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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.

Original publication

DOI

10.1093/hmg/ddm174

Type

Journal article

Journal

Human molecular genetics

Publication Date

09/2007

Volume

16

Pages

2226 - 2232

Addresses

Botnar Research Centre, University of Oxford, UK.

Keywords

Cartilage, Articular, Humans, Osteoarthritis, Genetic Predisposition to Disease, Bone Morphogenetic Proteins, 5' Untranslated Regions, Gene Expression Regulation, Polymorphism, Single Nucleotide, Alleles, Aged, Aged, 80 and over, Middle Aged, Asian Continental Ancestry Group, European Continental Ancestry Group, China, Japan, Spain, Female, Male, Growth Differentiation Factor 5, United Kingdom