. 2017 Mar 1;72(3):309-318.

doi: 10.1093/gerona/glw074.

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

Kumpei Tanisawa^{1

2

3}, Yasumichi Arai⁴, Nobuyoshi Hirose⁴, Hiroshi Shimokata^{5

6}, Yoshiji Yamada⁷, Hisashi Kawai⁸, Motonaga Kojima⁸, Shuichi Obuchi⁸, Hirohiko Hirano⁹, Hideyo Yoshida⁹, Hiroyuki Suzuki¹⁰, Yoshinori Fujiwara¹⁰, Kazushige Ihara¹¹, Maki Sugaya¹, Tomio Arai¹², Seijiro Mori¹³, Motoji Sawabe¹⁴, Noriko Sato¹⁵, Masaaki Muramatsu¹⁵, Mitsuru Higuchi^{2

16}, Yao-Wen Liu¹⁷, Qing-Peng Kong¹⁷, Masashi Tanaka¹⁸

Affiliations

¹ Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan.
² Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.
³ Japan Society for the Promotion of Science, Tokyo, Japan.
⁴ Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan.
⁵ Section of Longitudinal Study of Aging, National Institute for Longevity Sciences (NILS-LSA), National Center for Geriatrics and Gerontology, Obu, Japan.
⁶ Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan.
⁷ Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan.
⁸ Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
⁹ Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Japan.
¹⁰ Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Japan.
¹¹ Department of Public Health, Toho University School of Medicine, Tokyo, Japan.
¹² Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Japan.
¹³ Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Japan.
¹⁴ Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Japan.
¹⁵ Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
¹⁶ Institute of Advanced Active Aging Research, Waseda University, Tokorozawa, Japan.
¹⁷ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.
¹⁸ Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Japan.

PMID: 27154906
PMCID: PMC5861862
DOI: 10.1093/gerona/glw074

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

Kumpei Tanisawa et al. J Gerontol A Biol Sci Med Sci. 2017.

. 2017 Mar 1;72(3):309-318.

doi: 10.1093/gerona/glw074.

Authors

Affiliations

¹ Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan.
² Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.
³ Japan Society for the Promotion of Science, Tokyo, Japan.
⁴ Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan.
⁵ Section of Longitudinal Study of Aging, National Institute for Longevity Sciences (NILS-LSA), National Center for Geriatrics and Gerontology, Obu, Japan.
⁶ Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan.
⁷ Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan.
⁸ Human Care Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
⁹ Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Japan.
¹⁰ Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Japan.
¹¹ Department of Public Health, Toho University School of Medicine, Tokyo, Japan.
¹² Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Japan.
¹³ Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Japan.
¹⁴ Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Japan.
¹⁵ Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
¹⁶ Institute of Advanced Active Aging Research, Waseda University, Tokorozawa, Japan.
¹⁷ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.
¹⁸ Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Japan.

PMID: 27154906
PMCID: PMC5861862
DOI: 10.1093/gerona/glw074

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.

Keywords: Centenarian; Human aging; Human genetics; Longevity.

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Figures

**Figure 1.**
Flow diagram of the study.

**Figure 2.**
Manhattan plot of the p values from the combined analysis of Cohorts 1 and 2. (A) Additive genetic model. (B) Dominant genetic model.

See this image and copyright information in PMC

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References

1. Salomon JA, Wang H, Freeman MK, et al. Healthy life expectancy for 187 countries, 1990–2010: a systematic analysis for the Global Burden Disease Study 2010. Lancet. 2012;380:2144–2162. doi:10.1016/S0140-6736(12)61690-0 - PubMed
1. Herskind AM, McGue M, Holm NV, Sørensen TI, Harvald B, Vaupel JW. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum Genet. 1996;97:319–323. doi:10.1007/BF02185763 - PubMed
1. Mitchell BD, Hsueh WC, King TM, et al. Heritability of life span in the Old Order Amish. Am J Med Genet. 2001;102:346–352. doi:10.1002/ajmg.1483 - PubMed
1. Skytthe A, Pedersen NL, Kaprio J, et al. Longevity studies in GenomEUtwin. Twin Res. 2003;6:448–454. doi:10.1375/136905203770326457 - PubMed
1. Schoenmaker M, de Craen AJ, de Meijer PH, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet. 2006;14:79–84. doi:10.1038/sj.ejhg.5201508 - PubMed

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

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

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