Human Molecular Genetics Advance Access originally published online on February 24, 2008
Human Molecular Genetics 2008 17(10):1497-1504; doi:10.1093/hmg/ddn038
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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
1 Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK 2 Laboratory for Statistical Analysis 3 Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, Tokyo, Japan 4 Department of Molecular Epidemiology 5 Department of Rheumatology 6 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands 7 The School of Translational Medicine, University of Manchester, Manchester, UK 8 Laboratorio de Investigacion and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain 9 Department of Biology 10 Department of Orthopaedics, University of Thessalia Medical School, Larissa, Greece 11 Institute for Biomedical Research and Technology, Larissa, Greece 12 The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China 13 Academic Rheumatology, City Hospital, University of Nottingham, Nottingham, UK
* To whom correspondence should be addressed at: Laboratory for Bone and Joint Diseases, SNP Research Center, Riken, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel/Fax: +81 354495393; Email: sikegawa{at}ims.u-tokyo.ac.jp
Received December 12, 2007; Accepted February 2, 2008
We have performed a meta-analysis combining data for more than 11 000 individuals. It provides compelling evidence for a positive association between a functional single-nucleotide polymorphism (SNP) in the 5'-UTR of GDF5 (+104T/C; rs143383) and osteoarthritis (OA) in European and Asian populations. This SNP has recently been reported to be associated with OA in Japanese and Han Chinese populations. Attempts to replicate this association in European samples have been inconclusive, as no association was found in the case–control cohorts from the UK, Spain and Greece when studied individually. However, the pooled data of UK and Spain found an association of the T-allele with an odds ratio (OR) of 1.10. Although the European studies had adequate power to replicate the original findings from the Japanese cohort (OR = 1.79), these results suggest that the role of the GDF5 polymorphism may not be as strong in Europeans. To clarify whether the European studies were hampered by insufficient power, we combined new data from the UK and the Netherlands with the three published studies of Europe and Asia. The results provide strong evidence of a positive association of the GDF5 SNP with knee OA for Europeans as well as for Asians. The combined association for both ethnic groups is highly significant for the allele frequency model (P = 0.0004, OR = 1.21) and the dominant model (P < 0.0001, OR = 1.48). These findings represent the first highly significant evidence for a risk factor for the development of OA which affects two highly diverse ethnic groups.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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