Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8644505 | Gene | 2018 | 35 Pages |
Abstract
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 (nâ¯=â¯381) and healthy controls (nâ¯=â¯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 (Pâ¯<â¯0.05). Further electrophoretic mobility shift assay indicated that the SNPs significantly affected the binding of transcription factors. In contrast, the DSVs and SNPs found only in controls or in both AMI patients and controls did not significantly change the SIRT5 gene promoter activity (Pâ¯>â¯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.
Keywords
NFATC2Foxc1HEK-293NF-κBCEBPBSNPsSIRT5NRF-1Klf5DNA sequence variantsDSVsH9c2AmISp1Electrophoretic mobility shift assaycoronary artery diseaseEMSA یا electrophoretic mobility shift assay Acute myocardial infarctionCADnuclear respiratory factor-1nuclear factor-κBSpecificity protein 1CCAAT/enhancer binding protein βPromoterSingle-nucleotide polymorphismsSNP
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Authors
Lu Chen, Haiyan Wang, Feng Gao, Jie Zhang, Yexin Zhang, Ruchao Ma, Shuchao Pang, Yinghua Cui, Jian Yang, Bo Yan,