Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis

Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is characterized by degeneration of articular cartilage. Sulfation of extr acellular matrix proteins in articular cartilage is an important step in ma intaining normal cartilage metabolism. Two sulfation-related genes have bee n reported as the causal genes of severe chondrodysplasias: mutations in PA PSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epim etaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier famil y 26, member 2) cause diastrophic dysplasia. Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations i n these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility l oci for OA. We identified sequence polymorphisms in the coding and core pro moter regions of these genes and analyzed their potential association with knee OA within the Japanese population. Ten sequence polymorphisms were det ected in PAPSS2 and five in SLC26A2. An association analysis showed suggest ive association of one minor polymorphism in the promoter region of SLC26A2 . This 4-bp adenine deletion allele, del4A, was over-represented in knee OA (P = 0.043, odds ratio = 3.43) and is thought to confer a minor susceptibi lity to knee OA within the Japanese population. Haplotype analysis showed n o evidence of association with the two genes, however, excluding them as ma jor susceptibility loci for knee OA.