Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 6, 1231-1240, 08 May 2008
doi:10.1016/j.ajhg.2008.04.006
Article
Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis
Ana M. Valdes1, 
, 
, John Loughlin2, 3, Kirsten M. Timms4, Joyce J.B. van Meurs5, Lorraine Southam2, Scott G. Wilson6, Sally Doherty7, Rik J. Lories8, Frank P. Luyten8, Alexander Gutin4, Victor Abkevich4, Dongliang Ge9, Albert Hofman10, André G. Uitterlinden5, 10, Deborah J. Hart1, Feng Zhang1, Guangju Zhai1, Rainer J. Egli2, Michael Doherty7, Jerry Lanchbury4 and Tim D. Spector1
1 Twin Research Unit, St. Thomas' Hospital Campus, Kings College London School of Medicine, London SE1 7EH, UK
2 University of Oxford, Institute of Musculoskeletal Sciences, Oxford OX3 7LD, UK
3 Newcastle University, Institute of Cellular Medicine, Newcastle upon Tyne NE1 7RU, UK
4 Myriad Genetics, Inc., Salt Lake City, UT 84108, USA
5 Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, The Netherlands
6 School of Medicine & Pharmacology, University of Western Australia and Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009 WA, Australia
7 Academic Rheumatology, University of Nottingham, City Hospital Nottingham, Nottingham NG5 1PB, UK
8 Laboratory for Skeletal Development and Joint Disorders, Division of Rheumatology, Department of Musculoskeletal Sciences, Katholieke Universiteit Leuven, Leuven 3000, Belgium
9 Center for Population Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA
10 Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, Rotterdam 3015 GE, The Netherlands
Corresponding authorAbstract
Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 × 10−5 were estimated to have probabilities of being false positives ≤0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5′ to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio ORmh = 1.55 95% C.I. 1.30–1.85, p < 6.9 × 10−7). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p < 1.0 × 10−6). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.
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