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

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

Affiliations

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

Authors

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Abstract

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References

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