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Functional variants of the ATG7 gene promoter in acute myocardial infarction.

ABSTRACT: BACKGROUND:Coronary artery disease including acute myocardial infarction (AMI) is mainly caused by atherosclerosis, an inflammatory and metabolic disease. Autophagy has been demonstrated to play critical roles in lipid metabolism and inflammation. Altered autophagic activity has been reported in AMI patients. However, molecular basis for dysfunctional autophagy in AMI remains unexplained. METHODS:In this study, the promoter of the ATG7 gene, encoding a core protein for autophagy, was genetically and functionally analyzed in large cohorts of AMI patients (n = 355) and ethnic-matched healthy controls (n = 363). Related molecular mechanisms were also explored. RESULTS:A total of 19 DNA sequence variants (DSVs) including single-nucleotide polymorphisms (SNPs) were found in the ATG7 gene promoter. Two novel DSVs and five SNPs were only identified in AMI patients group. These DSVs and SNPs, except one SNP, significantly altered the transcriptional activity of the ATG7 gene promoter in both HEK-293 and H9c2 cells (p < 0.05). Further electrophoretic mobility shift assay revealed that the DSVs and SNPs evidently affected the binding of transcription factors. CONCLUSIONS:ATG7 gene DSVs and SNPs identified in AMI patients may alter the transcriptional activity of the ATG7 gene promoter and change ATG7 level, contributing to the AMI development as a rare risk factor.

SUBMITTER: Zhang P

PROVIDER: S-EPMC6305654 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Functional variants of the ATG7 gene promoter in acute myocardial infarction.

Zhang Pei P Zhang Jie J Zhang Yexin Y Wang Shuai S Pang Shuchao S Yan Bo B

Molecular genetics & genomic medicine 20181108 6

<h4>Background</h4>Coronary artery disease including acute myocardial infarction (AMI) is mainly caused by atherosclerosis, an inflammatory and metabolic disease. Autophagy has been demonstrated to play critical roles in lipid metabolism and inflammation. Altered autophagic activity has been reported in AMI patients. However, molecular basis for dysfunctional autophagy in AMI remains unexplained.<h4>Methods</h4>In this study, the promoter of the ATG7 gene, encoding a core protein for autophagy, ...[more]

PMID: 30407747

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Project description:Background: Acute myocardial infarction (AMI) which is a specific type of coronary artery disease (CAD), is caused by the combination of genetic factors and acquired environment. Although some common genetic variations have been recorded to contribute to the development of CAD and AMI, more genetic factors and potential molecular mechanisms remain largely unknown. The GATA6 gene is expressed in the heart during embryogenesis and is also detected in vascular smooth muscle cells (VSMCs), different human primary endothelial cells (ECs), and vascular ECs in mice. To date, no studies have directly linked GATA6 gene with regulation of the CAD. Methods: In this study, we used a case-control study to investigate and analyze the genetic variations and functional variations of the GATA6 gene promoter region in AMI patients and controls. A variety of statistical analysis methods were utilized to analyze the association of single nucleotide polymorphisms (SNPs) with AMI. Functional analysis of DNA sequence variants (DSVs) was performed using a dual luciferase reporter assay. In vitro, electrophoretic mobility shift assay (EMSA) was selected to examine DNA-protein interactions. Results: A total of 705 subjects were enrolled in the study. Ten DSVs were found in AMI patients (n = 352) and controls (n = 353), including seven SNPs. One novel heterozygous DSV, (g.22168409 A > G), and two SNPs, [g.22168362 C > A(rs1416421760) and g.22168521 G > T(rs1445501474)], were reported in three AMI patients, which were not found in controls. The relevant statistical analysis, including allele and genotype frequencies between AMI patients and controls, five genetic models, linkage disequilibrium (LD) and haplotype analysis, and SNP-SNP interactions, suggested no statistical significance (P > 0.05). The transcriptional activity of GATA6 gene promoter was significantly increased by the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)]. The EMSA revealed that the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)] evidently influenced the binding of transcription factors. Conclusion: In conclusion, the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)] may increase GATA6 levels in both HEK-293 and H9c2 cell lines by affecting the binding of transcription factors. Whether the two variants identified in the GATA6 gene promoter can promote the development and progression of human AMI by altering GATA6 levels still requires further studies to verify.

Dataset Information

Functional variants of the ATG7 gene promoter in acute myocardial infarction.

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Functional variants of the ATG7 gene promoter in acute myocardial infarction.

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