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

Nature Genetics volume 39, pages 529–533 (2007)Cite this article

Abstract

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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Figure 1: LD blocks, genomic structures and allelic association around GDF5.
Figure 2: Analysis of GDF5 promoter activity in HCS-2/8 cells.

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Acknowledgements

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

  1. Susumu Saito

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

  2. Yoshinari Miyamoto and Akihiko Mabuchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, 108-8639, Tokyo, 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, 602-8566, Kyoto, Japan

    Toshikazu Kubo & Mikihiro Fujioka

  4. Department of Orthopaedic Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan

    Yoshio Takatori

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

    Susumu Saito

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

    Akihiro Sudo & Atsumasa Uchida

  7. Department of Orthopedic Surgery, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, 173-0015, Tokyo, Japan

    Seizo Yamamoto

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

    Yusuke Nakamura

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  1. Yoshinari Miyamoto
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Contributions

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.

Corresponding author

Correspondence to Shiro Ikegawa.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Confirmation of the allelic difference of rs143383 (+104C/T) in OUMS-27 and HeLa cells (PDF 73 kb)

Supplementary Table 1

Initial association of GDF5 with osteoarthritis of the hip joint (PDF 20 kb)

Supplementary Table 2

Replication of association of GDF5 with osteoarthritis of the hip joint in an independent population (PDF 20 kb)

Supplementary Table 3

List of polymorphisms in GDF5 and flanking regions (PDF 24 kb)

Supplementary Table 4

Clinical parameters and and the genotype of rs143383 (+104T/C) (PDF 19 kb)

Supplementary Table 5

Association of rs143383 with osteoarthritis after stratification by sex (PDF 95 kb)

Supplementary Table 6

Assessment of the population stratification (PDF 25 kb)

Supplementary Table 7

Haplotype association analysis (PDF 17 kb)

Supplementary Table 8

Clinical parameters (PDF 44 kb)

Supplementary Note (PDF 13 kb)

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Miyamoto, Y., Mabuchi, A., Shi, D. et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 39, 529–533 (2007). https://doi.org/10.1038/2005

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