Human Molecular Genetics Advance Access originally published online on January 30, 2009
Human Molecular Genetics 2009 18(8):1518-1523; doi:10.1093/hmg/ddp053
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Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations
1 Department of Molecular Epidemiology 2 Department of Rheumatology 3 Department of Clinical Epidemiology, Leiden University Medical Center, Postzone S-05-P, PO Box 9600, 2300 RC, Leiden, The Netherlands 4 Botnar Research Centre, Nuffield Orthopaedic Center, Institute of Musculoskeletal Sciences, University of Oxford, OX3 7LD Oxford, UK 5 Laboratorio Investigacion and Rheumatology Unit, Hospital Clinico Universitario Santiago, 15706 Santiago de Compostela, Spain 6 The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, Jiangsu, People's Republic of China 7 Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing 210061, Jiangsu, People's Republic of China 8 Department of Biology and Genetics 9 Department of Orthopaedics 10 Institute for Biomedical Research and Technology, University of Thessaly, Larissa, Greece 11 Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo 108-8639, Japan 12 Department of Medicine, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain 13 Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
* To whom correspondence should be addressed. Tel: +31 71 526 9734; Fax: +31 71 526 8280; Email: i.meulenbelt{at}lumc.nl
Received December 9, 2008; Revised January 26, 2009; Accepted January 26, 2009
Recently, through a genome wide association study in Japanese knee osteoarthritis (OA) cases, a previously unknown gene, DVWA, was identified. The non-synonymous single nucleotide polymorphism (SNP) rs7639618 was subsequently found to be consistent and most significantly associated in Japanese and Han Chinese knee OA studies and functional relevant. Here, the association of the DVWA polymorphisms (rs7639618, rs11718863 and rs9864422) was genotyped in 1120 knee OA cases, 1482 hip OA cases and 2147 controls, all of white European descent from the Netherlands, the UK, Spain and Greece. Random effect DerSimonian and Laird meta-analyses were performed to assess the association in the different strata. To assess a more global effect, the original Japanese and Chinese data were included with the European. The meta-analyses provided evidence for global association of rs7639618 with knee OA with an odds ratio (OR) of 1.29, 95% confidence interval (CI) of 1.15–1.45 and a P-value of 2.70 x 10–5. This effect, however, showed moderate heterogeneity, and rs7639618 was not independently associated with knee OA in Europeans, with an OR of 1.16, 95% CI of 0.99–1.35 and a P-value of 0.063. Furthermore, no association was observed with hip OA in Europeans, with a P-value of 0.851. Our results suggest that there may be global relevance for the DVWA SNP rs7639618 among knee OA cases, however, the apparent lower effect size in combination with the higher risk allele frequency in the European samples highlights again the ethnic differences in effects of discovered OA susceptibility genes.