A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese.
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.
Mototani
Hideyuki
H
Laboratory for Bone and Joint Diseases, RIKEN SNP Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Iida
Aritoshi
A
Nakajima
Masahiro
M
Furuichi
Tatsuya
T
Miyamoto
Yoshinari
Y
Tsunoda
Tatsuhiko
T
Sudo
Akihiro
A
Kotani
Akihiro
A
Uchida
Atsumasa
A
Ozaki
Kouichi
K
Tanaka
Yoshiya
Y
Nakamura
Yusuke
Y
Tanaka
Toshihiro
T
Notoya
Kohei
K
Ikegawa
Shiro
S
D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism
D049368:Receptors, Lysophosphatidic Acid