Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.

摘要: Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in (OA) specifically HOA have yielded only few loci, which partly explained by heterogeneity OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), proxy for cartilage thickness an important underlying intermediate trait HOA. In GWAS 6,523 individuals hip-JSW, identified G allele rs12982744 chromosome 19p13.3 to be associated 5% larger JSW (P = 4.8 × 10−10). The was replicated 4,442 from three United Kingdom cohorts overall meta-analysis P value 1.1 10−11. SNP also strongly 12% reduced risk 1 10−4). located DOT1L gene, evolutionarily conserved histone methyltransferase, recently as potentially dedicated enzyme Wnt target-gene activation leukemia. Immunohistochemical staining protein mouse limbs supports role chondrogenic differentiation adult articular cartilage. expressed chondrocytes. Silencing Dot1l inhibited chondrogenesis vitro. knockdown reduces proteoglycan collagen content, mineralization during chondrogenesis. ATDC5 model system, interacts TCF signaling. These data are further step better understand Wnt-signaling homeostasis. may represent therapeutic target OA.