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Definitions

• This invention relates to the identification of chromosomal regions linked to susceptibility to osteoarthritis using linkage and association analysis.
• Osteoarthritis is a debilitating disease involving degeneration of the articular cartilage of synovial joints 5 - 6 .
• OA Osteoarthritis
• OA has long been considered an inevitable consequence of ageing, it has become increasingly apparent that OA does have a genetic component.
• Early-onset forms of the disease are associated with several osteochondrodysplasias, rare diseases involving abnormal bone and cartilage development that are transmitted as Mendelian traits 7 .
• the OA in these conditions is secondary to the main dysplastic phenotype .
• the common late-onset form -of the disease idiopathic OA
• association mapping has been used in over a dozen examples of rare single gene traits, and particularly in genetically isolated populations such as Finland to fine map disease mutations. Nevertheless, association mapping is fundamentally different from straightforward linkage mapping because even though the degree of association between two markers or a marker and a disease mutation is proportional to the physical distance along the chromosome this relationship can be unpredictable because it is dependent on the allele frequencies of the markers, the history of the population and the age and number of mutations at the disease locus. For rare, highly penetrant single gene diseases there is usually one major founder chromosome in the population under study, making it relatively feasible to locate an interval that is smaller than one that can be defined by standard recombination events within living families.
• the resolution of this method in monogenic diseases in which there is one main founder chromosome is certainly less than 2cM, and in certain examples the resolution is down to 100 kb of DNA (Hastbacka et al . (1994) Cell 78,1-20).
• the present inventors have identified regions on chromosome 2q that may harbour susceptibility loci for OA. This region was identified following a two-stage non-parametric linkage analysis. The first stage involved a random screen of the genome using 272 microsatellite markers in 297 OA families. The second stage was more selective and involved genotyping an additional 184 families for those markers that demonstrated moderate evidence of linkage in stage 1. This revealed one microsatellite on chromosome 2 for which the evidence for linkage increased as the number of families studied increased. Finer mapping in and around this microsatellite was performed which provided enhanced evidence for linkage and enabled linked regions to be defined. Stratification analysis suggested that the chromosome 2 loci may have differential penetrance between males and females and between the two different joint groups examined (hips and knees) .
• Linkage on chromosome 2 may encompass three distinct loci: a locus close to D2S114, a locus in-between D2S2330 and D2S326 and a locus close to or in-between D2S117 and D2S325. None of the single or multipoint LOD scores for these three regions are particularly high, with the highest single point LOD score being 2.36 at marker D2S202 and the highest MLS
• ORFs Open reading frames
• Host gopher. hgmp . mrc .ac.uk
• Port 70 or URL: gopher : //gopher . hgmp .mrc . ac .us : 70/ or by anonymous ftp from
• the present invention relates to chromosomal regions linked to genetic sequences which affect susceptibilty to osteoarthritis .
• a first aspect of the present invention is a method for identifying individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and detecting the presence or absence of any one of the 190bp and 200bp alleles of D2S325 from chromosome 2.
• Another aspect of the present invention is a method for identifying male individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and detecting the presence or absence of any one of the 190bp and 200bp alleles of D2S325 from chromosome 2.
• Another aspect of the present invention is a method for identifying male individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and detecting the presence or absence of the 208bp allele of D2S117 from chromosome 2.
• a further aspect of the present invention is a method for identifying female individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and detecting the presence or absence of any one of the 192bp, 202bp and 208bp alleles of D2S117 from chromosome 2.
• a further aspect of the present invention is a method for identifying male individuals susceptible to osteoarthritis of the hip comprising obtaining a sample of genomic DNA and detecting the presence or absence of the 208 bp allele of D2S117 from chromosome 2.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening genomic libraries with sequence from any one of the 190bp and 200bp alleles of D2S325 and identifying open reading frames in regions adjacent to said allele.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening a genomic library from an individual who is homozygote for any one of the 190bp and 200bp alleles of D2S325 and identifying open reading frames in regions adjacent to said allele.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening a genomic library from an individual who is homozygote for any one of the 190bp and the 200bp alleles of D2S325 and identifying open reading frames located within 500 Kb of D2S325, or more preferably within 100 Kb of D2S325, or even more preferably within 50 Kb of D2S325 or most preferably within 10 Kb of D2S325.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising identifying open reading frames in regions ad acent to D2S325 and comparing said open reading frames in individuals carrying any one of the 190 bp and 200bp alleles of D2S325 with said open reading frames in individuals with other alleles of D2S325.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising identifying open reading frames located within 500 Kb of D2S325, or more preferably within 100 Kb of D2S325, or even more preferably within 50 Kb of D2S325 or most preferably within 10 Kb of D2S325 and comparing said open reading frames in individuals carrying any one of the 190 bp and 200 bp alleles of D2S325 with said open reading frames in individuals with other alleles of D2S325.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening genomic libraries with sequence from the 192bp and 202bp alleles of D2S117 and identifying open reading frames in regions adjacent to said allele.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening a genomic library from an individual who is homozygote for any one of the 192bp, the 202bp and the 208bp alleles of D2S117 and identifying open reading frames in regions adjacent to said allele
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening a genomic library from an individual who is homozygote for any one of the 192bp, 202bp and 208bp alleles of D2S117 and identifying open reading frames located within 500 Kb of D2S117, or more preferably within 100 Kb of D2S117, or even more preferably within 50 Kb of D2S117 or most preferably within 10 Kb of D2S117.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising identifying open reading frames in regions adjacent to D2S117 and comparing said open reading frames in individuals carrying any one of the 192bp, 202bp and 208bp alleles of D2S117 with said open reading frames in individuals with other alleles of D2S117.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising identifying open reading frames located within 500 Kb of D2S117, or more preferably within 100 Kb of D2S117, or even more preferably within 50 Kb of D2S117 or most preferably within 10 Kb of D2S117 and comparing said open reading frames in individuals carrying any one of the 192bp, 202bp and 208bp alleles of D2S117 with said open reading frames in individuals with other alleles of D2S117.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening genomic libraries with sequence from any one of the 190bp and 200bp alleles of D2S325 and identifying open reading frames located within 500 Kb of D2S325, or more preferably within 100 Kb of D2S325, or even more preferably within 50 Kb of D2S325 or most preferably within 10 Kb of D2S325.
• Another aspect of the present invention is a method for isolating genetic loci associated with susceptability to OA comprising screening genomic libraries with sequence from any one of the 192bp, 202bp and 208bp alleles of D2S117 and identifying open reading frames located within 500 Kb of
• D2S117 or more preferably within 100 Kb of D2S117, or even more preferably within 50 Kb of D2S117 or most preferably within 10 Kb of D2S117.
• Another aspect of the present invention is the use of the 190bp and 200bp alleles of D2S325 as markers for the identification of loci influencing susceptibility to OA.
• Another aspect of the present invention is the use of any one of the 192bp, 202bp and 208bp alleles of D2S117 as a marker for the identification of loci influencing susceptibility to OA.
• Another aspect of the present invention is a method for mapping loci which affect susceptability to OA by comparing genomic regions containing the 208 bp allele of D2S117 with genomic regions containing other alleles of D2S117.
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising a polymorphic marker, said region being located on chromosome 2q between D2S117 and D2S325, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis.
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis analysing a region of their genomic DNA comprising a polymorphic marker, said region being located on chromosome 2q between D2S117 and D2S325, and additionally analysing one or more of the following; a genomic region comprising the polymorphic marker D6S273 and a genomic region comprising the polymorphic marker DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis analysing a region of their genomic DNA comprising a polymorphic marker, said region being located on chromosome 2q between D2S202 and D2S72, and additionally analysing one or more of the following; a genomic region comprising the polymorphic marker D6S273 and a genomic region comprising the polymorphic marker DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising the polymorphic marker D2S114, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising the polymorphic marker D2S114, and additionally analysing one or more of the following; a genomic region comprising the polymorphic marker D6S273 and a genomic region comprising the polymorphic marker DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising a polymorphic marker, said region being located on chromosome 2q between D2S330 and D2S326, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising a polymorphic marker, said region being located on chromosome 2q between D2S330 and D2S326,and additionally analysing one or more of the following; a genomic region comprising the polymorphic marker D6S273 and a genomic region comprising the polymorphic marker DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising any one of the polymorphic markers; D2S202, D2S72, D3S1266, D4S231, D4S415, D6S260, D6S273, D6S286, D6S281, D7S669, D7S530, D11S907, D11S903, D11S901, D17S807, D17S789, DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing .
• LOD maximum log of the odds
• Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising any one of the polymorphic markers D6S273, DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
• LOD maximum log of the odds
• Another aspect of the present invention is a method for identifying loci conferring susceptibilty to osteoarthritis comprising screening a genomic library with genetic sequence derived from one or more of the following polymorphic markers; D2S202, D3S1266, D4S231, D4S415, D6S260, D6S273, D6S286, D6S281, D7S669, D7S530, D11S907, D11S903, D11S901, D17S807, D17S789, DXS1068 and identifying those isolated clones which additionally contain open reading frames
• Another aspect of the present invention is a method for identifying loci conferring susceptibilty to osteoarthritis comprising screening a genomic library with genetic sequence derived from one or more of the following polymorphic markers; D2S202, D3S1266, D4S231, D4S415, D6S260, D6S273, D6S286, D6S281, D7S669, D7S530, D11S907, D11S903, D11S901, D17S807, D17S789, DXS1068 and identifying open reading frames located within 500 Kb, more preferably within 100 Kb, even more preferably within 50 Kb or most preferably within 10 Kb of any of these polymorphic markers.
• Another aspect of the present invention is a method for identifying loci conferring susceptibilty to osteoarthritis comprising screening a genomic library with genetic sequence derived from one or more of the polymorphic markers D6S273, DXS1068 and identifying open reading frames located within 500 Kb, more preferably within 100 Kb, even more preferably within 50 Kb or most preferably within 10 Kb of either of these polymorphic markers.
• Figure 1 shows a multipoint log of the odds (LOD) analysis on the unstratified data.
• Figure 2 shows a multipoint log of the odds (LOD) analysis on stratified data from male sibling pairs only.
• Figure 3 shows a multipoint log of the odds (LOD) analysis on stratified data from hip pairs only.
• Figure 4 shows a multipoint log of the odds (LOD) analysis on stratified data from male/hip pairs only.
• the present inventors collected 481 families in which at least two siblings have undergone joint replacement surgery of the hip or knee for severe, end-stage idiopathic OA (Table 1) . Due to the late onset of the disease, none of these families contained parents who could participate in the study. In stage 1, 272 microsatellite markers were genotyped in 297 of the 481 families. The microsatellites were essentially those used by Reed et al B with the replacement of certain markers that amplified unreliably. Sixteen markers from stage 1 had evidence of linkage at p ⁇ 0.05 (Table 2) . These markers were then genotyped in the remaining 184 families.
• D2S72 was genotyped in stage 2 there was further evidence for linkage with a p-value of 0.024.
• results were stratified into six categories: those families that were affected female-only pairs (196 families) , affected male-only pairs (male and/or female) (54 families) , affected female-only pairs who had undergone hip replacement but not knee replacement (female/hip pairs) (132 families) and affected male-only pairs who had undergone hip replacement but not knee replacement (male/hip pairs) (72 families) (Table 1) .
• the linkage to chromosome 2 was restricted to pairs with hip-only disease with a p-value of 0.005 at D2S202 in hip-only pairs versus 0.34 in knee-only pairs. Again, however, the absence of linkage in knee-only pairs could be due to their relatively low number.
• the MMLS in hip-only pairs was 2.07, also in- between markers D2S117 and D2S72 ( Figure 3) .
• This linkage in hip-only pairs was restricted to males, with a p-value at D2S202 of 0.0016 in male/hips versus 0.20 in female/hips.
• the MMLS in male/hips was 1.54, also in-between markers D2S117 and D2S72 ( Figure 4) .
• Leppavuon et al 13 have also reported linkage to chromosome 2q in 42 affected sib pairs who have distal interphalangeal (DIP) OA, with a maximum LOD score of 4.06. They do not report the markers that they used in their study but instead give a cytogenetic location of 2ql2-ql4.2. This is at least 70cM proximal to our major linkage at D2S202/D2S72 , which cytogenetically map to 2q31.
• D2S202/D2S72 distal interphalangeal
• D6S273 maps close to the HLA complex on chromosome 6p and
• Pattrick et al li have reported association of nodal OA with a specific allele of the HLA-A gene. Furthermore, the COL11A2 gene, which encodes the 2 chain of the cartilage collagen type XI, is tightly linked to the HLA complex. This gene has been linked to and found to harbour causal mutations for the osteochondrodysplasia Stickler syndrome 15 . This syndrome has severe, precocious OA as one of its many phenotypic components .
• Leppavuori et al 13 have reported linkage of DIP OA to chromosome 2ql2-ql4.2. A second linkage that they also reported maps to cytogenetic band Xpll.3. DXS1068 also maps to Xpll.3.
• chromosome 2 markers were then tested for association.
• D2S325 demonstrated positive disequilibrium in male-only pairs with global ⁇ 2 2df ⁇ 6.89 (0.05>p>0.02) .
• This disequilibrium was accounted for by the significant (0.05>p>0.02) distorted transmission of two alleles (200bp allele [allele 1] as listed in the GDB and 190bp allele [allele 4] as listed in the GDB) , one of which (the 190 bp allele) demonstrated excess transmission.
• the positive disequilibrium in the female- only pairs was accounted for by the significant distorted transmission of three alleles, two of which demonstrated excess transmission (0.05>p>0.01) (192 bp allele [allele 3] as listed in the GDB and 202 bp allele [allele 6] as listed in the GDB) whilst the third demonstrated reduced transmission (0.05>p>0.02) (208bp allele [allele 9] as listed in the GDB) .
• Families were recruited which contained at least two siblings two had undergone one or more total hip (THR) and/or total knee replacements (TKR) for idiopathic OA. Clinically these patients are at the severe end of the OA spectrum with advanced radiological changes. The idiopathic diagnosis was supported by clinical, radiological, operative and histological findings: patients who had undergone joint replacement surgery secondary to other factors, such as intra-articular fracture or rheumatoid arthritis, were excluded. Families were ascertained at three centres within the United Kingdom: The Nuffield Orthopaedic Centre in Oxford, the Royal Orthopaedic Hospital in Birmingham and Musgrave Park Hospital in Harbor. Idiopathic OA is typically a late-onset disease and parents of affected siblings are rarely available.
• THR total hip
• TKR total knee replacements
• the 481 families used in the study None contained a parent who was able to participate. We therefore collected siblings who had not undergone joint replacement to assist in the determination of identity-by-descent (IBD) allele transmittance .
• the 481 families were comprised of 1052 affected individuals plus an additional 302 unaffected siblings (Table 1). 59.3% of the affected individuals were female, 40.7% were male. For each individual, 25ml of venous blood was collected into EDTA tubes and DNA was extracted by conventional techniques.
• microsatellite markers were essentially the panel used by Reed et al 8 .
• the additional microsatellite markers used to provide a denser coverage of chromosome 11 were obtained from the GDB or from the ABI Prism Linkage Mapping Set (Version 2) .
• the markers were amplified using conventional conditions with either the forward or the reverse primer in a PCR pair fluorescently labelled.
• the amplification products were electrophoresed through 6% acrylamide using an Applied Biosystems 377
• Non parametric linkage analysis was performed using the SIBPAIR module of the ANALYZE package 18 .
• This module is able to use data from siblings to determine identity-by-descent (IBD) allele transmittance . In this way it is appropriate to our study since we were unable to collect parents of our affected siblings. In the linkage analysis, siblings who had not undergone joint replacement were given a clinical status of unknown.
• the SIBPAIR module produces a singlepoint LOD score and its asymptotic P-value. Allele frequencies were calculated from the input data using either GAS or Downfreq (part of the ANALYZE package) .
• ASPEX which calculates its own allele frequencies from the data set, using a maximum likelihood method, and employs marker information across the chromosome simultanenously 19 .
• ASPEX produces maximum LOD score (MLS) under an additive model. In addition it produces an exclusion map along the entire chromosome based on a fixed value for ⁇ .
• a hip-only pair were siblings who had each undergone joint replacement of the hip only (mono or bi-lateral) whilst a knee-only pair had undergone joint replacement of the knee only (mono or bi-lateral) . If an affected pair was composed of one sibling who had undergone joint replacement of one joint type only (hip or knee) whilst their affected sibling had undergone joint replacement of the hip and knee then that pair were excluded. For an affected trio, if a pair of the siblings had both undergone joint replacement of the same joint type only (hip or knee) whilst the third sibling had undergone both hip and knee replacement, then the concordant pair were used in the stratification study whilst the third sibling was given an unaffected status in the linkage analysis. Again, we were attempting to maximise our determination of IBD allele transmittance.
• Table 1 a) The families used in stages 1 and 2 together with the combined total figure. Also listed are the pairs concordant for different stratification criteria, b) A list of the individuals in the study. a)
• stage 1 excluding the chromosome 2 and 1 1 markers

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