Genetic and Functional Sequence Variants of the SIRT3 Gene Promoter in Myocardial Infarction.

Xiaoyun Yin,Jian Huang,Bo Yan,Shuchao Pang,Yinghua Cui,Hoon Ryu

doi:10.1371/journal.pone.0153815

Abstract

Coronary artery disease (CAD), including myocardial infarction (MI), is a common complex disease that is caused by atherosclerosis. Although a large number of genetic variants have been associated with CAD, only 10% of CAD cases could be explained. It has been proposed that low frequent and rare genetic variants may be main causes for CAD. SIRT3, a mitochondrial deacetylase, plays important roles in mitochondrial function and metabolism. Lack of SIRT3 in experimental animal leads to several age-related diseases, including cardiovascular diseases. Therefore, SIRT3 gene variants may contribute to the MI development. In this study, SIRT3 gene promoter was genetically and functionally analyzed in large cohorts of MI patients (n = 319) and ethnic-matched controls (n = 322). Total twenty-three DNA sequence variants (DSVs) were identified, including 10 single-nucleotide polymorphisms (SNPs). Six novel heterozygous DSVs, g.237307A>G, g.237270G>A, g.237023_25del, g.236653C>A, g.236628G>C, g.236557T>C, and two SNPs g.237030C>T (rs12293349) and g.237022C>G (rs369344513), were identified in nine MI patients, but in none of controls. Three SNPs, g.236473C>T (rs11246029), g.236380_81ins (rs71019893) and g.236370C>G (rs185277566), were more significantly frequent in MI patients than controls (P<0.05). These DSVs and SNPs, except g.236557T>C, significantly decreased the transcriptional activity of the SIRT3 gene promoter in cultured HEK-293 cells and H9c2 cells. Therefore, these DSVs identified in MI patients may change SIRT3 level by affecting the transcriptional activity of SIRT3 gene promoter, contributing to the MI development as a risk factor.

Highlights

Coronary artery disease (CAD) is a common complex disease, which is a leading cause of human death around the world
The locations and frequencies of the DNA sequence variants (DSVs) and single-nucleotide polymorphisms (SNPs) were shown in Fig 1 and Table 2
We further examined effects of the DSVs on the transcriptional activities of the SIRT3 gene promoter in HEK-293 cells

Summary

Introduction

Coronary artery disease (CAD) is a common complex disease, which is a leading cause of human death around the world. Myocardial infarction (MI) is a specific type of CAD. Atherosclerosis, an inflammatory and metabolic disease, is the main cause for CAD and MI. Though genome-wide association studies have identified more than 50 genetic loci to CAD, these genetic variants account for only 10% of cases [1,2,3]. Genetic causes and underlying molecular mechanisms for CAD remain largely unclear. It has been hypothesized that low frequency and rare variants with large effects may account for some of the missing heritability for CAD. Epigenetic factors have been suggested to contribute to aging and age-associated diseases [4]

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Discussion

Conclusion