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A compelling genetic association with osteoarthritis (OA) of a functional SNP (rs143383, T/C) in the 5'-UTR of the GDF5 gene was recently reported in case-control cohorts from Japan and China. GDF5 is a pro-chondrogenic growth factor. The T-allele frequency of the gene was elevated in cases, with an odds ratio (OR) of 1.79, and in vitro functional studies demonstrated that this allele mediated a moderate but significant reduction in the activity of the GDF5 promoter in several cell lines. Our initial objective was to assess whether the SNP was also associated with OA in a broad European population by genotyping the SNP in 2487 cases and 2018 age-matched controls from the UK and Spain. The T-allele was associated with OA (P = 0.03, OR = 1.10) as was carrier status for this allele (P = 0.004, OR = 1.28), demonstrating that the SNP is associated with OA in two diverse ethnic groups, Asians and Europeans. We subsequently assessed the functional effect of the SNP on GDF5 allelic expression using RNA extracted from the cartilage of OA patients who had undergone joint-replacement surgery. The associated T-allele showed up to a 27% reduction in expression relative to the C-allele (P = 0.00007), revealing that the functional effect mediated by SNP rs143383 on GDF5 expression is active in patients who have severe disease up to the point at which they require surgery. A small but persistent imbalance of GDF5 expression throughout life therefore appears to render an individual more susceptible to OA.

A recent genetic association study has identified a microsatellite in the coding sequence of the asporin gene as a susceptibility factor for osteoarthritis (OA). Alleles of this microsatellite determine the variable number of aspartic acid residues in the amino-terminal end of the asporin protein. Asporin binds directly to the growth factor transforming growth factor beta and inhibits its anabolic effects in cartilage, which include stimulation of collagen and aggrecan synthesis. The OA-associated allele, with 14 aspartic acid residues, inhibits the anabolic effects of transforming growth factor beta more strongly than other asporin alleles, leading to increased OA liability. We have explored whether the association found in several cohorts of Japanese hip OA and knee OA patients was also present in Spanish Caucasians. We studied patients that had undergone total joint replacement for primary OA in the hip (n = 303) or the knee (n = 188) and patients with hand OA (n = 233), and we compared their results with controls (n = 294) lacking overt OA clinical symptoms. No significant differences were observed in any of the multiple comparisons performed, which included global tests of allele frequency distributions and specific comparisons as well as stratification by affected joint and by sex. Our results, together with reports from the United Kingdom and Greece, indicate that the stretch of aspartic acid residues in asporin is not an important factor in OA susceptibility among European Caucasians. It remains possible that lifestyle, environmental or genetic differences allow for an important effect of asporin variants in other ethnic groups as has been reported in the Japanese, but this should be supported by additional studies.