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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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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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.
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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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DOI: https://doi.org/10.1038/ng.176