Genetic and Functional Sequence Variants of the SIRT3 Gene Promoter in Myocardial Infarction.
Genetic and Functional Sequence Variants of the SIRT3 Gene Promoter in Myocardial Infarction.
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心肌梗塞中 SIRT3 基因启动子的遗传和功能序列变异
DOI：
10.1371/journal.pone.0153815
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yan B
中科院分区：
文献类型：
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作者：
Yin X;Pang S;Huang J;Cui Y;Yan B
冠状动脉疾病(CAD)，包括心肌梗死(MI)，是一种常见的复杂疾病，由动脉粥样硬化引起。虽然大量的遗传变异与CAD有关，但只有10%的CAD病例可以解释。低频率和罕见的遗传变异可能是冠心病的主要原因。SIRT3是一种线粒体脱乙酰酶，在线粒体功能和代谢中发挥重要作用。在实验动物中缺乏SIRT3会导致一些与年龄相关的疾病，包括心血管疾病。因此，SIRT3基因变异可能与心肌梗死的发生有关。在本研究中，我们对319例心肌梗塞患者和322例种族匹配的对照组进行了SIRT3基因启动子的遗传和功能分析。共鉴定出23个DNA序列变异(DSV)，包括10个单核苷酸多态(SNPs)。在9例心肌梗塞患者中发现了6个新的杂合子DSV：g.237307A>；G，g.237270G>；A，g.237023_25del，g.236653C>；A，g.236628G>；C，g.236557T>；C，以及2个SNPs g.237030C>；T(Rs12293349)和g.237022C>；G(Rs369344513)。心肌梗死组中236473C>；T(Rs11246029)、g.236380_81ins(Rs71019893)和g.236370C>；G(Rs185277566)三个SNPs频率显著高于对照组(P<；0.05)。除g.236557T和gt；C外，这些DSVs和SNPs显著降低了SIRT3基因启动子在HEK-293细胞和H9c2细胞中的转录活性。因此，在MI患者中发现的这些DSV可能通过影响SIRT3基因启动子的转录活性而改变SIRT3的水平，从而作为一种危险因素参与MI的发展。
Coronary artery disease (CAD), including myocardial infarction (MI), is a common complex disease that is caused by atherosclerosis. Although a large number of genetic variants have been associated with CAD, only 10% of CAD cases could be explained. It has been proposed that low frequent and rare genetic variants may be main causes for CAD. SIRT3, a mitochondrial deacetylase, plays important roles in mitochondrial function and metabolism. Lack of SIRT3 in experimental animal leads to several age-related diseases, including cardiovascular diseases. Therefore, SIRT3 gene variants may contribute to the MI development. In this study, SIRT3 gene promoter was genetically and functionally analyzed in large cohorts of MI patients (n = 319) and ethnic-matched controls (n = 322). Total twenty-three DNA sequence variants (DSVs) were identified, including 10 single-nucleotide polymorphisms (SNPs). Six novel heterozygous DSVs, g.237307A>G, g.237270G>A, g.237023_25del, g.236653C>A, g.236628G>C, g.236557T>C, and two SNPs g.237030C>T (rs12293349) and g.237022C>G (rs369344513), were identified in nine MI patients, but in none of controls. Three SNPs, g.236473C>T (rs11246029), g.236380_81ins (rs71019893) and g.236370C>G (rs185277566), were more significantly frequent in MI patients than controls (P<0.05). These DSVs and SNPs, except g.236557T>C, significantly decreased the transcriptional activity of the SIRT3 gene promoter in cultured HEK-293 cells and H9c2 cells. Therefore, these DSVs identified in MI patients may change SIRT3 level by affecting the transcriptional activity of SIRT3 gene promoter, contributing to the MI development as a risk factor.