title: Exome-wide Association Study Identifies CLEC3B Missense Variant p.S106G as Being Associated With Extreme Longevity in East Asian Populations.
abstract: 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.
authors.affiliation: Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan.|Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.|Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tanisawa
authors.affiliation: Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hirose
authors.affiliation: Section of Longitudinal Study of Aging, National Institute for Longevity Sciences (NILS-LSA), National Center for Geriatrics and Gerontology, Obu, Japan.|Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimokata
authors.affiliation: Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan.
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kawai
authors.affiliation: Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Motonaga
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Obuchi
authors.affiliation: Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hirano
authors.affiliation: Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Public Health, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Sugaya
authors.affiliation: Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Arai
authors.affiliation: Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Japan.
authors.forename: Seijiro
authors.initials: S
authors.lastname: Mori
authors.affiliation: Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Japan.
authors.forename: Motoji
authors.initials: M
authors.lastname: Sawabe
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
authors.affiliation: Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.|Institute of Advanced Active Aging Research, Waseda University, Tokorozawa, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.
authors.forename: Qing-Peng
authors.initials: QP
authors.lastname: Kong
authors.affiliation: Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged
chemical_list: D037181:Lectins, C-Type; C048648:tetranectin
keywords: Centenarian; Human aging; Human genetics; Longevity