血清AngⅡ、KLK1水平及ACE和KLK1基因多态性与急性心肌梗死的关联研究

发布时间：2018-06-28 03:14

本文选题：冠状动脉狭窄 + 急性心肌梗死　；参考：《山东大学》2017年硕士论文

【摘要】：研究背景急性心肌梗死(Acute myocardial infarction,AMI)是冠心病中最严重的类型之一。临床发现AMI患者血清血管紧张素Ⅱ(Angiotensin Ⅱ,AngⅡ)升高。尽管大量研究表明激肽释放酶1(The human tissue kallikrein1,KLK1)为心血管疾病发生的保护性因素,近年来研究发现在不稳定动脉硬化斑块中KLK1表达也增加。基因学研究发现血清中AngⅡ水平受血管紧张素转化酶(Angiotensinogenenzyme,ACE)及糜蛋白酶等的调控,他们催化无活性的血管紧张素I(Angiotensin I,AngⅠ)转化为具有血管活性的AngⅡ,发挥生物学作用。KLK1是丝氨酸蛋白家族中唯一生成缓激肽的关键酶。多数研究表明,AMI的发生与ACE基因的多态性有关,具有ACEDD基因型发生冠心病或AMI的危险性明显增加。另外,也有meta分析显示ACEDD基因型增加冠脉内支架再狭窄(OR = 2.18,95%CI:1.08-4.40)。血清中KLK1为KLK1基因的表达产物,它同样存在多态性,我们前期研究发现KLK1 GG基因型的个体较AA基因型冠状动脉狭窄(coronary artery stenosis,CAS)发生率高。AC和KLK1基因及表达在维持机体心血管正常功能方面起着关键作用。AMI是多基因疾病,单独的基因作用可能相对较微弱。本研究以冠脉造影发现CAS诱发的AMI患者与冠脉造影确定无狭窄的个体为研究对象,测定血清AngⅡ和KLK1水平及ACE和KLK1基因多态性4项指标,采用病例-对照分析方法,探讨他们与AMI的关联。目的探讨血清AngⅡ、KLK1水平及ACE和KLK1基因多态性与急性心肌梗死(AMI)的关联。方法冠脉造影确诊的208例AMI患者和216例正常对照为研究对象,采用酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)测定血清 AngⅡ、KLK1 水平;聚合酶链反应(PCR)扩增测定ACE(rs4646994)插入/缺失(insertion/deletion,I/D)基因型,PCR-TaqMan-MGB探针基因分型技术检测KLK1(rs5517)A/G基因型,基因直接测序法分析验证基因分型准确性。应用二元Logistic回归分析他们与AMI的关联。结果1.病例组和对照组血清AngⅡ水平分别为119.83±52.80和185.04±61.55(ng/L),血清KLK1水平分别为21.68±13.64和22.63±8.69(ng/ml),其中2组KLK1均值差异无统计学意义。2.血清指标高低值组合分层(AngⅡ"f120KLK1"f22、AngⅡ120KLK122、AngⅡ120KLK1"f22和AngⅡ120KLK122)构成比差异有统计学意义(x2=17.724,P0.001)。3.2组ACE DD基因型频率分别为23.1%和9.3%;KLK1 GG基因型频率分别为31.5%和40.4%;差异有统计学意义。ACE和KLK1基因型的组合分层频率差异也有统计学意义(x2=10.573,P=0.005)。4.在包括14个混杂因素(性别、年龄、吸烟史、糖尿病史、血生化和血凝指标(ALT、GGT、TP、DBIL、TBA、CHO、HDL、GLU、CR 和 TT))和 2 血清指标及2个基因型组合分层的回归模型中,与血清AngⅡ"f 120KLK1 "f22层比较,后3层与AMI都有显著性关联,其OR(95%CI)分别为4.62(1.11-19.33)、11.32(3.47-37.00)和 23.85(6.88-82.65)。5.在多因素Logistic回归模型中,调整上述14个混杂因素后,ACEDD基因型增加AMI的危险,然而单独的KLK1基因多态性不增加AMI的患病风险。6.与具有ACE和KLK1基因其他型的个体比较,具有ACEDD型和KLK1 GG基因型的个体发生AMI的风险显著增高(OR=8.77、95%CI=1.74-44.16)。结论1.血清AngⅡ水平增高发生AMI的危险性增加;2.2血清AngⅡ与KLK1水平同时升高则AMI的危险性显著增加;3.ACEDD基因型增加AMI的危险,具有ACEDD和KLK1 GG基因型的个体发生AMI的风险较其它型型显著增高,2基因型与AMI的易感性存在协同作用。
[Abstract]:Background acute myocardial infarction (Acute myocardial infarction, AMI) is one of the most serious types of coronary heart disease. It is found that serum angiotensin II (Angiotensin II, Ang II) in serum of AMI patients is elevated. Although a large number of studies have shown that kallikrein 1 (The human tissue kallikrein1, KLK1) is a protective factor for the occurrence of cardiovascular disease, Recent studies have found that the expression of KLK1 in unstable atherosclerotic plaques also increased. The genetic study found that the levels of Ang II in serum were regulated by the angiotensin converting enzyme (Angiotensinogenenzyme, ACE) and chymotrypsin, which catalyze the transformation of inactive angiotensin I (Angiotensin I, Ang I) into vasoactive Ang II. .KLK1 is a key enzyme in the serine protein family. Most studies have shown that the occurrence of AMI is associated with the polymorphism of the ACE gene, and the risk of ACEDD genotype in coronary heart disease or AMI is significantly increased. In addition, meta analysis shows that the ACEDD genotype increases the stent restenosis (OR = 2.18). 95%CI:1.08-4.40). The serum KLK1 is the expression product of the KLK1 gene. It also has polymorphism. Our previous study found that the individuals of the KLK1 GG genotype were higher than the AA genotype coronary stenosis (coronary artery stenosis, CAS), and the KLK1 genes and expressions played a key role in maintaining the normal cardiovascular function of the body. In this study, CAS induced AMI patients and individuals with no stenosis were determined by coronary angiography, and 4 indexes of serum Ang II and KLK1 and ACE and KLK1 gene polymorphisms were measured by coronary angiography. A case control analysis was used to explore their association with AMI. The association of serum Ang II, KLK1 level and ACE and KLK1 polymorphisms with acute myocardial infarction (AMI) was investigated. Methods 208 patients with AMI and 216 normal controls were studied. Enzyme linked immunosorbent assay (enzyme-linked immunosorbent assay, ELISA) was used to determine Ang II, KLK1 level, and polymerase chain reaction (polymerase chain reaction). The ACE (rs4646994) insertion / deletion (insertion/deletion, I/D) genotypes were amplified and the KLK1 (rs5517) A/G genotypes were detected by PCR-TaqMan-MGB probe genotyping technology. The accuracy of genotyping was verified by direct sequencing of genes. The correlation between them and AMI was analyzed by two yuan Logistic regression. The serum Ang II level of the 1. case group and the control group was determined. The levels of serum KLK1 were 119.83 + 52.80 and 185.04 + 61.55 (ng/L) respectively, and the levels of serum KLK1 were 21.68 + 13.64 and 22.63 + (ng/ml) respectively, and there was no statistically significant difference in the composition of the KLK1 mean of the 2 groups with no statistically significant difference between the.2. sera and the low value combined stratification (Ang II "f120KLK1" F22, Ang II 120KLK122, Ang II 120KLK1. 4, P0.001).3.2 group ACE DD genotype frequencies were 23.1% and 9.3%, KLK1 GG genotype frequencies were 31.5% and 40.4%, respectively. The difference was statistically significant (x2=10.573, P=0.005).4. was included in 14 melange (sex, age, smoking history, diabetes history, blood biochemistry and blood. The coagulant indexes (ALT, GGT, TP, DBIL, TBA, CHO, HDL, GLU, CR and TT)) and the regression model of the 2 serum index and the 2 genotype combination stratification were compared with the sera Ang II "f), and the latter 3 had a significant correlation with 4.62, 11.32 and 23.85 respectively in multiple factors regression. In the model, after adjusting the above 14 confounding factors, the ACEDD genotype increased the risk of AMI. However, the individual KLK1 gene polymorphism did not increase the risk of AMI,.6. was compared with those with ACE and KLK1 genes, and the risk of AMI in ACEDD and KLK1 GG genotypes increased significantly (OR=8.77,95%CI=1.74-44.16). Conclusion 1. The increase of serum Ang II level increased the risk of AMI; 2.2 serum Ang II and KLK1 level increased at the same time, the risk of AMI increased significantly; 3.ACEDD genotype increased the risk of AMI, and the risk of ACEDD and KLK1 GG genotype was significantly higher than that of other types, and the 2 genotypes had synergistic effect with the susceptibility of AMI.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R542.22

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