Genomic approaches to bone and joint diseases. Current status of genetic study of osteoarthritis

Abstract

Osteoarthritis (OA) is the most common human arthritis characterized by the degeneration of articular cartilage. OA is a major concern for aging societies worldwide. Epidemiological and genetic studies have revealed that OA is a polygenic disease. Growth differentiation factor 5 (GDF5 ) is a good candidate gene for OA. We have recently found a novel ENU-mutagenesis mouse that presents early onset OA in the elbow joint in homozygotes. Through case-control association studies, we have found that GDF5 is associated with OA in the Japanese population. A single nucleotide polymorphism (SNP) in the 5'-UTR of GDF5 (+ 104T/C ; rs143383) showed a significant association (p = 1.8 x 10(- 13)) in hip OA. This association was replicated for knee OA in both Japanese and Han Chinese populations as well as in West European Caucasians. This SNP is located in the core promoter of GDF5 and exerted allelic differences on transcription, with the susceptibility allele showing reduced transcriptional activity. Our findings implicate GDF5 as a susceptibility gene for OA in worldwide populations and suggest that decreased GDF5 expression is involved in OA pathogenesis.