Dataset Information

Genetic variation in CDH13 is associated with lower plasma adiponectin levels but greater adiponectin sensitivity in East Asian populations.

ABSTRACT: Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized ? [?] = -0.34, 95% CI -0.38 to -0.30, P = 2.0 × 10(-70)), HMW adiponectin (? = -0.40, 95% CI -0.43 to -0.36, P = 1.1 × 10(-117)), and the HMW-to-total adiponectin ratio (? = -0.44, 95% CI -0.49 to -0.40, P = 3.2 × 10(-83)). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (? = -0.15, 95% CI -0.19 to -0.11, P = 3.5 × 10(-14)), homeostasis model assessment-insulin resistance index (? = -0.16, 95% CI -0.20 to -0.12, P = 9.2 × 10(-16)), and triglycerides (? = -0.16, 95% CI -0.19 to -0.12, P = 1.3 × 10(-16)) and with higher HDL (? = 0.16, 95% CI 0.12 to 0.19, P = 2.1 × 10(-17)). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels.

SUBMITTER: Gao H

PROVIDER: S-EPMC3837060 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Genetic variation in CDH13 is associated with lower plasma adiponectin levels but greater adiponectin sensitivity in East Asian populations.

Gao He H Kim Yu-Mi YM Chen Peng P Igase Michiya M Kawamoto Ryuichi R Kim Mi Kyung MK Kohara Katsuhiko K Lee Jeannette J Miki Tetsuro T Ong Rick Twee-Hee RT Onuma Hiroshi H Osawa Haruhiko H Sim Xueling X Teo Yik Ying YY Tabara Yasuharu Y Tai E Shyong ES van Dam Rob M RM

Diabetes 20130905 12

Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong as ...[more]

PMID: 24009259

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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

Genetic variation in CDH13 is associated with lower plasma adiponectin levels but greater adiponectin sensitivity in East Asian populations.

Publications

Genetic variation in CDH13 is associated with lower plasma adiponectin levels but greater adiponectin sensitivity in East Asian populations.

Similar Datasets

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