Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts

Objective: To examine the association of genetic variation in key players in the Wnt signaling pathway with aspects of osteoarthritis (OA) in two population-based cohort studies: the Rotterdam Study and the Chingford Study. Methods: Radiographic OA (ROA) was defined as a Kellgren/Lawrence score (K/L) score ≥ 2 for the knee and hip. Total hip replacement (THR) was scored. Hand OA was defined as presence of ROA (K/L ≥ 2) in two out of three hand joint groups [distal interphalangeal (DIPs), proximal interphalangeal (PIPs), first carpometacarpal (CMC1)/trapezio-scaphoid joint (TS)] of each hand. The concentration of urinary C-terminal cross-linked telopeptide of type II collagen (CTX-II) was standardized to the total urine creatinine. Genotypes for the amino acid variants, Arg200Trp and Arg324Gly of Frizzled-Related protein gene (FRZB), Ala1330Val of Low-density lipoprotein receptor-related protein 5 (LRP5) and Ile1062Val of Low-density lipoprotein receptor-related protein 6 (LRP6), were obtained using the Taqman allelic discrimination assay. A meta-analysis was performed for the FRZB Arg324Gly polymorphism and hip- and knee-OA using RevMan version 4.3. Results: No consistent associations were observed between the FRZB, LRP5 and LRP6 amino acid variants and radiographic hip-, knee-, or hand-OA or THR, in either study population. While power was limited for most studies to date, a meta-analysis of all published studies regarding the FRZB Arg324Gly polymorphism was performed for hip- and knee-OA seperately. This showed no significant associations between the Gly324 allele and risk for hip- or knee OA, although there was large heterogeneity between studies for hip OA in females. Conclusion: No association was seen between FRZB, LRP5 and LRP6 variants with radiographic osteoarthritic outcomes in two population-based cohorts. In future studies, increased power and standardization of OA-phenotypes are highly recommended for replication studies and to allow meta-analysis.

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