Human Molecular Genetics Advance Access originally published online on March 6, 2008
Human Molecular Genetics 2008 17(12):1790-1797; 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 2 Laboratory for Pharmacogenetics 3 Laboratory for Cardiovascular Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 4 Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takada Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan 5 Laboratory for Medical Informatics, RIKEN SNP Research Center, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan 6 Department of Orthopaedic Surgery, Mie University Faculty of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan 7 Department of Orthopaedic Surgery, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, 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 at: Laboratory for Bone and Joint Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel/Fax: +81 354495393; E-mail: sikegawa{at}ims.u-tokyo.ac.jp
Received November 19, 2007; 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 exists among G-protein-coupled receptors (GPCRs), we performed a stepwise association study for 167 single nucleotide polymorphisms (SNPs) in 44 GPCR genes that were present in cartilage. Through the stepwise association study, an SNP located in the promoter region of EDG2 [endothelial differentiation, lysophosphatidic acid (LPA) GPCR, 2] (–2,820G/A; rs10980705) showed significant association with knee OA in two independent populations (pooled P = 2.6 x 10–5). Luciferase and electrophoretic mobility shift assays 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 an LPA receptor dominantly expressed in the synovium. The LPA receptor increased the expression of inflammatory cytokines and matrix metalloproteases in synovial cells. Our findings suggest that the LPA–EDG2 signal is involved in the pathogenesis of OA via catabolic process.