Letter abstract
Nature Genetics 39, 529 - 533 (2007)
Published online: 25 March 2007 | doi:10.1038/2005
A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis
Yoshinari Miyamoto1,12, Akihiko Mabuchi1,12, Dongquan Shi2, Toshikazu Kubo3, Yoshio Takatori4, Susumu Saito5,11, Mikihiro Fujioka3, Akihiro Sudo6, Atsumasa Uchida6, Seizo Yamamoto7, Koichi Ozaki8, Masaharu Takigawa9, Toshihiro Tanaka8, Yusuke Nakamura10, Qing Jiang2 & Shiro Ikegawa1
Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide1, 2, 3. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease1, 4, 5. 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 
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.
- Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
- The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital affiliated with the Medical School of Nanjing University, Zhongshan Road 321, Nanjing 210008, Jiangsu, China.
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
- Department of Orthopaedic Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- Department of Orthopaedic Surgery, Sumitomo Hospital, Nakanoshima 5-3-20, Kita-ku, Osaka 530-0005, Japan.
- Department of Orthopaedic Surgery, Mie University Faculty of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
- Department of Orthopedic Surgery, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
- Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 5-1-2 Shikata-cho, Okayama 700-8525, Japan.
- Laboratory for Genotyping, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
- Present address: Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Osaka 591-8025, Japan.
- These authors contributed equally to this work.
Correspondence to: Shiro Ikegawa1 e-mail: sikegawa@ims.u-tokyo.ac.jp
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