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Exome-wide Association Study Identifies CLEC3B Missense Variant p.S106G as Being Associated With Extreme Longevity in East Asian Populations.

J. Gerontol. A Biol. Sci. Med. Sci.2017 Mar 01;72(3):309-318
Kumpei Tanisawa 1 , Yasumichi Arai 2 , Nobuyoshi Hirose 2 , Hiroshi Shimokata 3 , Yoshiji Yamada 4 , Hisashi Kawai 5 , Motonaga Kojima 5 , Shuichi Obuchi 5 , Hirohiko Hirano 6 , Hideyo Yoshida 6 , Hiroyuki Suzuki 7 , Yoshinori Fujiwara 7 , Kazushige Ihara 8 , Maki Sugaya 9 , Tomio Arai 10 , Seijiro Mori 11 , Motoji Sawabe 12 , Noriko Sato 13 , Masaaki Muramatsu 13 , Mitsuru Higuchi 14 , Yao-Wen Liu 15 , Qing-Peng Kong 15 , Masashi Tanaka 16
Kumpei Tanisawa 1 , Yasumichi Arai 2 , Nobuyoshi Hirose 2 , Hiroshi Shimokata 3 , Yoshiji Yamada 4 , Hisashi Kawai 5 , Motonaga Kojima 5 , Shuichi Obuchi 5 , Hirohiko Hirano 6 , Hideyo Yoshida 6 , Hiroyuki Suzuki 7 , Yoshinori Fujiwara 7 , Kazushige Ihara 8 , Maki Sugaya 9 , Tomio Arai 10 , Seijiro Mori 11 , Motoji Sawabe 12 , Noriko Sato 13 , Masaaki Muramatsu 13 , Mitsuru Higuchi 14 , Yao-Wen Liu 15 , Qing-Peng Kong 15 , Masashi Tanaka 16
+ et al

[No authors listed]

Author information
  • 1 Japan Society for the Promotion of Science, Tokyo, Japan.
  • 2 Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan.
  • 3 Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan.
  • 4 Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan.
  • 5 Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
  • 6 Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Japan.
  • 7 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Japan.
  • 8 Department of Public Health, Toho University School of Medicine, Tokyo, Japan.
  • 9 Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan.
  • 10 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Japan.
  • 11 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Japan.
  • 12 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Japan.
  • 13 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
  • 14 Institute of Advanced Active Aging Research, Waseda University, Tokorozawa, Japan.
  • 15 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.
  • 16 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Japan.

摘要

Life span is a complex trait regulated by multiple genetic and environmental factors; however, the genetic determinants of extreme longevity have been largely unknown. To identify the functional coding variants associated with extreme longevity, we performed an exome-wide association study (EWAS) on a Japanese population by using an Illumina HumanExome Beadchip and a focused replication study on a Chinese population. The EWAS on two independent Japanese cohorts consisting of 530 nonagenarians/centenarians demonstrated that the G allele of CLEC3B missense variant p.S106G was associated with extreme longevity at the exome-wide level of significance (p = 2.33×10-7, odds ratio [OR] = 1.50). The CLEC3B gene encodes tetranectin, a protein implicated in the mineralization process in osteogenesis as well as in the prognosis and metastasis of cancer. The replication study consisting of 448 Chinese nonagenarians/centenarians showed that the G allele of CLEC3B p.S106G was also associated with extreme longevity (p = .027, OR = 1.51), and the p value of this variant reached 1.87×10-8 in the meta-analysis of Japanese and Chinese populations. In conclusion, the present study identified the CLEC3B p.S106G as a novel longevity-associated variant, raising the novel hypothesis that tetranectin, encoded by CLEC3B, plays a role in human longevity and aging. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

KEYWORDS: Centenarian, Human aging, Human genetics, Longevity

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