title: An SNP in the 5'-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage.
abstract: 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.
authors.affiliation: Botnar Research Centre, University of Oxford, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.forename: Julio
authors.initials: J
authors.lastname: Rodriguez-Lopez
authors.forename: James M
authors.initials: JM
authors.lastname: Wilkins
authors.forename: Manuel
authors.initials: M
authors.lastname: Pombo-Suarez
authors.forename: Sarah
authors.initials: S
authors.lastname: Snelling
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gomez-Reino
authors.forename: Kay
authors.initials: K
authors.lastname: Chapman
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002681:China; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055428:Growth Differentiation Factor 5; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D020641:Polymorphism, Single Nucleotide; D013030:Spain; D006113:United Kingdom; D044465:White People
chemical_list: D020121:5' Untranslated Regions; D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5