Dysregulation Of SIRT6 Gene Expression In Myocadial Infarction

Objective: Coronary artery disease(CAD) is a common and complex disease caused by atherosclerosis, and acute myocardial infarction(AMI) is the severe type of CAD. The mortality and morbidity rates of CAD are very high worldwide. It has been suggested that CAD results from interactions of genetic and environmental factors. To date, more than 50 genetic loci and variants have been associated with CAD, which account for only 10% of CAD cases. Thus, low frequent and rare genetic variants have been proposed to be a main cause for CAD. SIRT6 is a member of highly conservative NAD-dependent deacetylase, which also functions as a mono-ADP-ribosyltransferase. Through its enzymatic activity, SIRT6 regulates genomic repair, telomere maintenance, glucose and lipid metabolism to maintain cellular metabolism. Dysfunctional SIRT6 has been associated with diabetes, obesity, heart disease, cancer and other diseases. In particularly,SIRT6 gene plays an essential role for the cardiovascular system and has been implicated in several heart diseases. In addition, SIRT6 genes is involved in inflammation, lipids and cholesterol metabolism. Therefore, genetic variants in SIRT6 gene may lead to the development and progression of AMI.Methods: Blood samples of AMI patients were collected from Division of Cardiac Care Unit, Division of Cardiology, Jining Medical University Affiliated Hospital. Blood samples of healthy controls were collected fromPhysical-examination Center in the same hospital. Subjects with diabetes,hyperlipidemia, and familial CAD history were excluded from controls.Leukocytes were isolated and DNAs extracted. PCR primers were designed on the SIRT6 gene genomic sequences. The promoter region of the SIRT6 gene was generated by PCR and directly sequenced. By comparing with the wild type, the DNA sequence variants were identified and analyzed. In this study, 371 AMI cases and 383 ethnic-matched controls were analyzed.Results: In this population, a total of 15 DNA sequence variation were found, including 7 single nucleotide polymorphisms(SNPs). Two heterozygous DNA sequence variants(g. 4183823 g > C and g. 4183742 g >A) were identified in two AMI cases, but in none of controls. Two SNPs, g.4183685 t > C(rs4359565) and g. 4182942 C > A(rs3760905), were found in AMI cases with significant higher frequency, compared with control group(P<0.05).Conclusion: We genetically analyzed the promoter region of the SIRT6 gene in AMI cases and controls, and two novel DNA sequence variants and two SNPs with higher frequencies were found in AMI cases. These DNA sequence variants may affect the transcriptional activity of SIRT6 gene promoter, and change SIRT6 gene expression level, leading to the AMI development as a risk factor.