Journal Article

A functional SNP in <i>EDG2</i> increases susceptibility to knee osteoarthritis in Japanese

Hideyuki Mototani, Aritoshi Iida, Masahiro Nakajima, Tatsuya Furuichi, Yoshinari Miyamoto, Tatsuhiko Tsunoda, Akihiro Sudo, Akihiro Kotani, Atsumasa Uchida, Kouichi Ozaki, Yoshiya Tanaka, Yusuke Nakamura, Toshihiro Tanaka, Kohei Notoya and Shiro Ikegawa

in Human Molecular Genetics

Volume 17, issue 12, pages 1790-1797
Published in print June 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn069
A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese

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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 × 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.

Journal Article.  4338 words.  Illustrated.

Subjects: Genetics and Genomics

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