OBJECTIVE: Osteoarthritis (OA), characterized by late-onset degeneration of articular cartilage, is recognized to have a genetic component. We examined the role of 26 single-nucleotide polymorphisms (SNPs) from 24 candidate genes in OA susceptibility and progression. METHODS: We compared human complementary DNA libraries from OA-affected and normal cartilage and synovium and selected 22 genes in addition to the estrogen receptor alpha and vitamin D receptor genes. Based on the availability of polymorphisms, we proceeded to test whether genetic variation at those genes affected susceptibility to or progression of radiographic knee OA over a 10-year period in 749 women (mean age 64 years) from the longitudinal Chingford Study. RESULTS: After adjusting for age and body mass index, we observed significant associations at ADAM12, BMP2, CD36, COX2, and NCOR2 with 3 OA susceptibility traits (presence/absence of joint space narrowing [JSN], presence/absence of osteophytes, and Kellgren/Lawrence [K/L] score). For the OA progression traits (change over 10 years in the K/L score, osteophyte grade, and JSN grade), we found significant associations with ADAM12, CILP, OPG, and TNA. Overall, we observed 15 associations with nominal significance (P < 0.05) and, by permutation analysis, found that such a number would be observed by chance only 3.8% of the time. Although these tests require replication, the stronger genetic associations observed are unlikely to be attributable simply to multiple comparisons. CONCLUSION: Our results suggest that OA severity and progression have a multigenic and feature-specific nature. These findings should encourage the development of genetic diagnostics for OA progression based on multiple SNPs and help unravel some of the complex disease mechanisms in OA.
OBJECTIVE: Osteoarthritis (OA), characterized by late-onset degeneration of articular cartilage, is recognized to have a genetic component. We examined the role of 26 single-nucleotide polymorphisms (SNPs) from 24 candidate genes in OA susceptibility and progression. METHODS: We compared human complementary DNA libraries from OA-affected and normal cartilage and synovium and selected 22 genes in addition to the estrogen receptor alpha and vitamin D receptor genes. Based on the availability of polymorphisms, we proceeded to test whether genetic variation at those genes affected susceptibility to or progression of radiographic knee OA over a 10-year period in 749 women (mean age 64 years) from the longitudinal Chingford Study. RESULTS: After adjusting for age and body mass index, we observed significant associations at ADAM12, BMP2, CD36, COX2, and NCOR2 with 3 OA susceptibility traits (presence/absence of joint space narrowing [JSN], presence/absence of osteophytes, and Kellgren/Lawrence [K/L] score). For the OA progression traits (change over 10 years in the K/L score, osteophyte grade, and JSN grade), we found significant associations with ADAM12, CILP, OPG, and TNA. Overall, we observed 15 associations with nominal significance (P < 0.05) and, by permutation analysis, found that such a number would be observed by chance only 3.8% of the time. Although these tests require replication, the stronger genetic associations observed are unlikely to be attributable simply to multiple comparisons. CONCLUSION: Our results suggest that OA severity and progression have a multigenic and feature-specific nature. These findings should encourage the development of genetic diagnostics for OA progression based on multiple SNPs and help unravel some of the complex disease mechanisms in OA.
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