SIRT6基因表达调控与急性心肌梗死的分子遗传学研究

发布时间：2018-07-25 18:32

【摘要】：目的:冠状动脉性心脏病(简称冠心病)是一种由冠状动脉粥样硬化引起的常见复杂性疾病,心肌梗死为冠心病的严重类型,在世界范围内致死率和致残率很高。目前认为,冠心病是由遗传因素和环境因素相互作用而导致。尽管大量研究已经证实,超过50个遗传位点和变异与人群冠心病发生风险具有显著相关性,但是这些位点仅占冠心病病例的10%左右。因此近来认为,少见和罕见的遗传变异可能是引发冠心病的重要原因。SIRT6是乙酰基化合物和长链酯酰基化合物的ADP依赖的核糖基转移酶酶,并具有高度保守的NAD依赖的第三类去乙酰化酶活性。基于其酶学作用,SIRT6通过调节基因组修复、端粒维持、葡萄糖和脂质代谢等过程影响细胞的代谢,其功能失调参与糖尿病、肥胖、心血管疾病和癌症等疾病的发生。最近,SIRT6基因与心血管系统功能以及心血管疾病的关系越来越引起重视。SIRT6调节心血管系统的生理功能,并参与炎症、脂质和胆固醇的代谢过程。因此,SIRT6基因的遗传变异可能导致冠心病,尤其是急性心肌梗死的发生和发展。方法:收集就诊于济宁医学院附属医院急性心肌梗死患者的血液样本,同时收集健康体检人群(排除了糖尿病、高脂血症和冠心病家族史等影响因素)的血液样本作为对照。通过分离白细胞,提取基因组DNA。根据SIRT6基因的基因组序列设计聚合酶链式反应(PCR)引物,对SIRT6基因的启动子区域进行扩增,并进行直接DNA序列测定。根据测序结果对371例急性心肌梗死患者和383例对照的SIRT6基因启动子区域进行遗传学分析,以期发现与急性心肌梗死相关的DNA变异位点。结果:在该研究人群中,共发现15个DNA序列变异,其中7个为单核苷酸多态性(SNPs)。在两个心肌梗死病人中发现了两个新的杂合子DNA序列变异(g.4183823GC和g.4183742GA),而在对照组中并没有发现。两个杂合子SNPs,g.4183685TC(rs4359565)和g.4182942CA(rs3760905),在急性心肌梗死病人中出现的频率显著高于对照组(P0.05)。结论:上述研究结果提示,在急性心肌梗死病人中,DNA序列变异可能影响SIRT6基因启动子的转录活性,并改变SIRT6基因的表达水平,然后通过不同的途径导致急性心肌梗死的发生和发展。
[Abstract]:Objective: coronary heart disease (CHD) is a common complex disease caused by coronary atherosclerosis. Myocardial infarction is a serious type of coronary heart disease. It is believed that coronary heart disease is caused by the interaction of genetic and environmental factors. Although a large number of studies have confirmed that more than 50 genetic loci and mutations are significantly associated with the risk of coronary heart disease, these loci account for only about 10% of coronary heart disease cases. Therefore, it has recently been suggested that rare and rare genetic variations may be an important cause of coronary heart disease. SIRT6 is an ADP dependent ribonyltransferase of acetyl compounds and long chain ester acyl compounds. And highly conserved NAD dependent deacetylase activity of the third type. Based on its enzymatic effects, SIRT6 affects cell metabolism by regulating genomic repair, telomere maintenance, glucose and lipid metabolism, and its dysfunction is involved in the occurrence of diabetes, obesity, cardiovascular disease and cancer. Recently, the relationship between SIRT6 gene and cardiovascular system function and cardiovascular disease has attracted more and more attention. SIRT6 regulates the physiological function of cardiovascular system and participates in the metabolism of inflammation, lipid and cholesterol. Therefore, the genetic variation of SIRT6 gene may lead to the occurrence and development of coronary heart disease, especially acute myocardial infarction. Methods: blood samples were collected from patients with acute myocardial infarction (AMI) in the affiliated Hospital of Jining Medical College, and blood samples from healthy people (excluding diabetes mellitus, hyperlipidemia and family history of coronary heart disease) were collected as control. The genome DNA was extracted by isolating white blood cells. Polymerase chain reaction (PCR) primers were designed according to the genomic sequence of SIRT6 gene. The promoter region of SIRT6 gene was amplified and the direct DNA sequence was sequenced. Genetic analysis of the promoter region of SIRT6 gene was performed in 371 patients with acute myocardial infarction and 383 controls according to the results of sequencing, in order to find the DNA mutation sites associated with acute myocardial infarction. Results: a total of 15 DNA sequence variations were found in the study population, of which 7 were single nucleotide polymorphisms (SNP) (SNPs). Two new heterozygous DNA mutations (g.4183823GC and g.4183742GA) were found in two myocardial infarction patients, but not in the control group. The frequency of two heterozygous SNPs (rs4359565) and g.4182942CA (rs3760905) in patients with acute myocardial infarction was significantly higher than that in the control group (P0.05). Conclusion: these results suggest that DNA sequence variation in patients with acute myocardial infarction may affect the transcriptional activity of SIRT6 promoter and change the expression level of SIRT6 gene. Then it leads to the occurrence and development of acute myocardial infarction in different ways.
【学位授予单位】：济宁医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R542.22

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