Human Molecular Genetics Advance Access published online on July 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm174
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A 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
1 University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 2 Laboratorio de Investigación and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain 3 Department of Medicine, University of Santiago, and Laboratorio de Investigación and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
* To whom correspondence should be addressed. University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, OX3 8LL, UK. Tel: +44 1865227961; Fax +44 1865227966; Email: john.loughlin{at}ndos.ox.ac.uk
Received June 8, 2007; Revised July 2, 2007; Accepted July 2, 2007
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.
The author wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R B A Vaes, F Rivadeneira, J M Kerkhof, A Hofman, H A P Pols, A G Uitterlinden, and J B J van Meurs Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study Ann Rheum Dis, November 1, 2009; 68(11): 1754 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Savas and G. Liu Studying Genetic Variations in Cancer Prognosis (and Risk): A Primer for Clinicians Oncologist, July 1, 2009; 14(7): 657 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kakuta, N. Ueki, Y. Kinouchi, K. Negoro, K. Endo, E. Nomura, S. Takagi, S. Takahashi, and T. Shimosegawa TNFSF15 transcripts from risk haplotype for Crohn's disease are overexpressed in stimulated T cells Hum. Mol. Genet., March 15, 2009; 18(6): 1089 - 1098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Martinez, J Varade, J R Lamas, M Fernandez-Arquero, J A Jover, E G de la Concha, B Fernandez-Gutierrez, and E Urcelay GDF5 Polymorphism associated with osteoarthritis: risk for rheumatoid arthritis Ann Rheum Dis, September 1, 2008; 67(9): 1352 - 1353. [Full Text] [PDF]
|
|
|
|
|
|
K. Chapman, A. Takahashi, I. Meulenbelt, C. Watson, J. Rodriguez-Lopez, R. Egli, A. Tsezou, K. N. Malizos, M. Kloppenburg, D. Shi, et al. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility Hum. Mol. Genet., May 15, 2008; 17(10): 1497 - 1504. [Abstract] [Full Text] [PDF]
|
|