Abstract
Primary osteoarthritis (OA) is a common late-onset disease that exhibits complex genetic transmittance. A previous genome-wide linkage scan of OA affected sibling pair families (ascertained by total joint replacement surgery) identified a region of suggestive linkage on chromosome 6, with a maximum multipoint-LOD score (MLS) of 2.9 in 194 families containing sibling pairs concordant for total hip replacement (THR-families). However, up to 50 cM of the chromosome had a multipoint-LOD score >2.0, vvindicating that the susceptibility locus was poorly mapped. We have now genotyped chromosome 6 to a higher density in an expanded cohort of 378 THR-families. We obtained an MLS of 2.8 to an 11.4 cM interval defined by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p-telomere. Stratification by gender revealed that this linkage was completely accounted for by female THR-families (n=146), with an MLS of 4.0 and with the highest two-point LOD score being 4.6 for marker D6S1573 (75.9 cM). The 11.4 cM interval just encompasses the candidate gene COL9A1 (81.9 cM). We identified and then genotyped twenty common single nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from our female THR-families and in 215 age-matched female controls. No SNP allele, genotype or haplotype demonstrated association to disease. Overall, we have narrowed the chromosome 6 OA susceptibility locus to a point at which linkage disequilibrium/association analysis is feasible, we have demonstrated that this locus is female specific, and found no evidence that COL9A1 encodes for the susceptibility.
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Acknowledgements
This work was funded by The Arthritis Research Campaign, The Wellcome Trust and the Nuffield Foundation (to J Loughlin), and by the Arthritis Foundation, the Academy of Finland, Louisiana Gene Therapy Research Consortium (New Orleans, LA, USA) and HCA-The Health Care Company (Nashville, TN, USA) (to L Ala-Kokko). J Loughlin is an Arthritis Research Campaign Fellow. We thank Professor Andrew Carr, Dr Jai Chitnavis and Ms Kim Clipsham who organised the collection of the patient and family samples used in this study. That collection was partly funded by The Wishbone Trust.
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Loughlin, J., Mustafa, Z., Dowling, B. et al. Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6. Eur J Hum Genet 10, 562–568 (2002). https://doi.org/10.1038/sj.ejhg.5200848
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DOI: https://doi.org/10.1038/sj.ejhg.5200848
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