摘要
背景
冠心病(CAD)是一种主要由冠状动脉血管壁粥样硬化所引起,由遗传和环境因素及两者之间相互作用引起的多基因疾病,而心肌梗死是冠心病的一种限制性表型,包括ST抬高型心肌梗死、非ST抬高型心肌梗死。目前,国内外通过对候选基因、连锁分析、全基因组关联研究(GWAS)等确定与心肌梗死相关联的基因及基因位点有十多个,但是其在心肌梗死中遗传因素及致病的分子机制仍不清楚。SIRT1是一种依赖NAD±的组蛋白去乙酰化酶,参与了体内许多生理功能的调节,包括众多基因转录、能量代谢、炎症反应、氧化应激以及细胞衰老过程的调节等,尤其在糖代谢、脂代谢、调节胰岛素分泌中发挥着重要的作用。SIRT1还可以通过去乙酰化自噬相关蛋白(ATG)和叉头框蛋白转录因子(FOXOs)诱导自噬,在心肌梗死病人中发现自噬减少。此外,SIRT1也参与调节血管内皮和动脉粥样硬化的形成。因此,我们假设SIRT1可能参与心肌梗死的发病。
目的
1)通过对心肌梗死病人进行SIRT1基因启动子的遗传学分析,明确SIRT1基因启动子基因变异与心肌梗死的关系。
2)通过荧光素酶报告基因载体系列pGL3测定SIRT1功能,检测其功能变化,为进一步从基因水平预测心肌梗死的发病风险,并作为预防和治疗靶位点提供理论基础。
方法
1)PCR法扩增SIRT1基因启动子DNA序列,测序后分析各组SIRT1基因启动子序列变化情况。
2)应用pMDR19-T载体扩增SIRT1突变基因,将SIRT1突变基因插入到pGL3-Basic载体,同pRL-TK载体共转染HEK-293细胞,分别测萤火虫荧光素酶和海肾荧光素酶的量,计算其比值,观察SIRT1基因功能变化。
结果
1)基因分析发现六个单核苷酸多态性(SNPs)和14DNA序列变异被确定。其中,五种异常杂合变异体(g.69643743Ins, g.69643840Ins, g.69643903G>C, g.69644235G>C and g.69644353G>T)在五个MI患者中被发现,但是在对照组没有异常。此外,在三个MI患者发现一个SNP(g.69643707A>C, rs35706870),但在对照组中没有。与此相反,五个异常杂合变异体(g.69643672G>A, g.69644226C＞T, g.69644278A>G, g.69644408G>A and g.69644408G>T)只在对照组中被确认。其余的单核苷酸多态性和序列变异在MI患者和对照组中均被发现,其频率相似。
2)心肌梗死患者中SIRT1突变基因功能与正常人比较差异有统计学意义(p<0.05),而健康对照组中SIRT1突变基因功能与正常人比较差异无统计学意义(p>0.05)
3)心肌梗死患者中SIRT1基因启动子的功能发生了变化,突变后其功能可以减弱亦可以增强。
结论
总之,我们认为,在心肌梗死患者中被确定的基因变异,可能导致SIRT1基因启动子转录活性的改变,从而导致SIRT1功能水平的变化,成为心肌梗死发病机制的一个危险因素。
Background
Coronary artery disease is a common complex disease that is caused by interactions of environmental and genetic factors. Myocardial infarction (MI) is a restrictive phenotype of coronary artery disease. To date, a group of genes and genetic loci have been associated to MI. However, the genetic causes and underlying molecular mechanisms for MI remain largely unknown. SIRT1, one of highly conserved NAD-dependent class III deacetylases, has been involved in several cellular processes and implicated in human diseases. SIRT1is involved in cell survival and differentiation, genomic stability, transcription, metabolism, stress response and aging. Clinically, SIRT1has been implicated in inflammation, obesity, type2diabetes, cardiovascular diseases, neurodegenerative disease and cancer. Autophagy is one of major cellular degradative pathways, which plays important roles in lipid metabolism. SIRT1has been shown to induce autophagy by deacetylating autophagy-related (ATG) proteins (ATG5and ATG7) and forkhead box O transcription factors (FOXOs). In addition, SIRT1also regulates endothelial angiogenesis and atherosclerosis. Recent studies have shown that SIRT1deacetylates autophagy-related genes, and the expressions of autophagic genes are altered in MI patients. Accordingly, we hypothesized that SIRT1may be linked to the MI pathogenesis.
Objective
1) Investigating the relation between the variants of SIRT1gene promoter and myocardial infarction by analyzing the genetic analysis of SIRT1promoter in myocardial infarction patients.
2) Detecting the SIRT1function and identifing its function changes by determinating the luciferase reporter gene vector series of pGL3. It could provide a theoretical basis for predicting the risk of myocardial infarction at the genetic level and open the door for novel treatment and prevention strategies for myocardial infarction.
Methods
1) Genomic DNAs were extracted from peripheral leukocytes. SIRT1gene promoter sequence was amplified by using polymerase chain reaction. The SIRT1gene promoter was analyzed by direct sequencing.
2) The SIRT1mutant gene was amplified with the pMDR19-T vector and then inserted into the pGL3-Basic Vector. The pGL3-Basic Vector with SIRT1mutant gene and PRL-TK vector together were contransfected to HEK-293. The amount of firefly luciferase and renilla luciferase were measured, and then its ratio was calculated, in order to observing the functional change of SIRT1gene promoter.
Results
1) The results showed that six single-nucleotide polymorphisms and14sequence variants were identified. Among these, five novel heterozygous variants (g.69643743Ins, g.69643840Ins, g.69643903G>C, g.69644235G>C and g.69644353G>T) and one single-nucleotide polymorphism (rs35706870) were identified in MI patients, but in none of controls. Moreover, five novel heterozygous variants (g.69643672G>A, g.69644226C＞T, g.69644278A>G, g.69644408G>A and g.69644408G>T) were only found in controls. The rest variants were found in MI patients and controls with similar frequencies.
2) The difference between the SIRT1mutant gene in myocardial infarction and normal subjects was statistically significant (p<0.05). However, comparing to the normal SIRT1, the SIRT1mutant genes in healthy control was not statistically significant (p>0.05).
3) The function of SIRT1gene is changed in myocardial infarction patients, compared to the normal control; the viariation of SIRT1can be weakened or be enhanced.
Conclusion
Taken together, the variants identified in MI patients may alter the transcriptional activities of SIRT1gene promoter, which may change SIRT1levels, contributing to the MI pathogenesis as a risk factor.
引文
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