發(fā)布時(shí)間：2018-03-17 02:04

  本文選題：動(dòng)脈粥樣硬化　切入點(diǎn)：心衰　出處：《華中科技大學(xué)》2010年博士論文　論文類型：學(xué)位論文

【摘要】：動(dòng)脈粥樣硬化(atherosclerosis)是一類嚴(yán)重影響人類身體健康的疾病,由動(dòng)脈粥樣硬化導(dǎo)致的心腦血管疾病包括冠心病、腦卒中已經(jīng)成為現(xiàn)代社會(huì)中最主要致死和致殘的原因。動(dòng)脈粥樣硬化疾病的發(fā)生由環(huán)境因素和遺傳因素共同決定,且多呈復(fù)雜性遺傳模式。通過家系定位克隆和候選基因關(guān)聯(lián)分析,已經(jīng)認(rèn)識(shí)到一些基因在動(dòng)脈粥樣硬化的過程中發(fā)揮著作用。近年來,隨著全基因組關(guān)聯(lián)分析(Genome-wide association study)的開展,發(fā)現(xiàn)了一些基因和SNP位點(diǎn)對(duì)于人群中動(dòng)脈粥樣硬化發(fā)生風(fēng)險(xiǎn)相關(guān),在很大程度上增加了我們對(duì)動(dòng)脈粥樣硬化分子遺傳機(jī)制的理解。但目前的大多數(shù)全基因組關(guān)聯(lián)分析是在歐洲裔白人群體中進(jìn)行,其研究結(jié)果并不一定能夠完全適用于中國人群,因此尋找中國人群特異性與動(dòng)脈粥樣硬化相關(guān)的基因和位點(diǎn),以及發(fā)現(xiàn)已報(bào)道位點(diǎn)在中國人群中是否具有不同的遺傳表現(xiàn)形式,是我們在動(dòng)脈粥樣硬化疾病分子遺傳學(xué)研究的重點(diǎn)之一。本研究通過病例-對(duì)照研究,對(duì)兩個(gè)SNP位點(diǎn)與中國漢族人群動(dòng)脈粥樣硬化的關(guān)聯(lián)進(jìn)行了研究。 第一部分：多態(tài)rs11206510與中國漢族人群冠心病、缺血性腦卒中和低密度脂蛋白濃度的關(guān)聯(lián)研究 之前的多個(gè)不同的全基因組關(guān)聯(lián)分析研究結(jié)果均顯示,位于染色體1p32區(qū)域的SNP位點(diǎn)rs11206510的大等位T與歐洲裔白人群體中血清低密度脂蛋白濃度(LDL-c)以及冠心病(CAD)的風(fēng)險(xiǎn)顯著相關(guān),但是該位點(diǎn)是否也與中國漢族人群LDL-c濃度和CAD風(fēng)險(xiǎn)相關(guān),以及是否與缺血性腦卒中相關(guān)需要進(jìn)一步的研究。 通過對(duì)一個(gè)1415例樣本的普通人群群體的研究,我們分析了rs11206510與中國漢族人群血清LDL-c是否存在關(guān)聯(lián),結(jié)果顯示rs11206510的小等位C,而非大等位T對(duì)于中國漢族人群血清LDL-c濃度的增加具有風(fēng)險(xiǎn)(矯正后P-adj=0.002)。同時(shí),我們在一個(gè)包含1543例CAD病例和1240例冠心病對(duì)照的群體中,研究了rs11206510與冠心病之間的關(guān)聯(lián)。結(jié)果顯示rs11206510小等位C顯著增加早發(fā)型冠心病群體中(男性≤50歲,女性≤55歲,病例380例,對(duì)照1240例)冠心病發(fā)生的風(fēng)險(xiǎn)(P-adj=0.002, OR=1.89),但在總冠心病群體和遲發(fā)型冠心病群體中二者沒有顯著關(guān)聯(lián)(總冠心病群體P-adj=0.82,遲發(fā)型冠心病群體P-adj=0.50)。為研究rs11206510是否也與缺血性腦卒中相關(guān),我們在兩個(gè)獨(dú)立的缺血性腦卒中群體中對(duì)rs11206510與缺血性腦卒中的關(guān)聯(lián)進(jìn)行了研究。在樣本主要來自中國北方地區(qū)居民的GeneID-north群體中(1205例病例樣本,1205例對(duì)照樣本),rs11206510小等位C顯著增加缺血性腦卒中發(fā)生的風(fēng)險(xiǎn)(P-adj=1.13×10-5,OR=1.71)。在另外一個(gè)獨(dú)立群體GeneID-central中,樣本主要來自華中地區(qū),其中病例692例,對(duì)照樣本882例,rs11206510小等位C亦與缺血性腦卒中發(fā)生風(fēng)險(xiǎn)顯著相關(guān)(P-adj=9.32×10-5,OR=1.70)。 我的研究結(jié)果顯示rs11206510的小等位C與中國漢族人群LDL-c濃度和早發(fā)型CAD是顯著相關(guān)的,并且,我們首次發(fā)現(xiàn)rs11206510與缺血性腦卒中顯著相關(guān)。 第二部分：APJ基因多態(tài)性與中國漢族人群動(dòng)脈粥樣硬化以及左室收縮功能不全的關(guān)聯(lián)分析 動(dòng)物模型和細(xì)胞學(xué)研究發(fā)現(xiàn),Apelin和其受體APJ組成的信號(hào)通路與心衰、血壓調(diào)節(jié)等顯著相關(guān),此外還發(fā)現(xiàn)其可能與動(dòng)脈粥樣硬化相關(guān)。之前的GWAS研究發(fā)現(xiàn),位于APJ受體基因5’上游的一系列SNP位點(diǎn)與腦卒中顯著相關(guān),且其中位于APJ核心啟動(dòng)區(qū)域的SNP位點(diǎn)rs9943582具有功能性改變,能夠通過改變與SP1轉(zhuǎn)錄因子的結(jié)合能力而影響啟動(dòng)子的轉(zhuǎn)錄活性,該位點(diǎn)可能是一個(gè)重要的具有功能學(xué)意義的致病位點(diǎn),其與動(dòng)脈粥樣硬化的關(guān)系需要進(jìn)一步研究,而且APJ受體與心衰的發(fā)生具有較強(qiáng)的聯(lián)系,rs9943582還可能與心衰具有關(guān)聯(lián)。 我們通過一個(gè)冠心病研究群體(1751例病例,1022例對(duì)照樣本)和一個(gè)缺血性腦卒中研究群體(1158例病例,1265例對(duì)照樣本),發(fā)現(xiàn)rs9943582與中國漢族冠心病和腦卒中均無顯著關(guān)聯(lián)(冠心病群體：P-adj=0.22,缺血性腦卒中：P-adj=0.86)。在兩個(gè)群體中,對(duì)性別和高血壓進(jìn)行分層分析之后,也沒有發(fā)現(xiàn)顯著關(guān)聯(lián)。將1751例CAD患者根據(jù)心臟超聲左室射血分?jǐn)?shù)(LVEF)分為CAD伴左室收縮功能障礙組(LVEF40%,431例)以及CAD且左室收縮功能正常組(LVEF50%,1046例)之后,發(fā)現(xiàn)CAD伴左室收縮功能障礙組與CAD且左室收縮功能正常組相比,rs9943582的A等位顯著增加CAD病人中左室收縮功能障礙的風(fēng)險(xiǎn)(P-adj=6.71×10-5,OR值為1.43)。此外,在rs9943582還與心臟超聲檢查數(shù)量性狀如舒張末期左室內(nèi)徑、左房大小以及LVEF顯著相關(guān)。 通過我們的研究,發(fā)現(xiàn)rs9943582可能與中國漢族人群冠心病和缺血性腦卒中無顯著關(guān)聯(lián),但是可能顯著增加冠心病發(fā)生后發(fā)生左室收縮功能障礙的風(fēng)險(xiǎn)。我們的研究結(jié)果從遺傳學(xué)的角度揭示APJ基因可能與心衰發(fā)生過程相關(guān),rs9943582可能用于預(yù)測冠心病的預(yù)后,特別是左室收縮功能障礙的發(fā)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.

【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R543;R394

【共引文獻(xiàn)】

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6 李湘;降脂消斑片治療頸動(dòng)脈粥樣硬化斑塊痰熱血瘀證的臨床觀察[D];湖南中醫(yī)藥大學(xué);2011年

7 劉湘杰;降脂消斑片對(duì)冠心病不穩(wěn)定型心絞痛痰熱血瘀證的臨床療效觀察以及MMP-9和LDL-C表達(dá)水平的影響[D];湖南中醫(yī)藥大學(xué);2011年

8 高智群;黃芩苷對(duì)高脂血癥及脂多糖誘導(dǎo)的NF-κB信號(hào)通路的影響[D];廣州中醫(yī)藥大學(xué);2011年

9 楊艷杰;側(cè)腦室注射apelin-13抑制小鼠遠(yuǎn)端結(jié)腸運(yùn)動(dòng)[D];蘭州大學(xué);2011年

10 趙乾;外源性Apelin-13對(duì)心力衰竭大鼠血漿血管緊張素Ⅱ和腎上腺髓質(zhì)素及心功能的影響[D];蘭州大學(xué);2011年

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