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A missense single nucleotide polymorphism, V114I of the Werner syndrome gene, is associated with risk of osteoporosis and femoral fracture in the Japanese population

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Abstract

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)—which results in a Val to Ile substitution—and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.

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Acknowledgments

This work was supported by a grant (no. 09042037) from the Leading Project for Personalized Medicine of the Ministry of Education, Culture, Sports, Science and Technology of Japan (to S.M.); Grants-in-Aid for Scientific Research (nos. 22240072, 21390459, and 21590411 [to M.T.], 18209023, 18018021, 19659149, and 24590746 [to YY], and 23240089 [to MM]); a Grant-in-Aid for the Global COE (Sport Sciences for the Promotion of Active Life to Waseda University) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to MT); a Grant-in-Aid for Scientific Research (to MM) and Grants-in-Aid (H23-016, H23-119, and H24-005) for Research on Intractable Diseases (Mitochondrial Disease) (to MT) from the Ministry of Health, Labour and Welfare of Japan; grants for scientific research from Mitsui Sumitomo Insurance Welfare Foundation (to SM); the Pfizer Academic Contribution Fund (to SM); Takeda Science Foundation (to MT); the Smoking Research Foundation (to TA and MS); and the Mie Medical Valley Project (to YY).

Conflict of interest

Heying Zhou, Seijiro Mori, Masashi Tanaka, Motoji Sawabe, Tomio Arai, Masaaki Muramatsu, Makiko Naka Mieno, Shoji Shinkai, Yoshiji Yamada, Motohiko Miyachi, Haruka Murakami, Kiyoshi Sanada, and Hideki Ito declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae, Itabashi, Tokyo, 173-0015, Japan

    Heying Zhou & Seijiro Mori

  2. Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Masashi Tanaka

  3. Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Motoji Sawabe

  4. Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

    Tomio Arai

  5. Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Masaaki Muramatsu

  6. Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Makiko Naka Mieno

  7. Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Shoji Shinkai

  8. Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie, Japan

    Yoshiji Yamada

  9. Department of Health Promotion and Exercise, National Institute of Health and Nutrition, Tokyo, Japan

    Motohiko Miyachi & Haruka Murakami

  10. Faculty of Sport and Health Science, Ritsumeikan University, Kita, Shiga, Japan

    Kiyoshi Sanada

  11. President, Local Independent Administrative Agency, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Hideki Ito

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  1. Heying Zhou
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  2. Seijiro Mori
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Corresponding author

Correspondence to Seijiro Mori.

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Zhou, H., Mori, S., Tanaka, M. et al. A missense single nucleotide polymorphism, V114I of the Werner syndrome gene, is associated with risk of osteoporosis and femoral fracture in the Japanese population. J Bone Miner Metab 33, 694–700 (2015). https://doi.org/10.1007/s00774-014-0636-0

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  • DOI: https://doi.org/10.1007/s00774-014-0636-0

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