Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis

Abstract

Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 x 10(-5) were estimated to have probabilities of being false positives <or=0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5' to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio OR(mh) = 1.55 95% C.I. 1.30-1.85, p < 6.9 x 10(-7)). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p < 1.0 x 10(-6)). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.

Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women

“…A recent genome-wide association study identified several regions of the genome that are potentially implicated in knee OA in women. One of the markers identified was located in chromosome 15 (6), and although the association was modest (P Ͻ 0.08 in replication samples), it mapped 46 kb 3Ј of the acidic leucine-rich nuclear phosphoprotein 32 (ANP32A) gene. ANP32A encodes a tumor suppressor (7) known to associate with both axin 1 (8,9) and phosphatase 2A (PPP2CA [10]), both of which are crucial for regulating the Wnt pathway (8,11).…”

Recent advances in association studies of osteoarthritis susceptibility genes

“…Valdes et al 19 examined knee OA susceptibility genes in women using pooled DNAs from 357 cases and 285 controls from the UK Caucasians and 410 000 SNPs in the Illumina550 Duo array (Illumina, San Diego, CA, USA). They checked replication of the top 28 SNPs in the UK, USA and Dutch Caucasian cohorts (a total of 1177 cases and 2355 controls).…”

Génétique des maladies du cartilage (arthrose, chondrodysplasies)

“…La méthode de GWAS, réalisée par le consortium TREAT-OA, a aussi permis d'identifier une association entre le polymorphisme rs716508 situé dans le premier intron du gène ataxin 2 binding protein gene 1 gene (A2BP1) et l'arthrose digitale dans différentes cohortes [16], ainsi qu'entre les gènes prostaglandin-endoperoxyde synthase 2 gène (PTGS2) et cyclooxygénase-2 et la gonarthrose (cf. infra) [17]. Une cohorte anglaise d'arthrose basée sur le recours à la prothèse est également en cours.…”