Dataset Information

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.

SUBMITTER: Tanisawa K

PROVIDER: S-EPMC5861862 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Tanisawa Kumpei K Arai Yasumichi Y Hirose Nobuyoshi N Shimokata Hiroshi H Yamada Yoshiji Y Kawai Hisashi H Kojima Motonaga M Obuchi Shuichi S Hirano Hirohiko H Yoshida Hideyo H Suzuki Hiroyuki H Fujiwara Yoshinori Y Ihara Kazushige K Sugaya Maki M Arai Tomio T Mori Seijiro S Sawabe Motoji M Sato Noriko N Muramatsu Masaaki M Higuchi Mitsuru M Liu Yao-Wen YW Kong Qing-Peng QP Tanaka Masashi M

The journals of gerontology. Series A, Biological sciences and medical sciences 20170301 3

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/ce ...[more]

PMID: 27154906

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Project description:The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB1 exposed. AFB1-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB1-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB1-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

Dataset Information

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

Publications

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

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