Functional genetic variants in the SIRT5 gene promoter in acute myocardial infarction

• Published in: Gene 2018-10, Vol.675, p.233-239
• Main Authors: Chen, Lu, Wang, Haiyan, Gao, Feng, Zhang, Jie, Zhang, Yexin, Ma, Ruchao, Pang, Shuchao, Cui, Yinghua, Yang, Jian, Yan, Bo
• Format: Article
• Language: English
• Subjects: Acute myocardial infarction; Adult; Aged; Aged, 80 and over; Animals; Case-Control Studies; Cells, Cultured; DNA sequence variants; Female; Genetic Predisposition to Disease; Genetic Variation; HEK293 Cells; Heterozygote; Humans; Male; Middle Aged; Myocardial Infarction - blood; Myocardial Infarction - epidemiology; Myocardial Infarction - genetics; Polymorphism, Single Nucleotide; Promoter; Promoter Regions, Genetic; Rats; SIRT5; Sirtuins - blood; Sirtuins - genetics; SNP; Young Adult
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2018.07.010

Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease. To date, genetic causes for atherosclerosis remain largely unknown. It has recently been proposed that low frequency and rare genetic variants may be the main causes. Mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, function as critical regulators of mitochondrial metabolism, oxidative stress and cell survival. We speculated that altered SIRT5 level resulting from DNA sequence variants (DSVs) within SIRT5 gene regulatory regions may contribute to the CAD and AMI development. In this study, the SIRT5 gene promoter was genetically and functionally analyzed in large cohorts of AMI patients (n = 381) and healthy controls (n = 391). A total of eleven DSVs and SNPs were found. Two novel heterozygous DSVs (g.13574131C>A and g.13574287G>C) and three heterozygous SNPs [g.13573450A>G (rs573515169), g.13574110G>A (rs2804924) and g.13574259G>C (rs112443954)] were identified only in AMI patients. The DSVs and SNPs significantly decreased the transcriptional activity of the SIRT5 gene promoter in both HEK-293 and H9c2 cells (P  0.05). Therefore, our data suggested that the DSVs and SNPs identified in AMI patients may change SIRT5 level by affecting activity of SIRT5 gene promoter, contributing to the AMI development as a risk factor. •SIRT5 gene promoter was genetically analyzed in AMI patients.•Two novel heterozygous DSVs and three SNPs were identified only in AMI patients.•The DSVs and SNPs significantly decreased the activity of SIRT5 gene promoter.•EMSA indicated that the SNPs affected the binding of transcription factors.•SIRT5 gene promoter DSVs and SNPs may contribute to AMI development.