The genetic epidemiology of human primary osteoarthritis: current status

Osteoarthritis (OA) is a common disease characterised by the degeneration of the cartilage of synovial joints such as the hip and knee. In the past ten years a large number of twin-pair, sibling-risk and segregation studies have been conducted on the disease, and these have revealed a major genetic component that is transmitted in a nonmendelian manner. OA therefore fits best into the complex, multifactorial class of common diseases. With a genetic component established, genome-wide linkage scans were performed, and these uncovered several genomic intervals likely to harbour OA susceptibility. In the past few years these intervals have started to yield genes containing OA-associated variants. This is therefore a very exciting period in the molecular genetic analysis of this common disease. The genes that have so far been implicated in susceptibility include the interleukin 1 gene (IL1) cluster at chromosome 2q11.2-q13, the matrilin 3 gene (MATN3) at 2p24.1, the IL-4 receptor alpha-chain gene (IL4R) at 16p12.1, the secreted frizzled-related protein 3 gene (FRZB) at 2q32.1, the metalloproteinase gene ADAM12 at 10q26.2 and, most recently, the asporin gene (ASPN) at 9q22.31. The evidence for involvement of these genes in OA is more compelling for some than others, with the IL1 and ASPN associations being the most convincing to date. It is imperative that the veracity of each of the associations be tested by genotyping additional cohorts and that their global relevance be assessed by genotyping OA cohorts from different ethnic backgrounds. The gene products of IL1, IL4R, FRZB and ASPN regulate cartilage chondrocyte differentiation and survival, and their effects on the chondrocyte are potentially amenable to therapeutic intervention. The latest genetics is therefore providing new insights for the development of novel OA treatments.