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Identification and functional analysis of genetic variants in TBX5 gene promoter in patients with acute myocardial infarction.

ABSTRACT: BACKGROUND:Coronary artery disease (CAD), including acute myocardial infarction (AMI), is a common complex disease. Although a great number of genetic loci and variants for CAD have been identified, genetic causes and underlying mechanisms remain largely unclear. Epidemiological studies have revealed that CAD incidence is strikingly higher in patients with congenital heart disease than that in normal population. T-box transcription factors play critical roles in embryonic development. In particular, TBX5 as a dosage-sensitive regulator is required for cardiac development and function. Thus, dysregulated TBX5 gene expression may be involved in CAD development. METHODS:TBX5 gene promoter was genetically and functionally analysed in large groups of AMI patients (n?=?432) and ethnic-matched healthy controls (n?=?448). RESULTS:Six novel heterozygous DNA sequence variants (DSVs) in the TBX5 gene promoter (g.4100A?>?G, g.4194G?>?A, g.4260?T?>?C, g.4367C?>?A, g.4581A?>?G and g.5004G?>?T) were found in AMI patients, but in none of controls. These DSVs significantly changed the activity of TBX5 gene promoter in cultured cells (P??G, g.4260?T?>?C and g.4581A?>?G) evidently modified the binding sites of unknown transcription factors. CONCLUSIONS:The DSVs identified in AMI patients may alter TBX5 gene promoter activity and change TBX5 level, contributing to AMI development as a rare risk factor.

SUBMITTER: Wang S

PROVIDER: S-EPMC6880377 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Identification and functional analysis of genetic variants in TBX5 gene promoter in patients with acute myocardial infarction.

Wang Shuai S Zhang Jie J He Xiaohui X Zhang Yexin Y Chen Jing J Su Qiang Q Pang Shuchao S Zhang Shufang S Cui Yinghua Y Yan Bo B

BMC cardiovascular disorders 20191127 1

<h4>Background</h4>Coronary artery disease (CAD), including acute myocardial infarction (AMI), is a common complex disease. Although a great number of genetic loci and variants for CAD have been identified, genetic causes and underlying mechanisms remain largely unclear. Epidemiological studies have revealed that CAD incidence is strikingly higher in patients with congenital heart disease than that in normal population. T-box transcription factors play critical roles in embryonic development. In ...[more]

PMID: 31775637

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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

Identification and functional analysis of genetic variants in TBX5 gene promoter in patients with acute myocardial infarction.

Publications

Identification and functional analysis of genetic variants in TBX5 gene promoter in patients with acute myocardial infarction.

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