A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis.
Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.
Miyamoto
Yoshinari
Y
Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Mabuchi
Akihiko
A
Shi
Dongquan
D
Kubo
Toshikazu
T
Takatori
Yoshio
Y
Saito
Susumu
S
Fujioka
Mikihiro
M
Sudo
Akihiro
A
Uchida
Atsumasa
A
Yamamoto
Seizo
S
Ozaki
Koichi
K
Takigawa
Masaharu
M
Tanaka
Toshihiro
T
Nakamura
Yusuke
Y
Jiang
Qing
Q
Ikegawa
Shiro
S
D020121:5' Untranslated Regions; D044466:Asian People / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055428:Growth Differentiation Factor 5; D006801:Humans; D015810:Linkage Disequilibrium; D010003:Osteoarthritis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D014162:Transfection
D020121:5' Untranslated Regions; D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5