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Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis

Nature Genetics volume 40, pages 994–998 (2008)Cite this article

Abstract

Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors1,2. Through a genome-wide association study using ∼100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain)3. Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 × 10−11). DVWA protein binds to β-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.

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Figure 1: DVWA binds to β-tubulin.

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GenBank/EMBL/DDBJ

References

  1. Ikegawa, S. New gene associations in osteoarthritis: what do they provide, and where are we going? Curr. Opin. Rheumatol. 19, 429–434 (2007).

    Article  PubMed  Google Scholar 

  2. Spector, T.D. & MacGregor, A.J. Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage (12 Suppl. A), S39–44 (2004).

  3. Celikel, R. et al. Crystal structure of the von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab. Nat. Struct. Biol. 5, 189–194 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Dieppe, P.A. & Lohmander, L.S. Pathogenesis and management of pain in osteoarthritis. Lancet 365, 965–973 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Hunter, D.J. & Felson, D.T. Osteoarthritis. Br. Med. J. 332, 639–642 (2006).

    Article  Google Scholar 

  6. Pollard, B. & Johnston, M. The assessment of disability associated with osteoarthritis. Curr. Opin. Rheumatol. 18, 531–536 (2006).

    Article  PubMed  Google Scholar 

  7. Gupta, S., Hawker, G.A., Laporte, A., Croxford, R. & Coyte, P.C. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford) 44, 1531–1537 (2005).

    Article  CAS  Google Scholar 

  8. Spector, T.D., Cicuttini, F., Baker, J., Loughlin, J. & Hart, D. Genetic influences on osteoarthritis in women: a twin study. Br. Med. J. 312, 940–943 (1996).

    Article  CAS  Google Scholar 

  9. Loughlin, J. et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc. Natl. Acad. Sci. USA 101, 9757–9762 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Kizawa, H. et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat. Genet. 37, 138–144 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Miyamoto, Y. et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat. Genet. 39, 529–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Jiang, Q. et al. Replication of the association of the aspartic acid repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese. J. Hum. Genet. 51, 1068–1072 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Valdes, A.M. et al. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum. 56, 137–146 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Ozaki, K. et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654 (2002).

    Article  CAS  Google Scholar 

  15. Mototani, H. et al. A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Hum. Mol. Genet. 14, 1009–1017 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Kubo, M. et al. A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction. Nat. Genet. 39, 212–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Haga, H., Yamada, R., Ohnishi, Y., Nakamura, Y. & Tanaka, T. Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome. Single-nucleotide polymorphism. J. Hum. Genet. 47, 605–610 (2002).

    Article  CAS  Google Scholar 

  18. Pritchard, J.K. & Rosenberg, N.A. Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet. 65, 220–228 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

    Article  CAS  Google Scholar 

  20. Tregouet, D.A. & Garelle, V. A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 23, 1038–1039 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Stefansson, S.E. et al. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am. J. Hum. Genet. 72, 1448–1459 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mabuchi, A. et al. Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Hum. Mutat. 24, 439–440 (2004).

    Article  PubMed  Google Scholar 

  23. Whittaker, C.A. & Hynes, R.O. Distribution and evolution of von Willebrand/integrin A domains: widely dispersed domains with roles in cell adhesion and elsewhere. Mol. Biol. Cell 13, 3369–3387 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Farquharson, C., Lester, D., Seawright, E., Jefferies, D. & Houston, B. Microtubules are potential regulators of growth-plate chondrocyte differentiation and hypertrophy. Bone 25, 405–412 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Capin-Gutierrez, N., Talamas-Rohana, P., Gonzalez-Robles, A., Lavalle-Montalvo, C. & Kouri, J.B. Cytoskeleton disruption in chondrocytes from a rat osteoarthrosic (OA) -induced model: its potential role in OA pathogenesis. Histol. Histopathol. 19, 1125–1132 (2004).

    CAS  PubMed  Google Scholar 

  26. Ikeda, T. et al. Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis. J. Hum. Genet. 46, 538–543 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Mabuchi, A. et al. Identification of sequence polymorphisms of the COMP (cartilage oligomeric matrix protein) gene and association study in osteoarthrosis of the knee and hip joints. J. Hum. Genet. 46, 456–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all individuals who participated in the study. We also thank S. Yamamoto, A. Fukuda, A. Kawakami, T. Kubo, Y. Takatori, S. Saito, A. Mabuchi, K. Nakamura and I. Kou for help with the research, and Y. Takanashi and T. Kusadokoro for excellent technical assistance.

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Authors and Affiliations

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

    Yoshinari Miyamoto, Masahiro Nakajima & Shiro Ikegawa

  2. The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, Jiangsu, China

    Dongquan Shi & Qing Jiang

  3. Laboratory for Cardiovascular Diseases, Center for Genomic Medicine, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Kouichi Ozaki & Toshihiro Tanaka

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

    Akihiro Sudo & Atsumasa Uchida

  5. Department of Orthopaedic Surgery, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611, Tokyo, Japan

    Akihiro Kotani

  6. Department of Pathomechanisms, Clinical Research Center for Rheumatology and Allergy, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara, 228-8522, Japan

    Naoshi Fukui

  7. The Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Tatsuhiko Tsunoda

  8. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Atsushi Takahashi

  9. Laboratory for Genotyping, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yusuke Nakamura

Authors
  1. Yoshinari Miyamoto
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Contributions

Y.M. carried out the Japanese knee osteoarthritis association study and in vitro functional assay together with M.N. and prepared the manuscript. D.S. carried out the Chinese association study. K.O., A.S., A.K., A.U., N.F., Y.N. and T.Tanaka managed DNA sample and clinical information and contributed data interpretation. A.T. and T.Tsunoda helped with statistic analysis. 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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Supplementary Tables 1–8, Supplementary Figures 1 and 2 (PDF 337 kb)

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Miyamoto, Y., Shi, D., Nakajima, M. et al. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nat Genet 40, 994–998 (2008). https://doi.org/10.1038/ng.176

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