中国人群动脉粥样硬化相关疾病的分子遗传学研究

发布时间：2018-03-17 02:04

本文选题：动脉粥样硬化　切入点：心衰　出处：《华中科技大学》2010年博士论文　论文类型：学位论文

【摘要】：动脉粥样硬化(atherosclerosis)是一类严重影响人类身体健康的疾病,由动脉粥样硬化导致的心脑血管疾病包括冠心病、脑卒中已经成为现代社会中最主要致死和致残的原因。动脉粥样硬化疾病的发生由环境因素和遗传因素共同决定,且多呈复杂性遗传模式。通过家系定位克隆和候选基因关联分析,已经认识到一些基因在动脉粥样硬化的过程中发挥着作用。近年来,随着全基因组关联分析(Genome-wide association study)的开展,发现了一些基因和SNP位点对于人群中动脉粥样硬化发生风险相关,在很大程度上增加了我们对动脉粥样硬化分子遗传机制的理解。但目前的大多数全基因组关联分析是在欧洲裔白人群体中进行,其研究结果并不一定能够完全适用于中国人群,因此寻找中国人群特异性与动脉粥样硬化相关的基因和位点,以及发现已报道位点在中国人群中是否具有不同的遗传表现形式,是我们在动脉粥样硬化疾病分子遗传学研究的重点之一。本研究通过病例-对照研究,对两个SNP位点与中国汉族人群动脉粥样硬化的关联进行了研究。第一部分：多态rs11206510与中国汉族人群冠心病、缺血性脑卒中和低密度脂蛋白浓度的关联研究之前的多个不同的全基因组关联分析研究结果均显示,位于染色体1p32区域的SNP位点rs11206510的大等位T与欧洲裔白人群体中血清低密度脂蛋白浓度(LDL-c)以及冠心病(CAD)的风险显著相关,但是该位点是否也与中国汉族人群LDL-c浓度和CAD风险相关,以及是否与缺血性脑卒中相关需要进一步的研究。通过对一个1415例样本的普通人群群体的研究,我们分析了rs11206510与中国汉族人群血清LDL-c是否存在关联,结果显示rs11206510的小等位C,而非大等位T对于中国汉族人群血清LDL-c浓度的增加具有风险(矫正后P-adj=0.002)。同时,我们在一个包含1543例CAD病例和1240例冠心病对照的群体中,研究了rs11206510与冠心病之间的关联。结果显示rs11206510小等位C显著增加早发型冠心病群体中(男性≤50岁,女性≤55岁,病例380例,对照1240例)冠心病发生的风险(P-adj=0.002, OR=1.89),但在总冠心病群体和迟发型冠心病群体中二者没有显著关联(总冠心病群体P-adj=0.82,迟发型冠心病群体P-adj=0.50)。为研究rs11206510是否也与缺血性脑卒中相关,我们在两个独立的缺血性脑卒中群体中对rs11206510与缺血性脑卒中的关联进行了研究。在样本主要来自中国北方地区居民的GeneID-north群体中(1205例病例样本,1205例对照样本),rs11206510小等位C显著增加缺血性脑卒中发生的风险(P-adj=1.13×10-5,OR=1.71)。在另外一个独立群体GeneID-central中,样本主要来自华中地区,其中病例692例,对照样本882例,rs11206510小等位C亦与缺血性脑卒中发生风险显著相关(P-adj=9.32×10-5,OR=1.70)。我的研究结果显示rs11206510的小等位C与中国汉族人群LDL-c浓度和早发型CAD是显著相关的,并且,我们首次发现rs11206510与缺血性脑卒中显著相关。第二部分：APJ基因多态性与中国汉族人群动脉粥样硬化以及左室收缩功能不全的关联分析动物模型和细胞学研究发现,Apelin和其受体APJ组成的信号通路与心衰、血压调节等显著相关,此外还发现其可能与动脉粥样硬化相关。之前的GWAS研究发现,位于APJ受体基因5’上游的一系列SNP位点与脑卒中显著相关,且其中位于APJ核心启动区域的SNP位点rs9943582具有功能性改变,能够通过改变与SP1转录因子的结合能力而影响启动子的转录活性,该位点可能是一个重要的具有功能学意义的致病位点,其与动脉粥样硬化的关系需要进一步研究,而且APJ受体与心衰的发生具有较强的联系,rs9943582还可能与心衰具有关联。我们通过一个冠心病研究群体(1751例病例,1022例对照样本)和一个缺血性脑卒中研究群体(1158例病例,1265例对照样本),发现rs9943582与中国汉族冠心病和脑卒中均无显著关联(冠心病群体：P-adj=0.22,缺血性脑卒中：P-adj=0.86)。在两个群体中,对性别和高血压进行分层分析之后,也没有发现显著关联。将1751例CAD患者根据心脏超声左室射血分数(LVEF)分为CAD伴左室收缩功能障碍组(LVEF40%,431例)以及CAD且左室收缩功能正常组(LVEF50%,1046例)之后,发现CAD伴左室收缩功能障碍组与CAD且左室收缩功能正常组相比,rs9943582的A等位显著增加CAD病人中左室收缩功能障碍的风险(P-adj=6.71×10-5,OR值为1.43)。此外,在rs9943582还与心脏超声检查数量性状如舒张末期左室内径、左房大小以及LVEF显著相关。通过我们的研究,发现rs9943582可能与中国汉族人群冠心病和缺血性脑卒中无显著关联,但是可能显著增加冠心病发生后发生左室收缩功能障碍的风险。我们的研究结果从遗传学的角度揭示APJ基因可能与心衰发生过程相关,rs9943582可能用于预测冠心病的预后,特别是左室收缩功能障碍的发生。
[Abstract]:Atherosclerosis (atherosclerosis) is a kind of serious impact on human health diseases, cardiovascular and cerebrovascular diseases caused by atherosclerosis including coronary heart disease, stroke in modern society has become the main cause of death and disability. Atherosclerosis disease is determined by both genetic and environmental factors, and a complex genetic model. Through family positioning cloning and analysis of candidate gene association, has been recognized by some genes play a role in the process of atherosclerosis. In recent years, along with the analysis of genome-wide association (Genome-wide association study) to carry out, found some genes and SNP loci for populations of atherosclerosis risk, our understanding of the molecular genetic mechanism of atherosclerosis in a large increase extent. But most genome-wide association analysis is currently In the European American Caucasian populations, the results are not necessarily able to fully apply to Chinese crowd, so looking for China population specific and atherosclerosis related genes and loci, and that has been reported in China sites whether populations with different genetic forms, is one of our research in genetics of atherosclerotic disease molecular focus. This study by a case-control study of two SNP loci associated with atherosclerosis Chinese Han population were studied.
Part one: association of polymorphic rs11206510 with coronary heart disease, ischemic stroke and low density lipoprotein in Chinese Han population
A genome-wide association analysis before experiment results showed that the serum low density lipoprotein concentration and T located on chromosome 1p32 region of the SNP locus rs11206510 and European descent white group (LDL-c) and coronary heart disease (CAD) were significantly related to the risk, but the site is also associated with China Han population LDL-c the concentration of CAD and risk, and whether it is associated with ischemic stroke needs further study.
Through the study of a sample of 1415 cases of the general population group, we analyzed rs11206510 and LDL-c in serum of Chinese Han population is associated, results show that the small C rs11206510, instead of the alleles of T has increased risk for China Han population serum LDL-c concentration (corrected P-adj=0.002). At the same time, we are in a 1543 CAD cases and 1240 cases of coronary heart disease control group, study the association between rs11206510 and coronary heart disease. The results showed that rs11206510 allele of C significantly increased the early onset of coronary heart disease group (male = 50 years, women less than 55 years old, 380 cases, 1240 cases of control the risk of coronary heart disease () P-adj=0.002, OR=1.89), but in total coronary heart disease group and delayed coronary heart disease group two were not significantly correlated (total coronary heart disease group P-adj=0.82, delayed coronary heart disease group P-adj=0.50). To investigate whether rs11206510 also Associated with ischemic stroke, we conducted a research on the relationship between rs11206510 and ischemic stroke in two independent ischemic stroke group. In the sample mainly from northern residents Chinese GeneID-north group (1205 cases of samples, 1205 cases of control samples), rs11206510 allele C significantly increased the risk of ischemic stroke the (P-adj=1.13 * 10-5, OR=1.71). In a separate group of GeneID-central in samples mainly from the central region, there were 692 cases, 882 cases of control samples, rs11206510 allele C and ischemic stroke risk was significantly correlated (P-adj=9.32 * 10-5, OR=1.70).
My research results showed that the small allele C of rs11206510 was significantly correlated with LDL-c concentration and early onset CAD in Chinese Han population, and we found for the first time that rs11206510 was significantly correlated with ischemic stroke.
The second part: the association analysis of APJ gene polymorphism with atherosclerosis and left ventricular systolic dysfunction in Chinese Han population
Animal model and cytological studies show that the signaling pathway and the failure of Apelin and its receptor APJ, blood pressure levels, in addition it may be associated with atherosclerosis. GWAS study found significant correlation in APJ receptor gene 5 'upstream of a series of SNP sites and stroke, which is located in APJ core promoter regional SNP site rs9943582 has the function of change, can affect the transcriptional activity of the promoter by combining ability changes with SP1 transcription factors, the site may be an important functional significance of pathogenic sites, the atherosclerosis needs further study, and APJ receptor and heart failure with strong rs9943582, also may be associated with heart failure.
Through a study of coronary heart disease group (1751 cases, 1022 cases of control samples) and an ischemic stroke study group (1158 cases, 1265 cases of control samples), found that rs9943582 and Chinese Han coronary heart disease and stroke were not significantly related (coronary heart disease group: ischemic stroke: P-adj=0.22, P-adj=0.86) in two. A group, after stratified analysis of gender and hypertension, also found no significant correlation. 1751 cases of CAD patients according to the left ventricular ejection fraction (LVEF) were divided into CAD with left ventricular systolic dysfunction group (LVEF40%, n = 431) and CAD and left ventricular systolic function in normal group (LVEF50%, 1046 cases after that, CAD) with left ventricular systolic dysfunction group with CAD and left ventricular systolic function compared to the normal group, the rs9943582 A allele significantly increased the risk of CAD patients with left ventricular systolic dysfunction (P-adj=6.71 * 10-5, OR = 1.43) in addition. Rs9943582 was also significantly associated with quantitative traits such as left ventricular diameter at the end of diastolic, left atrial size and LVEF at the end of diastolic echocardiography.
Through our study, found that rs9943582 may have no significant association with China Han population of coronary heart disease and ischemic stroke, but may increase the risk of occurrence of left ventricular systolic dysfunction after coronary heart disease. The results of our study revealed from the angle of genetics APJ gene may be associated with the process of heart failure, rs9943582 may be used to predict the prognosis of coronary heart disease, especially left ventricular systolic dysfunction.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R543;R394

【共引文献】