Yin Xiaoyun, Pang Shuchao, Huang Jian, Cui Yinghua, Yan Bo
Department of Medicine, Shandong University School of Medicine, Jinan, Shandong, China.
Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China.
PLoS One. 2016 Apr 14;11(4):e0153815. doi: 10.1371/journal.pone.0153815. eCollection 2016.
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.
冠状动脉疾病（CAD），包括心肌梗死（MI），是一种由动脉粥样硬化引起的常见复杂疾病。尽管大量基因变异与CAD相关，但仅能解释10%的CAD病例。有人提出低频和罕见基因变异可能是CAD的主要病因。SIRT3是一种线粒体去乙酰化酶，在 mitochondrial function and metabolism中起重要作用。实验动物中缺乏SIRT3会导致多种与年龄相关的疾病，包括心血管疾病。因此，SIRT3基因变异可能促成MI的发生发展。在本研究中，对大量MI患者队列（n = 319）和种族匹配的对照组（n = 322）进行了SIRT3基因启动子的遗传学和功能分析。共鉴定出23个DNA序列变异（DSV），包括10个单核苷酸多态性（SNP）。在9例MI患者中鉴定出6个新的杂合DSV，即g.237307A>G、g.237270G>A、g.237023_25del、g.236653C>A、g.236628G>C、g.236557T>C，以及2个SNP，即g.237030C>T（rs12293349）和g.237022C>G（rs369344513），而对照组中均未发现。3个SNP，即g.236473C>T（rs11246029）、g.236380_81ins（rs71019893）和g.236370C>G（rs185277566），在MI患者中的出现频率显著高于对照组（P<0.05）。除g.236557T>C外，这些DSV和SNP均显著降低了培养的HEK-293细胞和H9c2细胞中SIRT3基因启动子的转录活性。因此，在MI患者中鉴定出的这些DSV可能通过影响SIRT3基因启动子的转录活性来改变SIRT3水平，作为一个危险因素促成MI的发生发展。
