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Article

Genome-Wide Association Study on Adiponectin-Mediated Suppression of HDL-C Levels in Taiwanese Individuals Identifies Functional Haplotypes in CDH13

by 1,2, 3, 4,5, 2,5,6,* and 5,*
1
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei city 23142, Taiwan
2
School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
3
Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan
4
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA
5
Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
6
The Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Speranza Rubattu
Received: 2 September 2021 / Revised: 30 September 2021 / Accepted: 1 October 2021 / Published: 7 October 2021
(This article belongs to the Special Issue Cardiovascular Disease Risk Factors, Genetics, and Prevention)
CDH13 encodes T-cadherin, which is expressed in the vasculature and cardiac myocytes and is the receptor for hexameric and high-molecular-weight adiponectin. The CDH13 region is the most pivotal locus associated with adiponectin level. Mediation analysis is a method to explore the effect of a third variable, it is assumed that the magnitude of the relationship between the independent and dependent variables will be reduced by statistical adjustment for a third variable. In addition, mediation can further occur in the case when the mediator acts as a pathway-suppressor variable that means a suppression effect may be suggested if the statistical removal of a mediation effect could increase the magnitude of the relationship between the independent and dependent variables. Here, we aimed to explore the suppression effect in a genome-wide association study, and investigate possible mechanisms that may link adiponectin to CDH13 variants and high-density lipoprotein cholesterol (HDL-C). Genome-wide association data for adiponectin and HDL-C were accessible for 2349 Taiwan-biobank participants. The mediation analysis was conducted with the CDH13 lead single nucleotide polymorphism (SNP) rs4783244. The cloned constructs of CDH13 haplotypes (GG and TT) identified from the rs4783244 G/T and rs12051272 G/T SNPs were transiently expressed in HEK293T cells and investigated using the luciferase reporter assay. Genome-wide association analysis showed that HDL-C is significantly associated with variants in CDH13 after adjusting for the adiponectin level. The lead SNP rs4783244 was significantly associated with lower adiponectin levels and exhibited a suppression effect on HDL-C when adiponectin was included as a third factor in the mediation analysis. Luciferase reporter assay results further demonstrated that the GG haplotype increased enhancer activity, whereas the haplotype TT significantly reduced the activity of this enhancer. We present the first evidence of the suppressive role of adiponectin in the genome-wide association between CDH13 and HDL-C. CDH13 may increase the HDL-C levels, and its expression is suppressed by adiponectin. View Full-Text
Keywords: CDH13; adiponectin; HDL-C; GWAS; suppression effect CDH13; adiponectin; HDL-C; GWAS; suppression effect
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MDPI and ACS Style

Er, L.-K.; Wu, S.; Cheng, T.; Ko, Y.-L.; Teng, M.-S. Genome-Wide Association Study on Adiponectin-Mediated Suppression of HDL-C Levels in Taiwanese Individuals Identifies Functional Haplotypes in CDH13. Genes 2021, 12, 1582. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101582

AMA Style

Er L-K, Wu S, Cheng T, Ko Y-L, Teng M-S. Genome-Wide Association Study on Adiponectin-Mediated Suppression of HDL-C Levels in Taiwanese Individuals Identifies Functional Haplotypes in CDH13. Genes. 2021; 12(10):1582. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101582

Chicago/Turabian Style

Er, Leay-Kiaw, Semon Wu, Tzuyu Cheng, Yu-Lin Ko, and Ming-Sheng Teng. 2021. "Genome-Wide Association Study on Adiponectin-Mediated Suppression of HDL-C Levels in Taiwanese Individuals Identifies Functional Haplotypes in CDH13" Genes 12, no. 10: 1582. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101582

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