Human Molecular Genetics Advance Access published online on March 6, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn069
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A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese
1 Laboratory for Bone and Joint Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 2 Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takada Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan 3 Laboratory for Pharmacogenetics, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 4 Laboratory for Medical Informatics, RIKEN SNP Research Center, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan 5 Department of Orthopaedic Surgery, Mie University Faculty of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan 6 Department of Orthopaedic Surgery, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan 7 Laboratory for Cardiovascular Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 8 First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan 9 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
* To whom correspondence should be addressed. Shiro Ikegawa, M.D., Ph.D. Laboratory for Bone and Joint Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tel & Fax: +81-3-5449-5393 E-mail: sikegawa{at}ims.u-tokyo.ac.jp
Received November 19, 2007; Revised March 4, 2008; Accepted March 4, 2008
Osteoarthritis (OA) is the most common form of arthritis and is characterized by the gradual loss of articular cartilage. Several OA-susceptibility genes have been identified; however, there are few pharmaceutical targets that can be targeted with small-molecule compounds. To investigate whether a susceptibility gene for OA exist among G protein-coupled receptors (GPCRs), we performed step-wise association study for 167 SNPs in 44 GPCR genes that were present in cartilage. Through step-wise association study, a SNP located in the promoter region of EDG2 (endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor, 2) (–2,820G/A; rs10980705) showed significant association with knee OA in two independent populations (pooled P=2.6 x 10–5). Luciferase assay and electrophoretic mobility shift assay indicate that this SNP exerts an allelic difference on transcriptional activity and DNA binding in synovial cells, with the susceptibility allele showing increased activity and binding. EDG2 encodes a lysophosphatidic acid (LPA) receptor dominantly expressed in the synovium. LPA increased expression of inflammatory cytokines and matrix metalloproteases (MMPs) in synovial cells. Our findings suggest that the LPA-EDG2 signal is involved in the pathogenesis of OA via catabolic process.
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