0.921 83098262 584 rs6907015 0.959 83098329 585 rs6930014 0.959 83098352 586 rs9353067 0.875 83100260 587 rs9353068 1.0 83101000 588 rs2024996 0.879 83103870 589 rs796398 0.959 83113039 590 rs770904 0.916 83114887 591 rs770897 0.786 83120523 592 rs770898 0.755 83122607 593 rs770895 0.778 83127291 594 rs1570140 0.759 83129590 595 rs770911 0.759 83131084 596 rs1275806 0.664 83137358 597 rs770906 0.525 83140060 598 rs932614 0.525 83146661 599 rs9344274 0.517 83147795 600 rs1951006 0.528 83150543 601 rs9449462 0.515 83153296 602 rs9361914 0.514 83155501 603 rs714133 0.528 83162032 604 rs1998204 0.517 83163350 605 rs1853143 0.517 83165082 606 rs4706945 0.528 83165771 607 rs9449469 0.528 83167427 608 rs9449470 0.552 83167802 609 rs4706948 0.514 83168404 610 rs2875128 0.541 83169297 611 rs6912008 0.517 83169493 612 rs9449475 0.631 83170215 613 rs967730 0.562 83170490 614 rs967731 0.552 83170598 615 rs9361923 0.517 83172329 616 Example 23 For individuals with colon cancer, the distribution of polymorphic alleles at position 9440613 of chromosome 8, found within the TNKS gene, was different from those without colon cancer (Table 23). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0462 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.148 (Table 23). These data further suggest that this marker, located within the TNKS gene, is associated with colon cancer risk and that the A allele at position 9440613 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 23 rs no. 6601328 Chromosome; Position 8; 9440613 Gene Name TNKS
SEQ ID NO; Position 1132;
Genotype; Phenotype n=A; increased risk Hard -Weinber 0.162 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 26 263 950 Trend 0.0462e 1.148 Table 23A indicates SNPs found to be in strong linkage disequilibrium with rs6601328. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 23A Linked SNPs SNP r 2 Position on chr8 SEQ ID NO
rs17150201 0.88 9426711 617 rs1471203 0.803 9431741 618 rs7009486 0.891 9436057 619 rs13261395 1.0 9436101 620 rs4841169 0.891 9436786 621 rs4840423 1.0 9437029 622 rs4841171 1.0 9437099 623 rs11785485 1.0 9439838 624 rs7388554 0.88 9440072 625 rs6601328 - 9440613 626 rs11781665 1.0 9444872 627 rs7013834 1.0 9452052 628 rs13274310 1.0 9458679 629 rs13265363 0.891 9460336 630 rs11784858 0.785 9463104 631 rs13270240 0.847 9468129 632 rs11775432 1.0 9480306 633 rs4551359 1.0 9503674 634 rs11774818 1.0 9523873 635 rs4841186 1.0 9526021 636 rs4840432 1.0 9526193 637 rs11994018 1.0 9531111 638 rs11991547 1.0 9538857 639 rs7839648 0.891 9541393 640 rs4128324 1.0 9546289 641 rs11780274 1.0 9558649 642 rs13250838 1.0 9563755 643 rs13264510 1.0 9568067 644 rs13261385 1.0 9568084 645 rs4570159 1.0 9568712 646 rs13259379 0.891 9640154 647 rs4289816 0.88 9645506 648 rs 17734024 0.891 9673180 649 Example 24 For individuals with colon cancer, the distribution of polymorphic alleles at position 105447572 of chromosome 8 was different from those without colon cancer (Table 24). The dominant test for risk associated with carrying the G allele had an empirical p-value based on pertnutation analysis of 0.0432, and the corresponding dominant odds ratio is 1.206 (Table 24). These data further suggest that this marker is associated with colon cancer risk and that the G allele at position 105447572 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 24 rs no. 2853129 Chromosome; Position 8; 105447572 Gene Name SEQ ID NO; Position Genotype; Phenotype n=G; increased risk rg 0.127 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 941 269 28 Dominant 0.0432e 1.206 Table 24A indicates SNPs found to be in strong linkage disequilibrium with rs2853129. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 24A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs2853129 - 105447572 650 Example 25 For individuals with colon cancer, the distribution of polymorphic alleles at position 138583352 of chromosome 8 was different from those without colon cancer (Table 25). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0016 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.264 (Table 25). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 138583352 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 25 rs no. 1399176 Chromosome; Position 8; 138583352 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hardy-Weinberg 0.0940461 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 693 255 14 Trend 0.0016e 1.264 Table 25A indicates SNPs found to be in strong linkage disequilibrium with rs1:399176. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 25A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs4909649 0.835 138448609 651 rs4909652 0.835 138448978 652 rs7000235 0.835 138450507 653 rs7833216 0.835 138450935 654 rs6986763 0.835 138451287 655 rs4265216 0.821 138452272 656 rs4391470 0.835 138452507 657 rs13249389 0.834 138452835 658 rs10102751 0.835 138453471 659 rs4532628 0.835 138454113 660 rs4279630 0.829 138454197 661 rs4474054 0.835 138454235 662 rs4909654 0.835 138454833 663 rs4292724 0.835 138455486 664 rs12541665 0.835 138455728 665 rs4909657 0.82 138456184 666 rs4909367 0.652 138456296 667 rs7820493 0.835 138456395 668 rs7837229 0.835 138457265 669 rs13253269 0.83 138458205 670 rs7014387 0.835 138458287 671 rs7826913 0.835 138458607 672 rs6577786 0.835 138459228 673 rs7835685 0.835 138459736 674 rs4909658 0.833 138460258 675 rs4909659 0.835 138460320 676 rs4909660 0.835 138460491 677 rs6577788 0.835 138461455 678 rs6577789 0.835 138461471 679 rs7845225 0.835 138461926 680 rs7827162 0.835 138462319 681 rs4131207 0.796 138467267 682 rs4131208 0.835 138467277 683 rs7016247 0.835 138467539 684 rs7007938 0.835 138469853 685 rs10875404 0.835 138469883 686 rs6577790 0.835 138472916 687 rs4909665 0.835 138473941 688 rs6577792 0.828 138477490 689 rs4582597 0.835 138481482 690 rs10098545 0.819 138482393 691 rs2943199 0.86 138490184 692 rs2960100 0.835 138498734 693 rs11166725 0.958 138545196 694 rs17629911 0.958 138546484 695 rs10505682 0.837 138551497 696 rs17632067 1.0 138576626 697 rs11786383 1.0 138578139 698 rs11773949 0.628 138580074 699 rs1399176 - 138583352 700 rs10505684 0.628 138585809 701 rs7816962 0.628 138585968 702 rs6577803 0.606 138586498 703 rs6996799 0.606 138588282 704 rs17683816 0.959 138590203 705 rs12677749 0.959 138590751 706 rs6981747 0.957 138594903 707 rs4384013 0.958 138601596 708 rs4625065 0.959 138601771 709 rs11786764 0.959 138603600 710 rs11786786 0.959 138603658 711 rs11776612 0.959 138603708 712 rs1913453 0.959 138604408 713 rs17633935 0.959 138607169 714 rs12677813 0.959 138608732 715 rs11780534 0.959 138610100 716 rs11777429 0.958 138610110 717 rs17634044 0.959 138610517 718 rs11166729 0.959 138611185 719 rs1514199 0.959 138611655 720 rs1514200 0.954 138611699 721 rs1514201 0.953 138611757 722 rs11780105 0.954 138612308 723 rs12375358 0.959 138614096 724 rs10505685 0.958 138614490 725 rs11778762 0.959 138615852 726 rs1514202 0.954 138616621 727 rs1514203 0.959 138616711 728 rs1514204 0.959 138616778 729 Example 26 For individuals with colon cancer, the distribution of polymorphic alleles at position 138614490 of chromosome 8 was different from those without colon cancer (Table 26). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0017 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.289 (Table 26). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 138614490 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 26 rs no. 10505685 Chromosome; Position 8; 138614490 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hardy-Weinberg 0.2288 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 683 191 19 Trend 0.0017e 1.289 Table 26A indicates SNPs found to be in strong linkage disequilibrium with rs10505685. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 26A Linked SNPs SNP r 2 Position on chr8 SEQ ID NO
rs4909649 0.794 138448609 651 rs4909652 0.794 138448978 652 rs7000235 0.794 138450507 653 rs7833216 0.794 138450935 654 rs6986763 0.794 138451287 655 rs4265216 0.777 138452272 656 rs4391470 0.794 138452507 657 rs13249389 0.793 138452835 658 rs10102751 0.794 138453471 659 rs4532628 0.794 138454113 660 rs4279630 0.788 138454197 661 rs4474054 0.794 138454235 662 rs4909654 0.794 138454833 663 rs4292724 0.794 138455486 664 rs12541665 0.794 138455728 665 rs4909657 0.776 138456184 666 rs4909367 0.641 138456296 667 rs7820493 0.794 138456395 668 rs7837229 0.794 138457265 669 rs13253269 0.789 138458205 670 rs7014387 0.794 138458287 671 rs7826913 0.794 138458607 672 rs6577786 0.794 138459228 673 rs7835685 0.794 138459736 674 rs4909658 0.792 138460258 675 rs4909659 0.794 138460320 676 rs4909660 0.794 138460491 677 rs6577788 0.794 138461455 678 rs6577789 0.794 138461471 679 rs7845225 0.794 138461926 680 rs7827162 0.794 138462319 681 rs4131207 0.755 138467267 682 rs4131208 0.794 138467277 683 rs7016247 0.794 138467539 684 rs7007938 0.794 138469853 685 rs10875404 0.794 138469883 686 rs6577790 0.794 138472916 687 rs4909665 0.794 138473941 688 rs6577792 0.786 138477490 689 rs4582597 0.794 138481482 690 rs10098545 0.774 138482393 691 rs2943199 0.815 138490184 692 rs2960100 0.794 138498734 693 rs11166725 0.916 138545196 694 rs17629911 0.916 138546484 695 rs10505682 0.797 138551497 696 rs17632067 0.957 138576626 697 rs11786383 0.958 138578139 698 rs11773949 0.585 138580074 699 rs1399176 0.958 138583352 700 rs10505684 0.585 138585809 701 rs7816962 0.585 138585968 702 rs6577803 0.626 138586498 703 rs6996799 0.626 138588282 704 rs17683816 1.0 138590203 705 rs 12677749 1.0 13 8590751 706 rs6981747 1.0 138594903 707 rs4384013 0.957 138601596 708 rs4625065 1.0 138601771 709 rs11786764 1.0 138603600 710 rs11786786 1.0 138603658 711 rs11776612 1.0 138603708 712 rs1913453 1.0 138604408 713 rs17633935 1.0 138607169 714 rs12677813 1.0 138608732 715 rs11780534 1.0 138610100 716 rs11777429 1.0 138610110 717 rs17634044 1.0 138610517 718 rs11166729 1.0 138611185 719 rs1514199 1.0 138611655 720 rs1514200 1.0 138611699 721 rs1514201 1.0 138611757 722 rs11780105 1.0 138612308 723 rs12375358 1.0 138614096 724 rs10505685 - 138614490 725 rs11778762 1.0 138615852 726 rs1514202 1.0 138616621 727 rs1514203 1.0 138616711 728 rs1514204 1.0 138616778 729 Example 27 For individuals with colon cancer, the distribution of polymorphic alleles at position 141587219 of chromosome 8, found within the CHRACI gene, was different from those without colon cancer (Table 27). The dominant test for risk associated with carrying the A allele had an asymptotic p-value of 0.04448, and the corresponding dominant odds ratio is 1.697 (Table 27).
These data further suggest that this marker, located within the CHRAC I gene, is associated with colon cancer risk and that the A
allele at position 141587219 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 27 rs no. 1057083 Chromosome; Position 8; 141587219 Gene Name CHRAC 1 SEQ ID NO; Position 1133;
Genotype; Phenotype n=C; increased risk erg 0.012 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 39 288 912 Dominant 0.04448a 1.697 Table 27A indicates SNPs found to be in strong linkage disequilibrium with rs1057083. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 27A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs12676904 0.806 141567935 730 rs4961309 1.0 141583366 731 rs1057083 - 141587219 732 rs6578111 1.0 141589763 733 rs4961323 1.0 141595413 734 rs10216653 1.0 141596167 735 rs4610723 0.951 141596488 736 rs7388327 0.521 141597272 737 Example 28 For individuals with colon cancer, the distribution of polymorphic alleles at position 6355683 of chromosome 9, found within the NYD-SP25 gene, was different from those without colon cancer (Table 28). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0039 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.229 (Table 28). These data further suggest that this marker, located within the NYD-SP25 gene, is associated with colon cancer risk and that the A allele at position 6355683 of chromosome 9 is associated with an increased risk of developing colon cancer.

Table 28 rs no. 719725 Chromosome; Position 9; 6355683 Gene Name NYD-SP25 SEQ ID NO; Position 1134;
Genotype; Phenotype n=A; increased risk Hardy-Weinberg 0.628649 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 139 437 367 Trend 0.0039e 1.229 Table 28A indicates SNPs found to be in strong linkage disequilibrium with rs'719725. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 28A Linked SNPs SNP r 2 Position on chr9 SEQ ID NO
rs744567 0.509 6282602 738 rs17756142 0.553 6291578 739 rs1322166 0.57 6299862 740 rs4742179 0.518 6314376 741 rs10758764 0.511 6316825 742 rs10491836 0.649 6321421 743 rs16924356 0.615 6321610 744 rs721352 0.518 6322901 745 rs7850988 0.649 6325760 746 rs731585 0.546 6332328 747 rs2169282 0.717 6340235 748 rs16924428 0.624 6341111 749 rs10975552 0.966 6341834 750 rs10975553 1.0 6342819 751 rs7022186 1.0 6349144 752 rs7851246 0.649 6352365 753 rs10975558 0.649 6354449 754 rs7875812 1.0 6354533 755 rs719725 - 6355683 756 rs7860427 0.74 6375637 757 rs7025295 0.965 6385247 758 rs7850497 0.782 6385540 759 rs10217561 0.782 6386245 760 rs10815428 0.686 6390030 761 rs7045097 0.816 6392856 762 rs10739097 0.834 6397843 763 rs7865955 0.84 6398247 764 rs7857628 0.966 6399874 765 Example 29 For individuals with colon cancer, the distribution of polymorphic alleles at position 73642109 of chromosome 9 was different from those without colon cancer (Table 29). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0034 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.549 (Table 29). The recessive test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0054, and the corresponding recessive odds ratio is 1.574 (Table 29). These data further suggest that this marker is associated with colon cancer risk and that the A allele at position 73642109 of chromosome 9 is associated with an increased risk of developing colon cancer.
Table 29 rs no. 10512028 Chromosome; Position 9; 73642109 Gene Name SEQ ID NO; Position Genotype; Phenotype n=A; increased risk Hard -Weinber 0.258618 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 6 109 867 Trend 0.0034e 1.549 1 1 --42 72 878 11 Recessive 0.0054e 1.574 Table 29A indicates SNPs found to be in strong linkage disequilibrium with rs10512028. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 29A Linked SNPs SNP r 2 Position on chr9 SEQ ID NO
rs4288438 1.0 73606988 766 rs6560355 1.0 73607164 767 rs1585251 1.0 73607569 768 rs4745250 1.0 73612124 769 rs7044457 1.0 73613027 770 rs2061399 1.0 73614943 771 rs2061398 1.0 73615076 772 rs2061396 1.0 73615232 773 rs2061395 1.0 73616781 774 rs10781152 1.0 73617303 775 rs4745254 1.0 73618675 776 rs2168884 1.0 73619146 777 rs4745255 1.0 73622095 778 rs4745256 1.0 73622395 779 rs4745257 1.0 73622439 780 rs4745258 1.0 73625852 781 rs4745259 1.0 73626601 782 rs4745260 1.0 73626706 783 rs7389572 1.0 73627824 784 rs10746927 1.0 73628740 785 rs7048840 1.0 73629704 786 rs4744695 1.0 73633747 787 rs981197 1.0 73634385 788 rs1458489 1.0 73635467 789 rs1379909 1.0 73635691 790 rs1379910 1.0 73635782 791 rs1902976 1.0 73636447 792 rs1902978 1.0 73636612 793 rs7026566 1.0 73636831 794 rs1379911 1.0 73638980 795 rs7027893 1.0 73639771 796 rs7039655 1.0 73639895 797 rs4468001 1.0 73640222 798 rs10512028 - 73642109 799 rs999791 1.0 73642315 800 rs17059425 1.0 73643177 801 Example 30 For individuals with colon cancer, the distribution of polymorphic alleles at position 79353007 of chromosome 9 was different from those without colon cancer (Table 30). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0078 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.699 (Table 30). These data further suggest that this marker is associated with colon cancer risk and that the T allele at position 79353007 of chromosome 9 is associated with an increased risk of developing colon cancer.

Table 30 rs no. 946807 Chromosome; Position 9; 79353007 Gene Name SEQ ID NO; Position Genotype; Phenotype n=T; increased risk rg 0.394131 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 0 75 909 Trend 0.0078e 1.699 Table 30A indicates SNPs found to be in strong linkage disequilibrium with rs946807. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 30A Linked SNPs SNP r2 Position on chr9 SEQ ID NO
rs946807 - 79353007 802 rs7040700 0.59 79353924 803 rs12005727 1.0 79356465 804 rs12347524 1.0 79356737 805 rs10867398 0.536 79359981 806 Example 31 For individuals with colon cancer, the distribution of polymorphic alleles at position 5766249 of chromosome 11, found within the OR52N1 gene, was different from those without colon cancer (Table 31). The dominant test for risk associated with carrying the C allele had an empirical p-value of 0.0058 based on permutation analysis, and the corresponding dominant odds ratio is 1.561 (Table 31).
These data further suggest that this marker, located within the OR52N1 gene, is associated with colon cancer risk and that the C allele at position 5766249 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 31 rs no. 10769224 Chromosome; Position 11; 5766249 Gene Name OR52N1 SEQ ID NO; Position 1135; 374 Genotype; Phenotype n=C; increased risk Hardy-Weinberg 0.0827504 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 120 464 569 Dominant 0.0058e 1.561 Table 31A indicates SNPs found to be in strong linkage disequilibrium with rs10769224. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 31A Linked SNPs SNP r2 Position on chrll SEQ ID NO
rs7948009 0.825 5766124 807 rs10769224 - 5766249 808 rs10742787 1.0 5766322 809 rs7924824 1.0 5768065 810 rs7949986 1.0 5775192 811 rs7940926 1.0 5778275 812 rs10769235 1.0 5779169 813 rs4758099 1.0 5779725 814 rs4758100 0.804 5779774 815 rs7484069 0.826 5780048 816 rs11039085 0.524 5780227 817 rs7937133 1.0 5781044 818 rs1453418 1.0 5781526 819 rs1453417 0.688 5781557 820 rs11039096 0.845 5781753 821 rs10742793 0.672 5782739 822 rs11039102 0.704 5783829 823 rs11607346 0.634 5784028 824 rs6578689 0.71 5784528 825 rs1453415 0.67 5785595 826 rs1840175 0.67 5786072 827 rs4372479 0.67 5792979 828 rs10734554 0.861 5799485 829 rs7938541 1.0 5800361 830 rs4758444 0.524 5802527 831 rs1979197 0.51 5802898 832 Example 32 For individuals with colon cancer, the distribution of polymorphic alleles at position 43156746 of chromosome 11 was different from those without colon cancer (Table 32). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0141 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.213 (Table 32). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.0812, and the corresponding dominant odds ratio is 1.211 (Table 32). These data further suggest that this marker is associated with colon cancer risk and that the T allele at position 43156746 of chromosome 11 is associated with an increased risk of developing colon cancer.
Table 32 rs no. 890248 Chromosome; Position 11; 43156746 Gene Name SEQ ID NO; Position Genotype; Phenotype n=T; increased risk Hard -Weinber 0.536552 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 714 200 11 Trend 0.0141 e 1.213 1 4 637 200 28 Dominant 0.0812e 1211 Table 32A indicates SNPs found to be in strong linkage disequilibrium with rs890248. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 32A Linked SNPs SNP r 2 Position on chrll SEQ ID NO
rs11601828 0.646 43124098 833 rs11037302 0.704 43145953 834 rs7940185 0.669 43149399 835 rs6485403 0.715 43151108 836 rs2114089 0.688 43153254 837 rs1025168 1.0 43155303 838 rs1353463 1.0 43156052 839 rs890249 0.715 43156514 840 rs890248 - 43156746 841 rs890246 0.748 43156937 842 rs7935140 0.715 43158142 843 rs7938445 1.0 43158508 844 rs977439 1.0 43159402 845 rs7943295 1.0 43160243 846 rs2068405 1.0 43160762 847 rs7933421 0.715 43160895 848 rs959648 1.0 43160975 849 rs959647 0.715 43161066 850 rs10838055 0.715 43161471 851 rs10838056 1.0 43161777 852 rs7129867 1.0 43161927 853 rs7950242 1.0 43167395 854 rs7950144 0.715 43167433 855 rs1318986 1.0 43169005 856 rs1025166 1.0 43169462 857 rs1425857 1.0 43170570 858 rs10768938 1.0 43171231 859 Example 33 For individuals with colon cancer, the distribution of polymorphic alleles at position 73972614 of chromosome 11, found within the POLD3 gene, was different from those without colon cancer (Table 33). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0129 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.153 (Table 33). The recessive test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0286, and the corresponding recessive odds ratio is 1.223 (Table 33). These data further suggest that this marker, located within the POLD3 gene, is associated with colon cancer risk and that the A allele at position 73972614 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 33 rs no. 11236164 Chromosome; Position 11; 73972614 Gene Name POLD3 SEQ ID NO; Position 1136;
Genotype; Phenotype n=A; increased risk Hard rg 0.518 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 312 632 295 Trend 0.0129e 1.153 1 1 270 617 339 Recessive 0.0286e 1.223 Table 33A indicates SNPs found to be in strong linkage disequilibrium with rsl 1236164. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 33A Linked SNPs SNP r2 Position on chrll SEQ ID NO
rs10899009 1.0 73953815 860 rs10793093 0.832 73968600 861 rs11236164 - 73972614 862 rs7940880 0.966 73995062 867 rs10219203 0.96 74002571 868 rs10793094 1.0 74013473 873 rs2117222 0.966 74015333 874 rs2155935 0.966 74017225 876 rs2298792 0.966 74017844 877 rs11236178 0.966 74018984 878 rs3824999 0.966 74023198 879 rs7932922 0.68 74037678 885 rs1944933 0.923 74039262 886 rs11236185 0.928 74040179 887 rs4145954 0.669 74040814 888 rs6421715 0.966 74052598 889 rs11236203 0.966 74055648 890 rs11825804 0.964 74056519 891 rs6592590 0.649 74058677 892 rs11822234 0.631 74062794 893 rs11602237 0.604 74063339 894 rs7104802 0.572 74064448 895 rs17244949 0.632 74067429 897 Example 34 For individuals with colon cancer, the distribution of polymorphic alleles at position 73982157 of chromosome 11, found within the POLD3 gene, was different from those without colon cancer (Table 34). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.0396 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.177 (Table 34). The recessive test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.0531, and the corresponding recessive odds ratio is 1.193 (Table 34). These data further suggest that this marker, located within the POLD3 gene, is associated with colon cancer risk and that the C allele at position 73982157 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 34 rs no. 7939226 Chromosome; Position 11; 73982157 Gene Name POLD3 SEQ ID NO; Position 1136; 881 Genotype; Phenotype n=C; increased risk rg 0.724 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 34 330 875 Trend 0.0396e 1.177 1 2 25 292 909 Recessive 0.0531e 1.193 Table 34A indicates SNPs found to be in strong linkage disequilibrium with rs7939226. To generate this list, correlation coefficients (rZ) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 34A Linked SNPs SNP r 2 Position on chrll SEQ ID NO
rs7944514 0.516 73978840 863 rs7939226 - 73982157 864 rs10899013 0.543 73987190 865 rs6592573 0.543 73990610 866 rs4944051 0.673 74002983 869 rs4145953 0.66 74009527 872 rs1433970 0.673 74016841 875 rs3741127 1.0 74024581 880 rs1051058 0.673 74029849 881 rs7123887 0.636 74033737 882 rs4944922 0.635 74034353 883 rs4944925 0.636 74037177 884 rs12789086 0.747 74067075 896 rs11236208 0.727 74067969 898 rs12282262 0.707 74071586 899 Example 35 For individuals with colon cancer, the distribution of polymorphic alleles at position 74002983 of chromosome 11, found within the POLD3 gene, was different from those without colon cancer (Table 35). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0222 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.166 (Table 35). The dominant test for risk associated with carrying the T allele had an asymptotic p-value of 0.092236, and the corresponding dominant odds ratio is 1.365 (Table 35).
These data further suggest that this marker, located within the POLD3 gene, is associated with colon cancer risk and that the T allele at position 74002983 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 35 rs no. 4944051 Chromosome; Position 11; 74002983 Gene Name POLD3 SEQ ID NO; Position 1136; 21707 Genotype; Phenotype n=T; increased risk erg 0.232 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 72 420 747 Trend 0.0222e 1.166 1 4 53 385 788 Dominant 0.092236a 1.365 Table 35A indicates SNPs found to be in strong linkage disequilibrium with rs494405 1. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 35A Linked SNPs SNP r 2 Position on chril SEQ ID NO
rs7939226 0.673 73982157 864 rs4944051 - 74002983 869 rs7943085 0.582 74007856 870 rs10501417 0.582 74008628 871 rs4145953 1.0 74009527 872 rs1433970 1.0 74016841 875 rs3741127 0.659 74024581 880 rs1051058 1.0 74029849 881 rs7123887 0.945 74033737 882 rs4944922 0.945 74034353 883 rs4944925 0.945 74037177 884 Example 36 For individuals with colon cancer, the distribution of polymorphic alleles at position 83565887 of chromosome 11, found within the DLG2 gene, was different from those without colon cancer (Table 36). The recessive test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.002, and the corresponding recessive odds ratio is 1.443 (Table 36). These data further suggest that this marker, located within the DLG2 gene, is associated with colon cancer risk and that the T allele at position 83565887 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 36 rs no. 1454027 Chromosome; Position 11; 83565887 Gene Name DLG2 SEQ ID NO; Position 1137; 746200 Genotype; Phenotype n=T; increased risk Hard -Weinber 0.0879631 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 8 197 626 Recessive 0.002e 1.443 Table 36A indicates SNPs found to be in strong linkage disequilibrium with rs1454027. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 36A Linked SNPs SNP r 2 Position on chrll SEQ ID NO
rs790367 0.536 83325571 900 rs790368 0.536 83325870 901 rs1599914 0.535 83326348 902 rs790372 0.536 83331489 903 rs1471687 0.607 83333982 904 rs790351 0.536 83338726 905 rs2449592 0.536 83346857 906 rs2449594 0.536 83359180 907 rs2514171 0.536 83378990 908 rs2449575 0.536 83383578 909 rs1817515 0.536 83385447 910 rs7933909 0.534 83386501 911 rs1483387 0.536 83387013 912 rs1586143 0.536 83389630 913 rs1118277 0.508 83389983 914 rs1304480 0.536 83390829 915 rs2170707 0.536 83400665 916 rs1483388 0.536 83402660 917 rs2514167 0.536 83403491 918 rs2514166 0.536 83403720 919 rs10751101 0.536 83404929 920 rs2853026 0.536 83418135 921 rs1601094 0.536 83420693 922 rs1160818 0.536 83430317 923 rs7114261 0.773 83504794 924 rs7108582 0.773 83508907 925 rs1945824 0.749 83523059 926 rs10501555 0.773 83525615 927 rs1014066 0.773 83527163 928 rs2000961 0.773 83532440 929 rs1584854 0.536 83540697 930 rs1598073 0.536 83542042 931 rs1454019 0.773 83548041 932 rs1869472 1.0 83555723 933 rs1454027 - 83565887 934 rs970226 1.0 83569470 935 rs1670685 0.536 83570172 936 rs7943267 0.891 83572107 937 rs988322 1.0 83574800 938 rs1377746 1.0 83576676 939 rs7941004 0.881 83594342 940 rs4944472 0.784 83599752 941 rs10751109 0.773 83601427 942 Example 37 For individuals with colon cancer, the distribution of polymorphic alleles at position 31141128 of chromosome 12, found within the DDXI 1 gene, was different from those without colon cancer (Table 37). The dominant test for risk associated with carrying the G allele had an asymptotic p-value of 0.023884, and the corresponding dominant odds ratio is 1.222 (Table 37). These data further suggest that this marker, located within the DDX11 gene, is associated with colon cancer risk and that the G
allele at position 31141128 of chromosome 12 is associated with an increased risk of developing colon cancer.

Table 37 rs no. 2075322 Chromosome; Position 12; 31141128 Gene Name DDX 11 SEQ ID NO; Position 1138; 23052 Genotype; Phenotype n=G; increased risk Hard -Weinber 0.438 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 386 595 252 Dominant 0.023884a 1.222 Table 37A indicates SNPs found to be in strong linkage disequilibrium with rs2075322. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 37A Linked SNPs SNP r2 Position on chrl2 SEQ ID NO
rs2075322 - 31141128 945 Example 38 For individuals with colon cancer, the distribution of polymorphic alleles at position 31157554 of chromosome 12, found within the DDX11 gene, was different from those without colon cancer (Table 38). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0363 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.138 (Table 38). The dominant test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0451, and the corresponding dominant odds ratio is 1.179 (Table 38). These data further suggest that this marker, located within the DDX11 gene, is associated with colon cancer risk and that the A allele at position 31157554 of chromosome 12 is associated with an increased risk of developing colon cancer.

Table 38 rs no. 4931434 Chromosome; Position 12; 31157554 Gene Name DDX 11 SEQ ID NO; Position 1138;
Genotype; Phenotype n=A; increased risk Hard rg 0.928 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 548 554 137 Trend 0.0363e 1.138 1 1 493 577 156 Dominant 0.0451 e 1,.179 Table 38A indicates SNPs found to be in strong linkage disequilibrium with rs4931434. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 38A Linked SNPs SNP r2 Position on chr12 SEQ ID NO
rs11051239 0.534 31132974 943 rs1808348 0.515 31136113 944 rs4931432 0.588 31144153 946 rs11219 0.588 31148962 947 rs1974752 0.588 31149995 948 rs2111770 0.581 31152638 949 rs2005900 0.588 31152965 950 rs1053552 0.588 31156037 951 rs4931434 - 31157554 952 rs4244856 0.581 31157580 953 Example 39 For individuals with colon cancer, the distribution of polymorphic alleles at position 21875373 of chromosome 13 was different from those without colon cancer (Table 39). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0071 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.722 (Table 39). These data further suggest that this marker is associated with colon cancer risk and that the G allele at position 21875373 of chromosome 13 is associated with an increased risk of developing colon cancer.

Table 39 rs no. 10507308 Chromosome; Position 13; 21875373 Gene Name SEQ ID NO; Position Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.361024 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 941 40 1 Trend 0.0071 e 1.722 Table 39A indicates SNPs found to be in strong linkage disequilibrium with rs10507308. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An rZ cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 39A Linked SNPs SNP r 2 Position on chr13 SEQ ID NO
rs9506845 0.66 21846344 954 rs2038713 1.0 21860220 955 rs692783 0.59 21868669 956 rs573671 0.589 21868693 957 rs1886088 0.59 21870958 958 rs9316962 0.59 21873258 959 rs10507308 - 21875373 960 Example 40 For individuals with colon cancer, the distribution of polymorphic alleles at position 32659011 of chromosome 13, found within the STARD13 gene, was different from those without colon cancer (Table 40). The recessive test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0023, and the corresponding recessive odds ratio is 1.316 (Table 40). These data further suggest that this marker, located within the STARDI3 gene, is associated with colon cancer risk and that the A allele at position 32659011 of chromosome 13 is associated with an increased risk of developing colon cancer.

Table 40 rs no. 797206 Chromosome; Position 13; 32659011 Gene Name STARD 13 SEQ ID NO; Position 1139; 98882 Genotype; Phenotype n=A; increased risk Hard -Weinber 0.752433 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 1 75 401 507 Recessive 0.0023e 1.316 Table 40A indicates SNPs found to be in strong linkage disequilibrium with rs797206. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 40A Linked SNPs SNP r2 Position on chrl3 SEQ ID NO
rs797227 0.68 32643593 961 rs797211 0.636 32655052 962 rs797208 0.951 32658737 963 rs797206 - 32659011 964 rs797201 0.904 32665137 965 Example 41 For individuals with colon cancer, the distribution of polymorphic alleles at position 45440577 of chromosome 13, found within the KIAA0853 gene, was different from those without colon cancer (Table 41). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0962 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.110 (Table 41). These data further suggest that this marker, located within the KIAA0853 gene, is associated with colon cancer risk and that the G allele at position 45440577 of chromosome 13 is associated with an increased risk of developing colon cancer.

Table 41 rs no. 4941537 Chromosome; Position 13; 45440577 Gene Name KIAA0853 SEQ ID NO; Position 1140; 84319 Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.145 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 484 560 194 Trend 0.0962e 1.110 Table 41A indicates SNPs found to be in strong linkage disequilibrium with rs4941537. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 41A Linked SNPs SNP r2 Position on chrl3 SEQ ID NO
rs7325308 1.0 45412663 966 rs2075427 1.0 45413606 967 rs1080107 0.733 45414960 968 rs6561274 1.0 45416097 969 rs9534258 1.0 45418874 970 rs4460970 1.0 45438294 971 rs4941537 - 45440577 972 rs9534265 1.0 45445023 973 rs4942460 1.0 45448444 974 rs9316177 0.962 45459812 975 rs9534272 1.0 45464824 976 rs4941538 1.0 45484610 977 rs1409436 0.926 45512651 978 rs3783200 0.744 45514463 979 rs1087 0.636 45525440 980 rs9534304 0.568 45538603 981 rs9526136 0.642 45539148 982 rs9316179 0.578 45539467 983 rs9316180 0.578 45539686 984 rs9562635 0.591 45540993 986 rs7988836 0.655 45541374 987 rs7993537 0.578 45541562 988 rs9316181 0.578 45543741 989 rs1409434 0.578 45544445 990 rs3742264 0.601 45546095 991 rs9567615 0.607 45549081 992 rs9567618 0.578 45549309 993 rs1326398 0.523 45550691 994 rs723391 0.555 45553450 995 rs9534322 0.509 45568003 996 rs1952187 0.524 45572910 997 Example 42 For individuals with colon cancer, the distribution of polymorphic alleles at position 45525440 of chromosome 13, found within the CPB2 gene, was different from those without colon cancer (Table 42). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0119 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.167 (Table 42). These data further suggest that this marker, located within the CPB2 gene, is associated with colon cancer risk and that the T allele at position 45525440 of chromosome 13 is associated with an increased risk of developing colon cancer.

Table 42 rs no. 1087 Chromosome; Position 13; 45525440 Gene Name CPB2 SEQ ID NO; Position 1141; 51730 Genotype; Phenotype n=T; increased risk Hardy-Weinberg 0.478 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 576 529 134 Trend 0.0119e 1.167 Table 42A indicates SNPs found to be in strong linkage disequilibrium with rs1087. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An rZ cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 42A Linked SNPs SNP r2 Position on chrl3 SEQ ID NO
rs7325308 0.636 45412663 966 rs2075427 0.636 45413606 967 rs6561274 0.697 45416097 969 rs9534258 0.636 45418874 970 rs4460970 0.666 45438294 971 rs4941537 0.636 45440577 972 rs9534265 0.613 45445023 973 rs4942460 0.636 45448444 974 rs9316177 0.607 45459812 975 rs9534272 0.634 45464824 976 rs4941538 0.636 45484610 977 rs1409436 0.577 45512651 978 rs3783200 0.744 45514463 979 rs1087 - 45525440 980 rs9534304 0.96 45538603 981 rs9526136 0.957 45539148 982 rs9316179 0.961 45539467 983 rs9316180 0.961 45539686 984 rs9534305 0.724 45540157 985 rs9562635 0.958 45540993 986 rs7988836 0.917 45541374 987 rs7993537 0.961 45541562 988 rs9316181 0.961 45543741 989 rs1409434 0.961 45544445 990 rs3742264 0.961 45546095 991 rs9567615 0.956 45549081 992 rs9567618 0.961 45549309 993 rs1326398 0.885 45550691 994 rs723391 0.85 45553450 995 rs1952187 0.811 45572910 997 Example 43 For individuals with colon cancer, the distribution of polymorphic alleles at position 46146164 of chromosome 15 was different from those without colon cancer (Table 43). The dominant test for risk associated with carrying the C allele had an asymptotic p-value of 0.0017368, and the corresponding dominant odds ratio is 1.516 (Table 43). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 46146164 of chromosome 15 is associated with an increased risk of developing colon cancer.

Table 43 rs no. 2469583 Chromosome; Position 15; 46146164 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk Hardy-Weinber 0.0967368 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 161 486 293 Dominant 0.0017368a 1.516 Table 43A indicates SNPs found to be in strong linkage disequilibrium with rs2469583. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 43A Linked SNPs SNP r2 Position on chr15 SEQ ID NO
rs17423970 0.706 46089356 998 rs2081619 0.964 46101819 999 rs17424213 0.965 46103228 1000 rs11070622 0.965 46108382 1001 rs1869453 0.965 46111620 1002 rs17340116 0.965 46114858 1003 rs1453857 0.965 46116200 1004 rs1453856 0.965 46116311 1005 rsl2324567 0.965 46116717 1006 rs748848 0.965 46118326 1007 rs930016 0.962 46118529 1008 rs930017 0.965 46118841 1009 rs1453855 0.965 46120302 1010 rs1025199 1.0 46126798 1011 rs11070623 1.0 46136739 1012 rs2433363 1.0 46139544 1013 rs1426655 0.964 46145643 1014 rs2469583 - 46146164 1015 rs2469581 0.964 46149357 1016 Example 44 For individuals with colon cancer, the distribution of polymorphic alleles at position 93233505 of chromosome 15 was different from those without colon cancer (Table 44). The dominant test for risk associated with carrying the C allele had an empirical p-value of 0.021 based on permutation analysis, and the corresponding dominant odds ratio is 1.649 (Table 44). These data further suggest that this marker is associated with colon cancer risk and that the C allele at position 93233505 of chromosome is associated with an increased risk of developing colon cancer.

Table 44 rs no. 4372639 Chromosome; Position 15; 93233505 Gene Name SEQ ID NO; Position Genotype; Phenotype n=C; increased risk rg 0.48238 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 61 343 547 Dominant 0.021e 1.649 Table 44A indicates SNPs found to be in strong linkage disequilibrium with rs4372639. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 44A Linked SNPs SNP r 2 Position on chrl5 SEQ ID NO
rs6496053 0.795 93195638 1017 rs12439498 0.681 93202040 1018 rs4984579 1.0 93217814 1019 rs4489958 1.0 93221398 1020 rs6416529 1.0 93222123 1021 rs4247091 0.919 93226669 1022 rs6496059 1.0 93229804 1023 rs6496060 1.0 93231817 1024 rs6496061 1.0 93232312 1025 rs4372639 - 93233505 1026 rs766233 0.742 93238457 1027 rs12440481 1.0 93261273 1028 rs4306453 0.947 93263139 1029 rs4247087 1.0 93264699 1030 rs1562628 1.0 93265029 1031 rs6496067 1.0 93266435 1032 rs6496068 1.0 93266453 1033 rs11630913 1.0 93267466 1034 rs9920787 0.649 93277598 1035 rs6416531 0.569 93279847 1036 Example 45 For individuals with colon cancer, the distribution of polymorphic alleles at position 97282996 of chromosome 15, found within the IGF1R gene, was different from those without colon cancer (Table 45). The trend test for risk associated with carrying the C allele had an asymptotic p-value of 0.099586, and the corresponding Mantel-Haenszel odds ratio for trend is 1.300 (Table 45). The recessive test for risk associated with carrying the C allele had an asymptotic p-value of 0.049715, and the corresponding recessive odds ratio is 1.321 (Table 45). These data further suggest that this marker, located within the IGF1R gene, is associated with colon cancer risk and that the C allele at position 97282996 of chromosome 15 is associated with an increased risk of developing colon cancer.

Table 45 rs no. 3743262 Chromosome; Position 15; 97282996 Gene Name IGF 1 R
SEQ ID NO; Position 1142; 272709 Genotype; Phenotype n=C; increased risk Hardy-Weinberg 1 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 2 3 122 1114 Trend 0.099586- 1.300 1 2 6 90 1130 Recessive 0.049715a 1.321 Table 45A indicates SNPs found to be in strong linkage disequilibrium with rs3743262. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 45A Linked SNPs SNP r2 Position on chr15 SEQ ID NO
rs3743262 - 97282996 1037 Example 46 For individuals with colon cancer, the distribution of polymorphic alleles at position 99773203 of chromosome 15, found within the PCSK6 gene, was different from those without colon cancer (Table 46). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0095 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.181 (Table 46). The dominant test for risk associated with carrying the T allele had an empirical p-value of 0.0041 based on permutation analysis, and the corresponding dominant odds ratio is 1.667 (Table 46).
These data further suggest that this marker, located within the PCSK6 gene, is associated with colon cancer risk and that the T allele at position 99773203 of chromosome 15 is associated with an increased risk of developing colon cancer.

Table 46 rs no. 1994967 Chromosome; Position 15; 99773203 Gene Name PCSK6 SEQ ID NO; Position 1143; 74508 Genotype; Phenotype n=T; increased risk Hard -Weinber 0.0688478 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 90 366 493 Trend 0.0095e 1.181 1 4 55 355 520 Dominant 0.0041e 1.667 Table 46A indicates SNPs found to be in strong linkage disequilibrium with rs1994967. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 46A Linked SNPs SNP r 2 Position on chr15 SEQ ID NO
rs1532364 0.81 99768367 1038 rs1108993 0.81 99768718 1039 rs7172235 1.0 99772560 1040 rs12437488 1.0 99772834 1041 rs12912500 1.0 99773041 1042 rs1994967 - 99773203 1043 rs1994968 0.554 99773242 1044 rs4965856 1.0 99775105 1045 rs4965857 1.0 99775156 1046 rs12911482 1.0 99775985 1047 rs2277585 0.515 99785607 1048 Example 47 For individuals with colon cancer, the distribution of polymorphic alleles at position 23619426 of chromosome 16, found within the LOC388226 gene, was different from those without colon cancer (Table 47). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0021 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.234 (Table 47). These data further suggest that this marker, located within the LOC388226 gene, is associated with colon cancer risk and that the G allele at position 23619426 of chromosome 16 is associated with an increased risk of developing colon cancer.

Table 47 rs no. 26764 Chromosome; Position 16; 23619426 Gene Name LOC388226 SEQ ID NO; Position 1144; 12897 Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.678458 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 650 397 65 Trend 0.0021e 1.234 Table 47A indicates SNPs found to be in strong linkage disequilibrium with rs26764. To generate this list, correlation coefficients (rz) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 47A Linked SNPs SNP r2 Position on chr16 SEQ ID NO
rs249856 0.638 23566477 1049 rs249870 0.638 23573679 1050 rs249869 0.566 23574058 1051 rs249867 0.638 23576069 1052 rs34514 0.638 23578098 1053 rs34513 0.551 23579493 1054 rs35586 0.638 23584507 1055 rs7588 0.638 23588666 1056 rs40076 0.767 23599906 1057 rs42873 0.637 23602233 1058 rs35634 0.638 23605180 1059 rs26767 0.766 23605958 1060 rs27770 0.638 23609039 1061 rs35633 0.591 23611506 1062 rs26764 - 23619426 1063 rs26763 1.0 23619684 1064 rs26762 1.0 23619949 1065 rs11074570 0.857 23620229 1066 Example 48 For individuals with colon cancer, the distribution of polymorphic alleles at position 13110425 of chromosome 17 was different from those without colon cancer (Table 48). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0418 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.132 (Table 48). These data further suggest that this marker is associated with colon cancer risk and that the G allele at position 13110425 of chromosome 17 is associated with an increased risk of developing colon cancer.

Table 48 rs no. 1963296 Chromosome; Position 17; 13110425 Gene Name SEQ ID NO; Position Genotype; Phenotype n=G; increased risk Hardy-Weinberg 0.423012 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 80 378 510 Trend 0.0418e 1.132 Table 48A indicates SNPs found to be in strong linkage disequilibrium with rs1963296. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 48A Linked SNPs SNP r2 Position on chr17 SEQ ID NO
rs1963296 - 13110425 1067 rs3886341 1.0 13112831 1068 rs11869275 0.956 13114370 1069 rs7212267 0.955 13117081 1070 rs2188894 0.831 13117504 1071 rs2214260 0.831 13117537 1072 Example 49 For individuals with colon cancer, the distribution of polymorphic alleles at position 34299961 of chromosome 18 was different from those without colon cancer (Table 49). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.0015 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.331 (Table 49). These data further suggest that this marker is associated with colon cancer risk and that the T allele at position 34299961 of chromosome 18 is associated with an increased risk of developing colon cancer.

Table 49 rs no. 10502694 Chromosome; Position 18; 34299961 Gene Name SEQ ID NO; Position Genotype; Phenotype n=T; increased risk Hard -Weinber 0.785918 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 625 220 17 Trend 0.0015e 1.331 Table 49A indicates SNPs found to be in strong linkage disequilibrium with rs 10502694. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 49A Linked SNPs SNP r 2 Position on chr18 SEQ ID NO
rs10502692 1.0 34294350 1073 rs12373278 1.0 34294807 1074 rs9954810 1.0 34297013 1075 rs10502694 - 34299961 1076 Example 50 For individuals with colon cancer, the distribution of polymorphic alleles at position 64600521 of chromosome 18 was different from those without colon cancer (Table 50). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.0038 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 2.064 (Table 50). The recessive test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.0038, and the corresponding recessive odds ratio is 2.064 (Table 50). These data further suggest that this marker is associated with colon cancer risk and that the G allele at position 64600521 of chromosome 18 is associated with an increased risk of developing colon cancer.
Table 50 rs no. 10503122 Chromosome; Position 18; 64600521 Gene Name SEQ ID NO; Position Genotype; Phenotype n=G; increased risk Hardy-Weinber 1 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 3 0 50 931 Trend 0.0038e 2.064 1 3 0 23 884 Recessive 0.0038e 2.064 Table 50A indicates SNPs found to be in strong linkage disequilibrium with rs10503122. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 50A Linked SNPs SNP r2 Position on chr18 SEQ ID NO
rs646985 1.0 64574312 1077 rs17079646 1.0 64575303 1078 rs631470 1.0 64575455 1079 rs1676846 1.0 64577169 1080 rs12458298 1.0 64577779 1081 rs17079657 1.0 64578874 1082 rs679650 1.0 64579596 1083 rs12604145 1.0 64580779 1084 rs17079677 1.0 64584139 1085 rs491835 1.0 64586668 1086 rs12457185 1.0 64588166 1087 rs12454555 1.0 64588368 1088 rs12455204 1.0 64589299 1089 rs12607604 1.0 64591510 1090 rs595015 1.0 64592428 1091 rs607696 1.0 64592919 1092 rs12454311 1.0 64593139 1093 rs11151464 1.0 64595151 1094 rs17079696 1.0 64595371 1095 rs677592 1.0 64596256 1096 rs11151465 1.0 64596392 1097 rs499881 1.0 64596771 1098 rs1676853 1.0 64600350 1099 rs10503122 - 64600521 1100 rs656681 1.0 64601827 1101 rs17079705 1.0 64602989 1102 rs8092610 1.0 64612870 1103 rs17079717 1.0 64618545 1104 Example 51 For individuals with colon cancer, the distribution of polymorphic alleles at position 20272988 of chromosome 21 was different from those without colon cancer (Table 51). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.0012 based on permutation analysis, and the corresponding recessive odds ratio is 1.425 (Table 51).
These data ftirther suggest that this marker is associated with colon cancer risk and that the T allele at position 20272988 of chromosome 21 is associated with an increased risk of developing colon cancer.

Table 51 rs no. 377685 Chromosome; Position 21; 20272988 Gene Name SEQ ID NO; Position Genotype; Phenotype n=T; increased risk Hard -Weinberg 0.337514 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 4 259 506 217 Recessive 0.0012e 1.425 Table 51A indicates SNPs found to be in strong linkage disequilibrium with rs377685. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 51A Linked SNPs SNP r2 Position on chr2l SEQ ID NO
rs2825896 0.564 20218657 1105 rs2825899 0.571 20222308 1106 rs2825905 0.561 20226492 1107 rs2825910 0.591 20228734 1108 rs12482291 0.591 20232506 1109 rs2825922 0.714 20243479 1110 rs2205470 0.714 20251093 1111 rs13047152 0.714 20257959 1112 rs12482827 0.714 20261725 1113 rs377685 - 20272988 1114 rs7281221 0.51 20274521 1115 rs2825928 0.522 20274865 1116 rs2825930 1.0 20279236 1117 rs12482714 1.0 20282727 1118 rs2825941 0.966 20308050 1119 Another aspect of the invention is a method of diagnosing colorectal cancer in an individual, or determining whether the individual is at altered risk for colorectal cancer, by detecting polymorphism in a subject by treating a tissue sample from the subject with an antibody to a polymorphic genetic variant of the present invention and detecting binding of said antibody. A
person of skill in the art would know how to produce such an antibody (see, for instance, Harlow, E. and Lane, eds., 1988, "Antibodies: A Laboratory Manual", Cold Spring Harbor Press, Cold Spring Harbor). Such antibodies may include, but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. The present invention also provides an animal model to study colorectal cancer and susceptibility to colorectal cancer. Such studies can be performed using transgenic animals. For example, one can produce transgenic mice, which contain a specific allelic variant of a containing any of the SNPs disclosed herein. These mice can be created, e.g., by replacing their wild-type gene with an allele containing a SNP disclosed herein, or of the corresponding human gene containing such a SNP.

In a preferred embodiment, the present invention provides a transgenic mammalian animal, said animal having cells incorporating a recombinant expression system adapted to express a gene containing a SNP disclosed herein (preferably the human gene containing a SNP
disclosed herein).
Generally, the recombinant expression system will be stably integrated into the genome of the transgenic animal and will thus be heritable so that the offspring of such a transgenic animal may themselves contain the transgene. Transgenic animals can be engineered by introducing the a nucleic acid molecule containing only the coding portion of the gene into the genome of animals of interest, using standard techniques for producing transgenic animals. Animals that can serve as a target for transgenic manipulation include, without limitation, mice, rats, rabbits, guinea pigs, sheep, goats, pigs, and non-human primates, e.g. baboons, chimpanzees and monkeys. Techniques known in the art to introduce a transgene into such animals include pronucleic microinjection (U.S. Pat. No. 4,873,191);
retrovirus-mediated gene transfer into germ lines (e.g. Van der Putten et al.
1985, Proc. Natl. Acad.
Sci. USA 82: 6148-6152); gene targeting in embryonic stem cells (Thompson et al., Cell 56 (1989), 313-321); electroporation of embryos and sperm-mediated gene transfer (for a review, see for example, U.S. Pat. No. 4,736,866). For the purpose of the present invention, transgenic animals include those that carry the recombinant molecule only in part of their cells ("mosaic animals"). The molecule can be integrated either as a single transgene, or in concatamers.
Selective introduction of a nucleic acid molecule into a particular cell type is also possible by following, for example, the technique of Lasko et al., Proc. Natl. Acad. Sci. USA 89 (1992): 6232-6236.
Particular cells could also be targeted for molecular incorporation with tissue-specific enhancers.
The expression of the integrated molecule can be monitored by standard techniques such as in situ hybridization, Northern Blot analysis, PCR or immunocytochemistry. Transgenic animals that include a copy of such a nucleic acid molecule introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding the corresponding protein. In accordance with this facet of the invention, an animal is treated with the reagent and a reduceci incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.

The present invention has been described in detail by way of illustration and example in order to acquaint others skilled in the art with the invention, its principles and its practical application.
Particular formulations and processes of the present invention are not limited to the descriptions of the specific embodiments presented, but rather the descriptions and examples should be viewed in terms of the claims that follow and their equivalents. While some of the examples and descriptions above include some conclusions about the way the invention may function, the inventors do not intend to be bound by those conclusions and functions, but put them forth only as possible explanations.

It is to be further understood that the specific embodiments of the present invention as set forth are not intended as being exhaustive or limiting of the invention, and that many alternatives, modifications and variations will be apparent to those of ordinary skill in the art in light of the foregoing examples and detailed description. Accordingly, this invention is intended to embrace all such alternatives, modifications and variations that fall within the spirit and scope of the following claims.

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Claims (26)

1. A method for identifying an individual who has an altered risk for developing colorectal cancer, comprising detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases:
a base located at position 96911594 to position 97159204 on human chromosome 1;
a base located at position 97653506 to position 97659904 on human chromosome 1;
a base located at position 114947052 to position 115303040 on human chromosome 1;
a base located at position 142933600 to position 143040559 on human chromosome 1;
a base located at position 20250764 to position 20260227 on human chromosome

2;
a base located at position 186729521 to position 187050892 on human chromosome 2;
a base located at position 218767422 to position 218873288 on human chromosome 2;
a base located at position 230822818 to position 230842525 on human chromosome 2;
a base located at position 25052936 to position 25121605 on human chromosome

3;
a base located at position 62937809 to position 62985367 on human chromosome 3;
a base located at position 120013362 to position 120044441 on human chromosome 3;
a base located at position 120036240 to position 120044441 on human chromosome 3;
a base located at position 186008653 to position 186267820 on human chromosome 3;
a base located at position 187843111 to position 187878274 on human chromosome 3;
a base located at position 4857130 to position 4867970 on human chromosome 4;
a base located at position 73187634 to position 73501955 on human chromosome

4;
a base located at position 114716570 to position 114747490 on human chromosome

5;
a base located at position 121091463 to position 121153311 on human chromosome 5;
a base located at position 128103463 to position 128358774 on human chromosome 5;
a base located at position 1026731 to position 1037761 on human chromosome 6;
a base located at position 69379328 to position 69521107 on human chromosome

6;
a base located at position 82950808 to position 83172329 on human chromosome 6;
a base located at position 9426711 to position 9673180 on human chromosome 8;
a base located at position 105447572 on human chromosome 8;
a base located at position 138448609 to position 138616778 on human chromosome 8;
a base located at position 141567935 to position 141597272 on human chromosome 8;
a base located at position 6282602 to position 6399874 on human chromosome 9;
a base located at position 73606988 to position 73643177 on human chromosome 9;
a base located at position 79353007 to position 79359981 on human chromosome 9;
a base located at position 5766124 to position 5802898 on human chromosome 11;

a base located at position 43124098 to position 43171231 on human chromosome 11;
a base located at position 73953815 to position 74067429 on human chromosome 11;
a base located at position 73978840 to position 74071586 on human chromosome 11;
a base located at position 73982157 to position 74037177 on human chromosome 11;
a base located at position 83325571 to position 83601427 on human chromosome 11;
a base located at position 31132974 to position 31157580 on human chromosome 12;
a base located at position 31141128 on human chromosome 12;
a base located at position 21846344 to position 21875373 on human chromosome 13;
a base located at position 32643593 to position 32665137 on human chromosome 13;
a base located at position 45412663 to position 45572910 on human chromosome 13;
a base located at position 46089356 to position 46149357 on human chromosome 15;
a base located at position 93195638 to position 93279847 on human chromosome 15;
a base located at position 97282996 on human chromosome 15;
a base located at position 99768367 to position 99785607 on human chromosome 15;
a base located at position 23566477 to position 23620229 on human chromosome 16;
a base located at position 13110425 to position 13117537 on human chromosome 17;
a base located at position 34294350 to position 34299961 on human chromosome 18;
a base located at position 64574312 to position 64618545 on human chromosome 18; and a base located at position 20218657 to position 20308050 on human chromosome 21; or a base in strong linkage disequilibrium with at least one of the foregoing bases.

2. The method of claim 1, which comprises detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases:
a base located at position 96911594 to position 97159204 on human chromosome 1;
a base located at position 97653506 to position 97659904 on human chromosome 1;
a base located at position 114947052 to position 115303040 on human chromosome 1;
a base located at position 142933600 to position 143040559 on human chromosome 1;
a base located at position 20250764 to position 20260227 on human chromosome 2;
a base located at position 186729521 to position 187050892 on human chromosome 2;
a base located at position 218767422 to position 218873288 on human chromosome 2;
a base located at position 230822818 to position 230842525 on human chromosome 2;
a base located at position 25052936 to position 25121605 on human chromosome 3;
a base located at position 62937809 to position 62985367 on human chromosome 3;
a base located at position 120013362 to position 120044441 on human chromosome 3;
a base located at position 120036240 to position 120044441 on human chromosome 3;
a base located at position 186008653 to position 186267820 on human chromosome 3;

a base located at position 187843111 to position 187878274 on human chromosome 3;
a base located at position 4857130 to position 4867970 on human chromosome 4;
a base located at position 73187634 to position 73501955 on human chromosome 4;
a base located at position 114716570 to position 114747490 on human chromosome 5;
a base located at position 121091463 to position 121153311 on human chromosome 5;
a base located at position 128103463 to position 128358774 on human chromosome 5;
a base located at position 1026731 to position 1037761 on human chromosome 6;
a base located at position 69379328 to position 69521107 on human chromosome 6;
a base located at position 82950808 to position 83172329 on human chromosome 6;
a base located at position 9426711 to position 9673180 on human chromosome 8;
a base located at position 105447572 on human chromosome 8;
a base located at position 138448609 to position 138616778 on human chromosome 8;
a base located at position 141567935 to position 141597272 on human chromosome 8;
a base located at position 6282602 to position 6399874 on human chromosome 9;
a base located at position 73606988 to position 73643177 on human chromosome 9;
a base located at position 79353007 to position 79359981 on human chromosome 9;
a base located at position 5766124 to position 5802898 on human chromosome 11;
a base located at position 43124098 to position 43171231 on human chromosome 11;
a base located at position 73953815 to position 74067429 on human chromosome 11;
a base located at position 73978840 to position 74071586 on human chromosome 11;
a base located at position 73982157 to position 74037177 on human chromosome 11;
a base located at position 83325571 to position 83601427 on human chromosome 11;
a base located at position 31132974 to position 31157580 on human chromosome 12;
a base located at position 31141128 on human chromosome 12;
a base located at position 21846344 to position 21875373 on human chromosome 13;
a base located at position 32643593 to position 32665137 on human chromosome 13;
a base located at position 45412663 to position 45572910 on human chromosome 13;
a base located at position 46089356 to position 46149357 on human chromosome 15;
a base located at position 93195638 to position 93279847 on human chromosome 15;
a base located at position 97282996 on human chromosome 15;
a base located at position 99768367 to position 99785607 on human chromosome 15;
a base located at position 23566477 to position 23620229 on human chromosome 16;
a base located at position 13110425 to position 13117537 on human chromosome 17;
a base located at position 34294350 to position 34299961 on human chromosome 18;
a base located at position 64574312 to position 64618545 on human chromosome 18; and a base located at position 20218657 to position 20308050 on human chromosome 21; or a base in strong linkage disequilibrium with at least one of the foregoing bases.

3. The method of claim 2, wherein said base is in strong linkage disequilibrium with at least one of the nucleotide bases located as follows:
at position 96911594, 96961817, 97005044, 97141267, 97159204, 97653506, 97657313, 97659904, 114947052, 114968711, 114978348, 114981253, 114984296, 115004020, 115071842, 115075249, 115077252, 115081154, 115084567, 115087972, 115091656, 115100040, 115103811, 115104443, 115111982, 115116141, 115119103, 115125087, 115132157, 115132560, 1 1 5 1 32947, 115139005, 115141772, 115159909, 115166656, 115167322, 115171216, 115179531, 115180386, 115182953, 115183282, 115185601, 115200356, 115202960, 115209101, 115217819, 115226640, 115234779, 115236258, 115242333, 115242502, 115242740, 115244057, 115261728, 115268188, 115277042, 115278233, 115278345, 115278448, 115278686, 115279927, 115280070, 115281663, 115282510, 115284407, 115285912, 115287160, 115287345, 115289952, 115292582, 115298443, 115298798, 115303040, 142933600, 142994415, 142996870, 143024965, 143037007, 143039966, or 143040559 on human chromosome 1;
at position 20250764, 20250981, 20252966, 20254115, 20254650, 20255588, 20256013, 20257476, 20258973, 20259648, 20260227, 186729521, 186748482, 186752544, 186753368;
186759677, 186774634, 186783677, 186788675, 186795981, 186797056, 186797101, 186804008, 186822924, 186849447, 186854278, 186854406, 186856196, 186866149, 186869233, 186869364, 186870116, 186873391, 186873805, 186874321, 186876760, 186877596, 186878043, 186883056, 186887466, 186895423, 186898014, 186899824, 186903194, 186905158, 186910195, 186918660, 186933341, 186935034, 186937617, 186938372, 186938761, 186940537, 186942136, 186944471, 186945120, 186950816, 187032899, 187050892, 218767422, 218767819, 218767857, 218768482, 218770121, 218770314, 218770551, 218771180, 218773021, 218776751, 218777739, 218781315, 218784326, 218786186, 218789557, 218791821, 218814280, 218816511, 218823086, 218826240, 218830515, 218832566, 218833258, 218833506, 218833898, 218835652, 218852394, 218852478, 218871943, 218873288, 230822818, 230822908, 230823742, 230824051, 230825316, 230825613, 230825727, 230825877, 230827852, 230828862, 230829298, 230830081, 230830316, 230830886, 230832540, or 230842525 on human chromosome 2;
at position 25052936, 25054402, 25056885, 25061156, 25062781, 25068060, 25076452, 25084253, 25084806, 25086476, 25090198, 25090417, 25100369, 25102693, 25105990, 25108277, 25112900, 25114656, 25115540, 25117575, 25118394, 25121605, 62937809, 62941462, 62943033, 62943151, 62943547, 62945427, 62949979, 62952892, 62955440, 62957942, 62958060, 62959133, 62959399, 62960430, 62962215, 62964393, 62965607, 62966446, 62966549, 62968123, 62968779, 62968976, 62969677, 62970029, 62970190, 62970589, 62971291, 62972138, 62975188, 62981633, 62982901, 62983787, 62985367, 120013362, 120013382, 120036240, 120037273, 120037336, 120037804, 120039183, 120039851, 120044441, 186008653, 186008673, 186008910, 186012692, 186027445, 186032241, 186033203, 186038166, 186041770, 186043671, 186049741, 186052729, 186056257, 186058533, 186059022, 186060619, 186063619, 186070576, 186070838, 186072802, 186073295, 186076934, 186079782, 186081364, 186083378, 186090182, 186099834, 186104572, 186112996, 186115949, 186117351, 186119962, 186126928, 186131728, 186142625, 186146360, 186148006, 186149057, 186152026, 186156901, 186244971, 186252104, 186267820, 187843111, 187857373, 187873329, or 187878274 on human chromosome 3;
at position 4857130, 4857759, 4862109, 4867970, 73187634, 73200067, 73328055, 73346262, 73346848, 73348223, 73357454, 73363372, 73365920, 73368604, 73376981, 73386336, 73387894, 73401936, 73402263, 73403367, 73409745, 73418036, 73418955, 73419931, 73420592, 73420874, 73420904, 73420954, 73421198, 73421361, 73421626, 73421636, 73424191, 73426574, 73428206, 73428609, 73429022, 73429166, 73429961, 73430864, 73432371, 73432662, 73433172, 73435810, 73435851, 73437882, 73438096, 73440758, 73441001, 73441029, 73442206, 73445194, 73446950, 73448534, 73453617, 73454336, 73456969, 73461203, 73461427, 73468266, 73468802, 73469693, 73472897, 73473510, 73474331, 73475459, 73476824, 73481968, 73482388, 73484550, 73489468, 73491229, 73491598, 73492707, 73493192, 73493907, 73496343, 73496916, or 73501955 on human chromosome 4;
at position 114716570, 114718052, 114719100, 114719186, 114720973, 114721020, 114724952, 114727927, 114728598, 114729688, 114730035, 114730402, 114731087, 114734391, 114735264, 114735588, 114735981, 114736503, 114739954, 114741070, 114742706, 114743558, 114743576, 114744950, 114747047, 114747337, 114747490, 121091463, 121091499, 121091674, 121092163, 121092323, 121093100, 121093738, 121093873, 121095213, 121096396, 121097405, 121099073, 121099678, 121099771, 121100720, 121100858, 121101095, 121102610, 121102897, 121103646, 121103950, 121104009, 121104729, 121104747, 121105473, 121107768, 121110035, 121110284, 121110706, 121114213, 121115356, 121115515, 121116167, 121116191, 121116332, 121116360, 121119962, 121128383, 121137238, 121153311, 128103463, 128108152, 128113997, 128120050, 128134369, 128135572, 128139763, 128141175, 128145987, 128146786, 128156553, 128157693, 128160641, 128164258, 128197696, 128206257, 128220969, 128223084, 128227979, 128228401, 128232311, 128232320, 128233576, 128233727, 128234493, 128234617, 128234806, 128235438, 128235745, 128235767, 128236078, 128236528, 128238639, 128240119, 128241301, 128258653, 128260778, 128260800, 128263313, 128265259, 128269933, 128271956, 128273703, 128279649, 128280539, 128287628, 128289750, 128327389, 128340511, 128341528, 128345166, 128346380, 128348967, 128351543, 128352581, 128352924, 128353107, 128355391, 128355483, 128356081, or 128358774 on human chromosome 5;

at position 1026731, 1032864, 1032946, 1033885, 1033964, 1034131, 1034217, 1035056, 1035451, 1037138, 1037761, 69379328, 69411039, 69414352, 69414862, 69416925, 69420759, 69428738, 69429357, 69429728, 69435338, 69435377, 69435704, 69436412, 69437088, 69437132, 69437929, 69439747, 69440936, 69445347, 69447873, 69449271, 69454318, 69455343, 69461590, 69462851, 69463179, 69469800, 69471343, 69483117, 69483590, 69486083, 69490498, 69496298, 69497479, 69504298, 69504487, 69511710, 69513299, 69517615, 69518419, 69521107, 82950808, 83037702, 83052756, 83052893, 83059529, 83059811, 83063355, 83065585, 83065715, 83066965, 83067321, 83079412, 83086171, 83086772, 83087733, 83088471, 83089659, 83092525, 83092537, 83094274, 83094499, 83094576, 83095347, 83095565, 83095939, 83096974, 83097004, 83097222, 83098262, 83098329, 83098352, 83100260, 83101000, 83103870, 83113039, 83114887, 83120523, 83122607, 83127291, 83129590, 83131084, 83137358, 83140060, 83146661, 83147795, 83150543, 83153296, 83155501, 83162032, 83163350, 83165082, 83165771, 83167427, 83167802, 83168404, 83169297, 83169493, 83170215, 83170490, 83170598, or 83172329 on human chromosome 6;
at position 9426711, 9431741, 9436057, 9436101, 9436786, 9437029, 9437099, 9439838, 9440072, 9440613, 9444872, 9452052, 9458679, 9460336, 9463104, 9468129, 9480306, 9_503674, 9523873, 9526021, 9526193, 9531111, 9538857, 9541393, 9546289, 9558649, 9563755, 9_568067, 9568084, 9568712, 9640154, 9645506, 9673180, 105447572, 138448609, 138448978, 138450507, 138450935, 138451287, 138452272, 138452507, 138452835, 138453471, 138454113, 138454197, 138454235, 138454833, 138455486, 138455728, 138456184, 138456296, 138456395, 138457265, 138458205, 138458287, 138458607, 138459228, 138459736, 138460258, 138460320, 138460491, 138461455, 138461471, 138461926, 138462319, 138467267, 138467277, 138467539, 138469853, 138469883, 138472916, 138473941, 138477490, 138481482, 138482393, 138490184, 138498734, 138545196, 138546484, 138551497, 138576626, 138578139, 138580074, 138583352, 138585809, 138585968, 138586498, 138588282, 138590203, 138590751, 138594903, 138601596, 138601771, 138603600, 138603658, 138603708, 138604408, 138607169, 138608732, 138610100, 138610110, 138610517, 138611185, 138611655, 138611699, 138611757, 138612308, 138614096, 138614490, 138615852, 138616621, 138616711, 138616778, 141567935, 141583366, 141587219, 141589763, 141595413, 141596167, 141596488, or 141597272 on human chromosome 8;
at position 6282602, 6291578, 6299862, 6314376, 6316825, 6321421, 6321610, 6322901, 6325760, 6332328, 6340235, 6341111, 6341834, 6342819, 6349144, 6352365, 6354449, 6354533, 6355683, 6375637, 6385247, 6385540, 6386245, 6390030, 6392856, 6397843, 6398247, 6399874, 73606988, 73607164, 73607569, 73612124, 73613027, 73614943, 73615076, 73615232, 73616781, 73617303, 73618675, 73619146, 73622095, 73622395, 73622439, 73625852, 73626601, 73626706, 73627824, 73628740, 73629704, 73633747, 73634385, 73635467, 73635691, 73635782, 73636447, 73636612, 73636831, 73638980, 73639771, 73639895, 73640222, 73642109, 73642315, 73643177, 79353007, 79353924, 79356465, 79356737, or 79359981 on human chromosome 9;

at position 5766124, 5766249, 5766322, 5768065, 5775192, 5778275, 5779169, 5779725, 5779774, 5780048, 5780227, 5781044, 5781526, 5781557, 5781753, 5782739, 5783829, 5784028, 5784528, 5785595, 5786072, 5792979, 5799485, 5800361, 5802527, 5802898, 43124098, 43145953, 43149399, 43151108, 43153254, 43155303, 43156052, 43156514, 43156746, 43156937, 43158142, 43158508, 43159402, 43160243, 43160762, 43160895, 43160975, 43161066, 43161471, 43161777, 43161927, 43167395, 43167433, 43169005, 43169462, 43170570, 43171231, 73953815, 73968600, 73972614, 73978840, 73982157, 73987190, 73990610, 73995062, 74002571, 74002983, 74007856, 74008628, 74009527, 74013473, 74015333, 74016841, 74017225, 74017844, 74018984, 74023198, 74024581, 74029849, 74033737, 74034353, 74037177, 74037678, 74039262, 74040179, 74040814, 74052598, 74055648, 74056519, 74058677, 74062794, 74063339, 74064448, 74067075, 74067429, 74067969, 74071586, 83325571, 83325870, 83326348, 83331489, 83333982, 83338726, 83346857, 83359180, 83378990, 83383578, 83385447, 83386501, 83387013, 83389630, 83389983, 83390829, 83400665, 83402660, 83403491, 83403720, 83404929, 83418135, 83420693, 83430317, 83504794, 83508907, 83523059, 83525615, 83527163, 83532440, 83540697, 83542042, 83548041, 83555723, 83565887, 83569470, 83570172, 83572107, 83574800, 83576676, 83594342, 83599752, or 83601427 on human chromosome 11;
at position 31132974, 31136113, 31141128, 31144153, 31148962, 31149995, 31152638, 31152965, 31156037, 31157554, or 31157580 on human chromosome 12;
at position 21846344, 21860220, 21868669, 21868693, 21870958, 21873258, 21875373, 32643593, 32655052, 32658737, 32659011, 32665137, 45412663, 45413606, 45414960, 45416097, 45418874, 45438294, 45440577, 45445023, 45448444, 45459812, 45464824, 45484610, 45512651, 45514463, 45525440, 45538603, 45539148, 45539467, 45539686, 45540157, 45540993, 45541374, 45541562, 45543741, 45544445, 45546095, 45549081, 45549309, 45550691, 45553450, 45568003, or 45572910 on human chromosome 13;
at position 46089356, 46101819, 46103228, 46108382, 46111620, 46114858, 46116200, 46116311, 46116717, 46118326, 46118529, 46118841, 46120302, 46126798, 46136739, 46139544, 46145643, 46146164, 46149357, 93195638, 93202040, 93217814, 93221398, 93222123, 93226669, 93229804, 93231817, 93232312, 93233505, 93238457, 93261273, 93263139, 93264699, 93265029, 93266435, 93266453, 93267466, 93277598, 93279847, 97282996, 99768367, 99768718, 99772560, 99772834, 99773041, 99773203, 99773242, 99775105, 99775156, 99775985, or 99785607 on human chromosome 15;
at position 23566477, 23573679, 23574058, 23576069, 23578098, 23579493, 23584507, 23588666, 23599906, 23602233, 23605180, 23605958, 23609039, 23611506, 23619426, 23619684, 23619949, or 23620229 on human chromosome 16;
at position 13110425, 13112831, 13114370, 13117081, 13117504, or 13117537 on human chromosome 17;

at position 34294350, 34294807, 34297013, 34299961, 64574312, 64575303, 64575455, 64577169, 64577779, 64578874, 64579596, 64580779, 64584139, 64586668, 64588166, 64588368, 64589299, 64591510, 64592428, 64592919, 64593139, 64595151, 64595371, 64596256, 64596392, 64596771, 64600350, 64600521, 64601827, 64602989, 64612870, or 64618545 on human chromosome 18;
at position 20218657, 20222308, 20226492, 20228734, 20232506, 20243479, 20251093, 20257959, 20261725, 20272988, 20274521, 20274865, 20279236, 20282727, or 20308050 on human chromosome 21.

4. The method of claim 3, wherein:
when the base at position 96911594 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 96961817 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 97005044 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 97141267 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 97653506 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 97659904 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114947052 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114968711 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114978348 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114981253 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114984296 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115004020 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115071842 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 115075249 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115077252 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115081154 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115084567 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115087972 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115091656 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115100040 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115103811 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115104443 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115111982 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115116141 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115119103 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115125087 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115132157 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115132560 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115132947 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115139005 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115141772 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 115159909 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115167322 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115171216 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115179531 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115180386 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115182953 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115183282 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115185601 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115200356 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115202960 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115209101 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115217819 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115234779 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115236258 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115242333 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115242502 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115242740 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115244057 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 115261728 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115268188 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115277042 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115278233 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115278345 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115278448 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115278686 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115279927 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115280070 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115281663 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115282510 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115284407 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115285912 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115287160 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115287345 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115289952 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115292582 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115298443 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 115298798 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115303040 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 142933600 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 142994415 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 142996870 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 143024965 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 143037007 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 143039966 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20250764 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20250981 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20252966 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20254650 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20255588 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20256013 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20257476 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20258973 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20259648 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20260227 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 186729521 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186748482 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186752544 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186753368 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186759677 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186774634 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186783677 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186788675 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186795981 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186797056 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186797101 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186804008 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186822924 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186849447 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186854278 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186854406 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186856196 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186866149 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 186869233 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186870116 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186873391 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186873805 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186874321 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186876760 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186877596 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186878043 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186883056 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186887466 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186895423 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186898014 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186899824 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1 86903 1 94 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186905158 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186910195 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186918660 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186933341 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 186935034 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186937617 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186938372 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186938761 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186940537 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186942136 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186944471 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186945120 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186950816 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 187032899 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 187050892 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218767422 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218767819 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218767857 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218768482 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218770121 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218770314 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218770551 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 218771180 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218773021 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218777739 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218781315 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218784326 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218786186 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218789557 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218791821 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218814280 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218816511 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218823086 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218826240 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218830515 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218832566 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218833258 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218833506 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218833898 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218835652 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 218852394 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218852478 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218871943 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 218873288 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230822818 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230822908 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230823742 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230824051 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230825316 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230825613 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230825877 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230827852 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230828862 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230829298 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230830081 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230830316 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230830886 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 230832540 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 230842525 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25052936 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25054402 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25056885 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25061156 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25068060 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25076452 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25084253 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25084806 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25086476 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25090198 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25090417 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25100369 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25102693 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25105990 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25108277 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25112900 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25114656 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 25115540 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25117575 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25118394 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25121605 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62937809 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62941462 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62943033 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62943151 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62943547 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62945427 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62949979 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62955440 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62957942 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62958060 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62959133 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62959399 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62960430 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62962215 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 62964393 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62965607 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62966446 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62966549 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62968123 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62968779 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62968976 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62969677 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62970029 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62970190 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62970589 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62971291 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62972138 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62975188 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62981633 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62982901 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62983787 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 62985367 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 120013362 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120013382 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120036240 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120037273 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120037336 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120037804 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120039183 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120039851 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 120044441 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186008653 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186008673 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186008910 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186012692 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186027445 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186032241 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186038166 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186041770 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186043671 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 186049741 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186052729 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186056257 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186058533 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186059022 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186060619 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186063619 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186070576 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186070838 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186072802 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186073295 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186076934 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186079782 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186081364 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186083378 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186090182 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186099834 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186104572 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 186112996 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186115949 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186117351 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186119962 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186126928 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186131728 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186142625 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186146360 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186148006 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186149057 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186152026 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186156901 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186244971 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position. 186252104 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 186267820 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 187843 111 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 187857373 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 187878274 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 4857130 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4857759 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4867970 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73187634 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73200067 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73328055 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73346262 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73346848 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73348223 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73357454 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73363372 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73365920 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73368604 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position. 73376981 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73386336 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73387894 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73401936 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73402263 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73403367 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73409745 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73418036 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73419931 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73420592 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73420874 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73420904 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73420954 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73421198 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73421361 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73421626 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73421636 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73424191 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73426574 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73428206 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73428609 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73429022 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73429166 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73429961 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73430864 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73432371 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73432662 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73433172 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73435810 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73435851 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73437882 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73438096 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73440758 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73441001 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73441029 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73442206 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73445194 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73446950 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73448534 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73453617 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73454336 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73456969 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73461203 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73461427 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73468266 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73468802 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73469693 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73472897 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73473510 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73474331 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73475459 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73476824 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73481968 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73482388 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73484550 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73489468 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73491229 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73491598 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73492707 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73493192 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73493907 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73496343 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73496916 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73501955 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114716570 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114718052 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114719100 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114719186 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114721020 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114724952 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114727927 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114728598 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114729688 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114730035 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114730402 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114731087 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114734391 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 114735264 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114735588 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114735981 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114736503 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114739954 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114741070 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114742706 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114743558 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114743576 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114744950 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114747047 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114747337 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 114747490 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121091463 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121091499 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121091674 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121092163 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121092323 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 121093100 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121093738 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121093873 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121095213 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121096396 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121097405 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121099678 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121099771 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121100720 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121100858 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121101095 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121102610 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121102897 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121103646 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121103950 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121104009 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121104729 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121104747 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 121105473 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121107768 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121110035 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121110706 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121114213 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121115356 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121115515 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121116167 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121116191 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121116332 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121116360 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121119962 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121128383 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121137238 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 121153311 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128103463 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128108152 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128113997 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 128120050 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128134369 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128135572 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128139763 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128141175 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128146786 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128156553 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128157693 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128160641 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128164258 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128197696 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128206257 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128220969 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128223084 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128227979 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128228401 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128232311 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128232320 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 128233576 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128233727 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128234493 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128234617 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128234806 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128235438 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128235745 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128235767 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128236078 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128236528 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128238639 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128240119 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128241301 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128258653 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128260778 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128260800 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128263313 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128265259 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 128269933 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128271956 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128273703 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128279649 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128280539 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128287628 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128289750 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128327389 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128340511 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128341528 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128345166 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128346380 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128348967 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128351543 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128352581 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128352924 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128353107 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128355391 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 128355483 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128356081 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128358774 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1026731 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1032864 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1033885 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1033964 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1034131 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1034217 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1035056 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1035451 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1037138 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 1037761 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69379328 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69411039 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69414352 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69414862 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69416925 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 69420759 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69428738 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69429357 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69429728 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69435338 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69435377 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69435704 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69436412 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69437088 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69437132 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69437929 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69439747 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69440936 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69445347 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69447873 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69449271 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69454318 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69455343 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 69461590 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69462851 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69463179 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69469800 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69471343 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69483117 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69483590 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69486083 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69490498 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69496298 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69497479 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69504298 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69504487 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69511710 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69513299 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69517615 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 69518419 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 82950808 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83037702 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83052756 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83052893 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83059529 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83059811 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83063355 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83065585 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83065715 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83066965 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83067321 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83079412 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83086171 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83086772 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83087733 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83088471 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83089659 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83092525 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83092537 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83094499 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83094576 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095347 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095565 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095939 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83096974 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83097004 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83097222 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098262 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098352 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83100260 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83101000 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83103870 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83113039 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83114887 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83120523 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83122607 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83127291 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83129590 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83131084 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83137358 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83140060 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83146661 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83147795 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83150543 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83153296 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83155501 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83162032 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83163350 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83165082 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83165771 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83167427 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83167802 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83168404 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83169297 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83169493 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170215 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170490 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170598 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83172329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9426711 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9431741 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9436057 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9436101 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9436786 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9437029 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9437099 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9439838 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9440072 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9444872 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9452052 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9458679 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9460336 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 9463104 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9468129 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9480306 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9503674 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9523873 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9526021 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9526193 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9531111 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9538857 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9541393 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9546289 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9558649 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9563755 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9568067 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9568084 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9568712 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9640154 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9645506 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 9673180 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138448609 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138448978 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138450507 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138450935 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138451287 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138452272 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138452507 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138452835 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138453471 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138454113 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138454197 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138454235 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138454833 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138455486 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138455728 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138456184 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138456296 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 138456395 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138457265 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138458205 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138458287 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138458607 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138459228 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138459736 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138460258 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138460320 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138460491 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138461455 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138461471 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138461926 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138462319 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138467267 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138467277 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138467539 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138469853 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 138469883 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138472916 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138473941 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138477490 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138481482 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138482393 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138490184 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138498734 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138545196 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138546484 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138551497 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138576626 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138578139 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138580074 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138583352 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138585809 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138585968 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138586498 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 138588282 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138590203 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138590751 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138594903 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138601596 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138601771 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138603600 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138603658 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138603708 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138604408 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138607169 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138608732 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138610100 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138610110 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138610517 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138611185 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138611655 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138611699 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 138611757 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138612308 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138614096 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138614490 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138615852 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138616621 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138616711 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 138616778 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141567935 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141583366 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141589763 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141595413 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141596167 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141596488 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 141597272 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6282602 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6291578 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6299862 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 6314376 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6316825 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6321421 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6321610 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6322901 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6325760 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6332328 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6340235 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6341111 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6341834 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6342819 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6349144 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6352365 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6354449 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6354533 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6375637 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6385247 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6385540 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 6386245 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6390030 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6392856 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6397843 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6398247 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 6399874 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73606988 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73607164 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73607569 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73612124 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73613027 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73614943 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73615076 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73615232 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73616781 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73617303 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73618675 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73619146 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73622095 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73622395 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73622439 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73625852 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73626601 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73626706 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73627824 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73628740 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73629704 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73633747 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73634385 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73635467 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73635691 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73635782 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73636447 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73636612 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73636831 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73638980 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 73639771 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73639895 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73640222 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73642315 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73643177 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 79353924 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 79356465 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 79356737 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 79359981 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5766124 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5766322 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5768065 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5775192 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5778275 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5779169 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5779725 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5779774 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5780048 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 5780227 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5781044 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5781526 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5781557 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5781753 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5782739 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5783829 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5784028 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5784528 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5785595 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5786072 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5792979 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5799485 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5800361 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5802527 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5802898 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43124098 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43145953 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 43149399 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43151108 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43153254 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43155303 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43156052 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43156514 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43156937 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43158142 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43158508 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43159402 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43160243 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43160762 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43160895 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43160975 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43161066 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43161471 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43161777 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43161927 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 43167395 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43167433 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43169005 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43169462 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43170570 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 43171231 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73953815 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73968600 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73978840 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73982157 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73987190 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73990610 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 73995062 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74002571 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74002983 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74007856 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74008628 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74009527 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 74013473 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74015333 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74016841 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74017225 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74017844 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74018984 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74023198 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74024581 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74029849 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74033737 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74034353 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74037177 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74037678 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74039262 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74040179 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74040814 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74052598 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74055648 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 74056519 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74058677 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74062794 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74063339 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74064448 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74067075 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74067429 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74067969 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 74071586 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83325571 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83326348 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83331489 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83333982 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83338726 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83346857 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83359180 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83378990 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83383578 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83385447 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83386501 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83387013 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83389630 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83389983 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83390829 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83400665 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83402660 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83403491 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83403720 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83404929 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83418135 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83420693 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83430317 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83504794 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83508907 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83523059 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83525615 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83527163 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83532440 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83540697 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83542042 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83548041 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83555723 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83569470 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83570172 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83572107 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83574800 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83576676 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83594342 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83599752 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83601427 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31132974 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31136113 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31144153 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31148962 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 31149995 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31152638 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31152965 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31156037 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31157580 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21846344 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21860220 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21868669 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21868693 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21870958 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21873258 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 32643593 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 32655052 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 32658737 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 32665137 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45412663 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45413606 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45414960 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 45416097 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45418874 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45438294 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45440577 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45445023 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45448444 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45459812 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45464824 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45484610 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45512651 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45514463 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45525440 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45538603 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45539148 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45539467 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45539686 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45540157 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45540993 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 45541374 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45541562 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45543741 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45544445 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45546095 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45549081 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45549309 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45550691 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45553450 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45568003 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 45572910 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46089356 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46101819 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46103228 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46108382 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46111620 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46114858 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46116200 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 46116311 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46116717 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46118326 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46118529 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46118841 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46120302 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46126798 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46136739 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46139544 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46145643 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 46149357 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93195638 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93202040 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93217814 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93221398 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93222123 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93226669 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93229804 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 93231817 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93232312 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93238457 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93261273 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93263139 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93264699 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93265029 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93266435 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93266453 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93267466 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93277598 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 93279847 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99768367 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99768718 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99772560 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99772834 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99773041 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99773242 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 99775105 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99775156 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99775985 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 99785607 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23566477 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23573679 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23574058 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23576069 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23578098 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23579493 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23584507 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23588666 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23599906 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23602233 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23605180 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23605958 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23609039 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23611506 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 23619684 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23619949 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 23620229 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 13112831 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 13114370 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 13117081 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 13117504 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 13117537 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 34294350 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 34294807 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 34297013 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64574312 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64575303 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64575455 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64577169 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64577779 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64578874 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64579596 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 64580779 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64584139 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64586668 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64588166 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64588368 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64589299 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64591510 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64592428 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64592919 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64593139 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64595151 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64595371 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64596256 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64596392 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64596771 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64600350 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64601827 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64602989 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 64612870 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 64618545 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20218657 on human chromosome 21 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20222308 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20226492 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20228734 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20232506 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20243479 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20251093 on human chromosome 21 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20257959 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20261725 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20274521 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20274865 on human chromosome 21 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20279236 on human chromosome 21 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20282727 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20308050 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk.

5. The method of claim 4, wherein the base is selected from one of those specifically enumerated in claim 3.

6. The method of claim 5, wherein the allelic effect is as specified in any of Tables 1 to 51, as it applies to the specified base.

7. An isolated nucleic acid molecule comprising at least 8 (or at least 9, or at least 10, or at least 11, or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least 18, or at least 19, or at least 20, or at least 21, or at least 22, or at least 23, or at least 24, or at least 25, or at least 26, or at least 27, or at least 28, or at least 29, or at least 30, or at least 31, or at least 32, or at least 33, or at least 34, or at least 35, or at least 36, or at least 37, or at least 38, or at least 39, or at least 40, or at least 41, or at least 42, or at least 43, or at least 44, or at least 45, or at least 46, or at least 47, or at least 48, or at least 49, or at least 50, or at least 51, or at least 52, or at least 53, or at least 54, or at least 55, or at least 56, or at least 57, or at least 58, or at least 59, or at least 60, or at least 61, or at least 62, or at least 63, or at least 64, or at least 65, or at least 66, or at least 67, or at least 68, or at least 69, or at least 70, or at least 71, or at least 72, or at least 73, or at least 74, or at least 75, or at least 76, or at least 77, or at least 78, or at least 79, or at least 80, or at least 81, or at least 82, or at least 83, or at least 84, or at least 85, or at least 86, or at least 87, or at least 88, or at least 89, or at least 90, or at least 91, or at least 92, or at least 93, or at least 94, or at least 95, or at least 96, or at least 97, or at least 98, or at least 99, or at least 100 contiguous nucleotides wherein one of the nucleotides is a single nucleotide polymorphism (SNP) selected from those defined in any of claims 1 to 5, or a complement thereof, and optionally, wherein the isolated nucleic acid molecule has a maximum length of 100 said contiguous nucleotides, or a maximum length of 90 said contiguous nucleotides, or a maximum length of 80 said contiguous nucleotides, or a maximum length of 70 said contiguous nucleotides, or a maximum length of 60 said contiguous nucleotides, or a maximum length of 50 said contiguous nucleotides, or a maximum length of 40 said contiguous nucleotides, or a maximum length of 30 said contiguous nucleotides, or a maximum length of 20 said contiguous nucleotides.

8. An amplified polynucleotide containing a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences of claims 1 to 5, or a complement thereof, wherein the amplified polynucleotide is between about 16 and about 2000 nucleotides in length, or any length therebetween.

9. An isolated polynucleotide which specifically hybridizes to a nucleic acid molecule of claim 8.

10. The polynucleotide of claim 9 which is 8 to 100 nucleotides in length.

11. The polynucleotide of claim 9 or 10 which is an allele-specific probe.

12. The polynucleotide of any of claims 7 to 10 which is an allele-specific primer.

13. A kit for detecting a single nucleotide polymorphism (SNP) in a nucleic acid molecule, comprising the polynucleotide of any of claims 7 to 12, a buffer, and an enzyme.

14. A method of detecting a single nucleotide polymorphism (SNP) in a nucleic acid molecule, comprising contacting a test sample with a reagent which specifically hybridizes to a SNP in any one of the nucleotide sequences of SEQ ID NOs: 1 to 1144 under stringent hybridization conditions, and detecting the formation of a hybridized duplex.

15. The method of claim 14 in which detection is carried out by a process which may be selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.

16. A method of detecting a variant polypeptide, comprising contacting a reagent with a variant polypeptide encoded by a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOs: 1 to 1144 in a test sample, and detecting the binding of the reagent to the polypeptide.

17. A method for identifying an agent useful in therapeutically or prophylactically treating colorectal cancer, comprising contacting the polypeptide corresponding to all or part of the translated product of the gene comprising the polymorphic site, and may be synthetic or naturally occurring, with a candidate agent under conditions suitable to allow formation of a binding complex between the polypeptide and the candidate agent, and detecting the formation of the binding complex or its functional consequence, wherein the presence of the complex identifies said agent.

18. A method for identifying an individual who has an altered risk for developing colorectal cancer, comprising:
(a) providing a sample containing genetic material of the individual;
(b) amplifying the genetic material in the presence of a pair of primers wherein a first of the primers comprises at least 10 consecutive nucleotides selected from one of sequences of SEQ ID NOs: 1 to 1119, each located upstream of the base located at position 331 of each sequence and a second primer comprising at least 10 consecutive nucleotides selected from within the same sequence and located downstream of the base located at position 331; and (c) determining the identity of the base in the genetic material that corresponds to position 331.

19. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) accessing a database containing nucleotide sequence data on single nucleotide polymorphisms located between position 96911594 and position 97159204 on human chromosome 1;
(b) determining the position of a said single nucleotide polymorphism on the human chromosome;
(c) storing the position determined in step (b);
(d) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a clinical population that has been diagnosed as having colorectal cancer;
(e) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a control population; and (f) calculating the degree of correlation between the identities of the nucleotide bases provided in steps (d) and (e) and a diagnosis of colorectal cancer in the clinical population.

20. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for each member of a clinical population that has been diagnosed as having colorectal cancer wherein the sequence is located between position 96911594 and position 97159204 on human chromosome 1;
(b) storing the sequence;
(c) accessing a database containing nucleotide sequence data for said sequence;
(d) determining the position of a single nucleotide polymorphism within the sequence;
(e) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism determined in step (d) for each member of a control population; and (f) calculating the degree of correlation between the identities of the nucleotide bases provided in steps (c) and (d) and a diagnosis of colorectal cancer in the clinical population.

21. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for each member of a clinical population that has been diagnosed as having colorectal cancer wherein the sequence is located between position 96911594 and position 97159204 on human chromosome 1;
(b) storing the sequence;
(c) determining the nucleotide sequence, for each member of a control population, corresponding to the sequence stored in step (b);

(d) storing sequence determined in step (c);
(e) determining the position of a single nucleotide polymorphism within the sequence stored in step (b); and (f) calculating the degree of correlation between the identities of the nucleotide bases at the position determined in step (e) and a diagnosis of colorectal cancer in the clinical population.

22. The method of any of claims 19 to 21, wherein the position of step (a) is:

between position 97653506 and position 97659904 on human chromosome 1;
between position 114947052 and position 115303040 on human chromosome 1;
between position 142933600 and position 143040559 on human chromosome 1;
between position 20250764 and position 20260227 on human chromosome 2;
between position 186729521 and position 187050892 on human chromosome 2;
between position 218767422 and position 218873288 on human chromosome 2;
between position 230822818 and position 230842525 on human chromosome 2;
between position 25052936 and position 25121605 on human chromosome 3;
between position 62937809 and position 62985367 on human chromosome 3;
between position 120013362 and position 120044441 on human chromosome 3;
between position 120036240 and position 120044441 on human chromosome 3;
between position 186008653 and position 186267820 on human chromosome 3;
between position 187843111 and position 187878274 on human chromosome 3;
between position 4857130 and position 4867970 on human chromosome 4;
between position 73187634 and position 73501955 on human chromosome 4;
between position 114716570 and position 114747490 on human chromosome 5;
between position 121091463 and position 121153311 on human chromosome 5;
between position 128103463 and position 128358774 on human chromosome 5;

between position 1026731 and position 1037761 on human chromosome 6;
between position 69379328 and position 69521107 on human chromosome 6;
between position 82950808 and position 83172329 on human chromosome 6;
between position 9426711 and position 9673180 on human chromosome 8;
position 105447572 on human chromosome 8;
between position 138448609 and position 138616778 on human chromosome 8;
between position 141567935 and position 141597272 on human chromosome 8;
between position 6282602 and position 6399874 on human chromosome 9;
between position 73606988 and position 73643177 on human chromosome 9;
between position 79353007 and position 79359981 on human chromosome 9;
between position 5766124 and position 5802898 on human chromosome 11;

between position 43124098 and position 43171231 on human chromosome 11;
between position 73953815 and position 74067429 on human chromosome 11;
between position 73978840 and position 74071586 on human chromosome 11;
between position 73982157 and position 74037177 on human chromosome 11;
between position 83325571 and position 83601427 on human chromosome 11;
between position 31132974 and position 31157580 on human chromosome 12;
position 31141128 on human chromosome 12;
between position 21846344 and position 21875373 on human chromosome 13;
between position 32643593 and position 32665137 on human chromosome 13;
between position 45412663 and position 45572910 on human chromosome 13;
between position 46089356 and position 46149357 on human chromosome 15;
between position 93195638 and position 93279847 on human chromosome 15;
position 97282996 on human chromosome 15;
between position 99768367 and position 99785607 on human chromosome 15;
between position 23566477 and position 23620229 on human chromosome 16;
between position 13110425 and position 13117537 on human chromosome 17;
between position 34294350 and position 34299961 on human chromosome 18;
between position 64574312 and position 64618545 on human chromosome 18; or between position 20218657 and position 20308050 on human chromosome 21.

23. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) accessing a database that includes nucleotide sequence data on single nucleotide polymorphisms located between position 96911594 and position 97159204 on human chromosome 1 different from those listed in Table 1A;
(b) determining the position of a said single nucleotide polymorphism on the human chromosome;
(c) storing the position determined in step (b);
(d) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a population;
(e) determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 1A for each member of the population; and (f) determining whether the nucleotide bases determined in steps (b) and (e), respectively, are in strong linkage disequilibrium with each other, wherein, if the nucleotide bases are in strong disequilibrium with each other, then the single nucleotide polymorphism determined in step (b) can be used for predicting the susceptibility of an individual to colorectal cancer in the same way as the single nucleotide polymorphism of step (e).

24. The method of claim 23, wherein: in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 97653506 and 97659904 on human chromosome 1 different from those listed in Table 2A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 2A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 114947052 and 115303040 on human chromosome 1 different from those listed in Table 3A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 3A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 142933600 and 143040559 on human chromosome 1 different from those listed in Table 4A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 4A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 20250764 and 20260227 on human chromosome 2 different from those listed in Table 5A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 5A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 186729521 and 187050892 on human chromosome 2 different from those listed in Table 6A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 6A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 218767422 and 218873288 on human chromosome 2 different from those listed in Table 7A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 7A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position. 230822818 and 230842525 on human chromosome 2 different from those listed in Table 8A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 8A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 25052936 and 25121605 on human chromosome 3 different from those listed in Table 9A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 9A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 62937809 and 62985367 on human chromosome 3 different from those listed in Table 10A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 10A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 120036240 and 120044441 on human chromosome 3 different from those listed in Table 11A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 11A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 120013362 and 120044441 on human chromosome 3 different from those listed in Table 12A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 12A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 186008653 and 186267820 on human chromosome 3 different from those listed in Table 13A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 13A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 187843111 and 187878274 on human chromosome 3 different from those listed in Table 14A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 14A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 4857130 and 4867970 on human chromosome 4 different from those listed in Table 15A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 15A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 73187634 and 73501955 on human chromosome 4 different from those listed in Table 16A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 16A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 114716570 and 114747490 on human chromosome 5 different from those listed in Table 17A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 17A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 121091463 and 121153311 on human chromosome 5 different from those listed in Table 18A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 18A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 128103463 and 128358774 on human chromosome 5 different from those listed in Table 19A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 19A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 1026731 and 1037761 on human chromosome 6 different from those listed in Table 20A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 20A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 69379328 and 69521107 on human chromosome 6 different from those listed in Table 21A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 21A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 82950808 and 83172329 on human chromosome 6 different from those listed in Table 22A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 22A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 9426711 and 9673180 on human chromosome 8 different from those listed in Table 23A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 23A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 105447572 on human chromosome 8 different from those listed in Table 24A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 24A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 138448609 and 138616778 on human chromosome 8 different from those listed in Table 26A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 26A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 141567935 and 141597272 on human chromosome 8 different from those listed in Table 27A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 27A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 6282602 and 6399874 on human chromosome 9 different from those listed in Table 28A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 28A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 73606988 and 73643177 on human chromosome 9 different from those listed in Table 29A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 29A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 79353007 and 79359981 on human chromosome 9 different from those listed in Table 30A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 30A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 5766124 and 5802898 on human chromosome 11 different from those listed in Table 31A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 31A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 43124098 and 43171231 on human chromosome 11 different from those listed in Table 32A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 32A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 73953815 and 74067429 on human chromosome 11 different from those listed in Table 33A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 33A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 73978840 and 74071586 on human chromosome 11 different from those listed in Table 34A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 34A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position. 73982157 and 74037177 on human chromosome 11 different from those listed in Table 35A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 35A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 83325571 and 83601427 on human chromosome 11 different from those listed in Table 36A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 36A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 31141128 on human chromosome 12 different from those listed in Table 37A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 37A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 31132974 and 31157580 on human chromosome 12 different from those listed in Table 38A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 38A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 21846344 and 21875373 on human chromosome 13 different from those listed in Table 39A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 39A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 32643593 and 32665137 on human chromosome 13 different from those listed in Table 40A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 40A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 45412663 and 45572910 on human chromosome 13 different from those listed in Table 42A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 42A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 46089356 and 46149357 on human chromosome 15 different from those listed in Table 43A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 43A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 93195638 and 93279847 on human chromosome 15 different from those listed in Table 44A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 44A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 97282996 on human chromosome 15 different from those listed in Table 45A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 45A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 99768367 and 99785607 on human chromosome 15 different from those listed in Table 46A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 46A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 23566477 and 23620229 on human chromosome 16 different from those listed in Table 47A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 47A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 13110425 and 13117537 on human chromosome 17 different from those listed in Table 48A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 48A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 34294350 and 34299961 on human chromosome 18 different from those listed in Table 49A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 49A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 64574312 and 64618545 on human chromosome 18 different from those listed in Table 50A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 50A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 20218657 and 20308050 on human chromosome 21 different from those listed in Table 51A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 5 1A for each member of the population.

25. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for a member of a clinical population that has been diagnosed as having colorectal cancer, wherein the sequence is located between position 96911594 and position 97159204 on human chromosome 1;
(b) storing the sequence;
(c) determining the identity of the nucleotide base at a position of a single nucleotide polymorphism listed in Table 1A;
(d) accessing a database containing the nucleotide sequence corresponding to the sequence determined in step (a);
(e) comparing the sequence of step (b) with the sequence of step (d) to determine the position of any single nucleotide polymorphism in the sequence determined in step (a) and located at a position other than that of step (c); (f) providing the identity of a nucleotide base at the position determined in step (e) for each member of a population;
(g) providing the identity of a nucleotide base at the position of step (c) for each member of the population; and (h) determining whether the nucleotide bases provided in steps (f) and (g), respectively, are in linkage disequilibrium with each other with an r2 value of >0.05, wherein, if the nucleotide bases are in such disequilibrium with each other, then the single nucleotide polymorphism determined in step (e) can be used for predicting the susceptibility of an individual to colorectal cancer in the same way as the single nucleotide polymorphism of step (c).

26. The method of claim 25, wherein: in step (a), the sequence is located between position 97653506 and 97659904 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 2A is determined;
and/or in step (a), the sequence is located between position 114947052 and 115303040 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 3A is determined; and/or in step (a), the sequence is located between position 142933600 and 143040559 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 4A is determined; and/or in step (a), the sequence is located between position 20250764 and 20260227 on human chromosome 2, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 5A is determined; and/or in step (a), the sequence is located between position 186729521 and 187050892 on human chromosome 2, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 6A is determined; and/or in step (a), the sequence is located between position 218767422 and 218873288 on human chromosome 2, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 7A is determined; and/or in step (a), the sequence is located between position 230822818 and 230842525 on human chromosome 2, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 8A is determined; and/or in step (a), the sequence is located between position 25052936 and 25121605 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 9A is determined; and/or in step (a), the sequence is located between position 62937809 and 62985367 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 10A is determined; and/or in step (a), the sequence is located between position 120036240 and 120044441 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 11A is determined; and/or in step (a), the sequence is located between position 120013362 and 120044441 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 12A is determined; and/or in step (a), the sequence is located between position 186008653 and 186267820 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 13A is determined; and/or in step (a), the sequence is located between position 187843111 and 187878274 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 14A is determined; and/or in step (a), the sequence is located between position 4857130 and 4867970 on human chromosome 4, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 15A is determined; and/or in step (a), the sequence is located between position 73187634 and 73501955 on human chromosome 4, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 16A is determined; and/or in step (a), the sequence is located between position 114716570 and 114747490 on human chromosome 5, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 17A is determined; and/or in step (a), the sequence is located between position 121091463 and 121153311 on human chromosome 5, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 18A is determined; and/or in step (a), the sequence is located between position 128103463 and 128358774 on human chromosome 5, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 19A is determined; and/or in step (a), the sequence is located between position 1026731 and 1037761 on human chromosome 6, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 20A is determined; and/or in step (a), the sequence is located between position 69379328 and 69521107 on human chromosome 6, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 21A is determined; and/or in step (a), the sequence is located between position 82950808 and 83172329 on human chromosome 6, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 22A is determined; and/or in step (a), the sequence is located between position 9426711 and 9673180 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 23A is determined; and/or in step (a), the sequence is located at position 105447572 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 24A is determined; and/or in step (a), the sequence is located between position 138448609 and 138616778 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 26A is determined; and/or in step (a), the sequence is located between position 141567935 and 141597272 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 27A is determined; and/or in step (a), the sequence is located between position 6282602 and 6399874 on human chromosome 9, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 28A is determined; and/or in step (a), the sequence is located between position 73606988 and 73643177 on human chromosome 9, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 29A is determined; and/or in step (a), the sequence is located between position 79353007 and 79359981 on human chromosome 9, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 30A is determined; and/or in step (a), the sequence is located between position 5766124 and 5802898 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 31A is determined; and/or in step (a), the sequence is located between position 43124098 and 43171231 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 32A is determined; and/or in step (a), the sequence is located between position 73953815 and 74067429 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 33A is determined; and/or in step (a), the sequence is located between position 73978840 and 74071586 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 34A is determined; and/or in step (a), the sequence is located between position 73982157 and 74037177 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 35A is determined; and/or in step (a), the sequence is located between position 83325571 and 83601427 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 36A is determined; and/or in step (a), the sequence is located at position 31141128 on human chromosome 12, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 37A is determined; and/or in step (a), the sequence is located between position 31132974 and 31157580 on human chromosome 12, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 38A is determined; and/or in step (a), the sequence is located between position 21846344 and 21875373 on human chromosome 13, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 39A is determined; and/or in step (a), the sequence is located between position 32643593 and 32665137 on human chromosome 13, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 40A is determined; and/or in step (a), the sequence is located between position 45412663 and 45572910 on human chromosome 13, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 42A is determined; and/or in step (a), the sequence is located between position 46089356 and 46149357 on human chromosome 15, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 43A is determined; and/or in step (a), the sequence is located between position 93195638 and 93279847 on human chromosome 15, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 44A is determined; and/or in step (a), the sequence is located at position 97282996 on human chromosome 15, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 45A is determined; and/or in step (a), the sequence is located between position 99768367 and 99785607 on human chromosome 15, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 46A is determined; and/or in step (a), the sequence is located between position 23566477 and 23620229 on human chromosome 16, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 47A is determined; and/or in step (a), the sequence is located between position 13110425 and 13117537 on human chromosome 17, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 48A is determined; and/or in step (a), the sequence is located between position 34294350 and 34299961 on human chromosome 18, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 49A is determined; and/or in step (a), the sequence is located between position 64574312 and 64618545 on human chromosome 18, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 50A is determined; and/or in step (a), the sequence is located between position 20218657 and 20308050 on human chromosome 21, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 51A is determined.