Letter | Published:

A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis

Nature Genetics volume 39, pages 529533 (2007) | Download Citation



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.

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We thank individuals for participating the study. We also thank K. Toyoshima, A. Kotani, K. Nakamura, A. Fukuda, A. Kawakami, H. Mototani and E. Nakashima for help in collecting samples and performing the experimental study and Y. Takanashi and T. Kusadokoro for technical assistance.

Author information

Author notes

    • Susumu Saito

    Present address: Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Osaka 591-8025, Japan.

    • Yoshinari Miyamoto
    •  & Akihiko Mabuchi

    These authors contributed equally to this work.


  1. Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Yoshinari Miyamoto
    • , Akihiko Mabuchi
    •  & Shiro Ikegawa
  2. 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.

    • Dongquan Shi
    •  & Qing Jiang
  3. Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

    • Toshikazu Kubo
    •  & Mikihiro Fujioka
  4. Department of Orthopaedic Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

    • Yoshio Takatori
  5. Department of Orthopaedic Surgery, Sumitomo Hospital, Nakanoshima 5-3-20, Kita-ku, Osaka 530-0005, Japan.

    • Susumu Saito
  6. Department of Orthopaedic Surgery, Mie University Faculty of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

    • Akihiro Sudo
    •  & Atsumasa Uchida
  7. Department of Orthopedic Surgery, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.

    • Seizo Yamamoto
  8. Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Koichi Ozaki
    •  & Toshihiro Tanaka
  9. 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.

    • Masaharu Takigawa
  10. Laboratory for Genotyping, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Yusuke Nakamura


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Y.M. performed the Japanese knee osteoarthritis association study and prepared the manuscript. A.M. performed the hip association study, in vitro functional assay and prepared the manuscript. D.S. performed the Chinese association study. T.K., Y.T., S.S., M.F., A.S., A.U., S.Y., K.O. and Y.N. managed DNA sample and clinical information, and contributed data interpretation. K.O. and M.T. contributed to cell experiments. T.T. contributed to data analysis and manuscript preparation. Q.J. managed the Chinese association study. S.I. planned and supervised the whole project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shiro Ikegawa.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Confirmation of the allelic difference of rs143383 (+104C/T) in OUMS-27 and HeLa cells

  2. 2.

    Supplementary Table 1

    Initial association of GDF5 with osteoarthritis of the hip joint

  3. 3.

    Supplementary Table 2

    Replication of association of GDF5 with osteoarthritis of the hip joint in an independent population

  4. 4.

    Supplementary Table 3

    List of polymorphisms in GDF5 and flanking regions

  5. 5.

    Supplementary Table 4

    Clinical parameters and and the genotype of rs143383 (+104T/C)

  6. 6.

    Supplementary Table 5

    Association of rs143383 with osteoarthritis after stratification by sex

  7. 7.

    Supplementary Table 6

    Assessment of the population stratification

  8. 8.

    Supplementary Table 7

    Haplotype association analysis

  9. 9.

    Supplementary Table 8

    Clinical parameters

  10. 10.

    Supplementary Note

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