【摘要】：心血管疾病是西方國家發(fā)病率和死亡率的主要原因。在美國估計從2010到2030所有心血管疾病增加約10%,心力衰竭增加約25%。在多項(xiàng)隨機(jī)安慰劑對照臨床試驗(yàn)中已經(jīng)評估減少已知的心血管疾病危險因素如高脂血癥、高血壓,吸煙是關(guān)聯(lián)30%到40%少的臨床事件如死亡和心肌梗死。流行病學(xué)和家庭研究已經(jīng)多次表明遺傳易感性占40%至60%冠心病風(fēng)險。CAD的全基因組關(guān)聯(lián)研究(genome-wide association studies,GWAS)已發(fā)現(xiàn)多個易感基因位點(diǎn),常見變異與CAD的發(fā)病風(fēng)險相關(guān)。但是這些研究大多是針對歐洲人群。由于歐洲和亞洲人群的遺傳背景具有本質(zhì)區(qū)別,這些關(guān)聯(lián)需要進(jìn)一步的重復(fù)性研究,尤其是在其他種族進(jìn)行確認(rèn)。ADAMTS(a disintegrin and metalloprotease with thrombospondin motif,7[MIM 605009])是一種屬于解聚素及金屬蛋白酶與血小板1型重復(fù)序列(ADAMTS)家族的金屬蛋白酶。ADAMTS7的單核苷酸多態(tài)性(single nucleotide polymorphisms,SNP)與多個白種人研究人群的CAD的發(fā)病風(fēng)險相關(guān)。研究已在動物模型中證明,ADAMTS7通過降解細(xì)胞外基質(zhì)蛋白血小板-5(thrombospondin-5,TSP5)促進(jìn)血管平滑肌細(xì)胞(vascular smooth muscle cell,VSMC)的遷移,從而促進(jìn)了新內(nèi)膜形成和接下來的血管機(jī)械損傷。鑒于VSMC遷移是動脈粥樣硬化的重要過程,很可能ADAMTS7在動脈粥樣硬化和再狹窄的發(fā)生過程中發(fā)揮重要作用,而上述的病理生理過程參與大多數(shù)的CAD發(fā)生。肌肉的Ras(MRAS)基因駐留在3q22.3染色體和編碼膜結(jié)合的Ras小GTP酶蛋白,其用作在多個進(jìn)程信號轉(zhuǎn)導(dǎo),包括細(xì)胞生長和分化.曾有報道,MRAS基因內(nèi)四個單核苷酸多態(tài)性(SNP)(rs9818870,rs2306374,rs1720819和rs1199337)名義上與在歐洲人群的CAD遺傳易感性,并導(dǎo)致部分已在沙特人群復(fù)制.但是,不同于歐洲血統(tǒng)的人群,rs9818870的T等位基因和rs2306374 C-等位基因的頻率比較低(1%)在Hap Map計劃中國漢族北京(CHB)數(shù)據(jù)庫。提出一個問題是否這些變體是中國人群CAD的主要貢獻(xiàn)者的問題。此外,一直缺乏MRAS周圍的基因多態(tài)性與中國人群冠心病的關(guān)聯(lián)研究。乙醛脫氫酶2(ALDH2)是ALDH基因家族中19名成員的一員7。在酒精代謝中,它是催化乙醛氧化形成乙酸的第二大關(guān)鍵的酶8。ALDH2同時還參與其它的脫醛反應(yīng),比如4-羥基-2-壬烯醛(4-HNE)。GWASs已經(jīng)發(fā)現(xiàn)在ALDH2基因上12q24位置上的基因變異參與冠心病的發(fā)生發(fā)展。然而,由于潛在的遺傳異質(zhì)性,在不同的祖先群體中,關(guān)聯(lián)研究得到相當(dāng)多不同的結(jié)果,特別是白種人和亞洲人之間。人體肝臟的醛脫氫酶主要有胞質(zhì)和線粒體里兩個主要的同種型。大多數(shù)白種人有兩個主要的同功酶,而將近50%的亞洲人不具有線粒體的同工型12。體內(nèi)無催化活性的酶的個體乙醛暴露越多越易罹患各種疾病。第一部分基因ADAMTS7變異位點(diǎn)跨種族影響冠狀動脈粥樣斑塊的形成目的:冠狀動脈疾病(coronary artery disease,CAD)具有相當(dāng)大的遺傳成分是不完全表征。最近的CAD的全基因組關(guān)聯(lián)研究(genome-wide association studies,GWAS)在歐洲人群發(fā)現(xiàn)一個新的易感位點(diǎn)ADAMTS7。本項(xiàng)研究旨在評估位于蛋白酶ADAMTS7功能前區(qū)的非同義替換變異位點(diǎn)rs3825807對中國人群CAD的發(fā)病風(fēng)險和動脈粥樣硬化的嚴(yán)重程度的影響。方法:本研究納入兩個獨(dú)立的研究人群,分別來自石家莊和武漢,其中第一組包括1536例冠心病患者和1609正常對照人群,參與者為2012年9月和2013年9月間從河北醫(yī)科大學(xué)第二醫(yī)院連續(xù)招募的就醫(yī)者。第二組來源于武漢同濟(jì)醫(yī)院的5009例人群中進(jìn)行了獨(dú)立的重復(fù)研究,該人群包括2466例CAD患者和2543正常對照參與者。本組患者為2004年5月至2012年12月在同濟(jì)醫(yī)院連續(xù)招募的就診者,為了匹配種族及地區(qū)差異,正常對照組為同期來自武漢市社區(qū)收集的正常人群�？傆�8154例參與者,進(jìn)行遺傳關(guān)聯(lián)分析;此外,我們評估了ADAMTS7 rs3825807基因型在3支血管病變的CAD患者和1支血管病變的患者之間的分布。結(jié)果:我們發(fā)現(xiàn),ADAMTS7 rs3825807與中國人群對CAD的易感性相關(guān)(危險比=1.15,95%可信區(qū)間=1.05-1.26,P=0.002)。在調(diào)整了臨床協(xié)變量后,該關(guān)聯(lián)仍然顯著(調(diào)整后危險比=1.12,95%可信區(qū)間=1.02-1.24,P=0.02)。其中3741例參與者經(jīng)冠狀動脈血管造影證實(shí)為冠心病患者,rs3825807的風(fēng)險等位基因表現(xiàn)出與疾病的嚴(yán)重程度具有顯著相關(guān)性(P=0.04,趨勢P=0.02)。此外,3支血管病變患者表現(xiàn)出了很強(qiáng)的、直接的與ADAMTS7 rs3825807的基因劑量關(guān)聯(lián)(P=0.02)。結(jié)論:ADAMTS7是CAD的一個重要的易感位點(diǎn),不僅跨種族影響CAD的發(fā)病風(fēng)險,也預(yù)示冠狀動脈粥樣硬化病變的嚴(yán)重程度。第二部分MRAS在冠心病風(fēng)險中的遺傳學(xué)作用目的:研究發(fā)現(xiàn),在歐洲白種人,肌肉Ras基因(muscle Ras,MRAS)與冠心病相關(guān)。本研究的目的是確定MRAS基因多態(tài)性在冠心病患病風(fēng)險中的作用,并探討對中國人冠心病嚴(yán)重程度的影響。方法:在5009例中國樣本中(其中2466例冠心病患者和2543例正常對照個體),檢測MRAS基因周圍的8個單核苷酸多態(tài)性(single nucleotide polymorphisms,SNPs),采用邏輯回歸方法分析SNPs是否與冠心病發(fā)病有關(guān),并采用邏輯回歸和線性回歸研究SNPs與冠心病嚴(yán)重程度的關(guān)系。結(jié)果:研究結(jié)果顯示,內(nèi)含子SNP(RS 1199337)與CAD之間的關(guān)聯(lián)與先前在白種人中的報導(dǎo)一致(標(biāo)準(zhǔn)化的P=0.01,OR 1.10,95%CI1.01-1.20)。但是,在進(jìn)行Bonferroni校正后(校正P=0.08),該關(guān)聯(lián)就不存在了。在多因素分析,沒有找到與CAD相關(guān)的SNP位點(diǎn)(P0.05)。此外,我們還進(jìn)行了顯性和隱性模型的遺傳分析。然而,在顯性或隱性遺傳模式下,仍沒有找到與CAD相關(guān)聯(lián)的SNP(所有的P值0.05)。我們進(jìn)一步對SNPs與CAD之間的關(guān)聯(lián)進(jìn)行單倍體型分析。但仍沒有哪一種單倍體與CAD相關(guān)聯(lián),而且我們未發(fā)現(xiàn)SNPs與冠心病嚴(yán)重度有關(guān)聯(lián)(所有的P0.05)。結(jié)論:在中國人群,MRAS基因多態(tài)性可能對冠心病的患病風(fēng)險影響微乎其微。第三部分ALDH2基因變異對冠心病患者的影響目的:乙醛脫氫酶2基因變異對動脈粥樣硬化的影響之前已有報道,而在CVD患者中,這種常見變異對心血管事件的影響尚未被廣泛的研究。方法:在這項(xiàng)研究中,我們隨訪了兩個隊(duì)列,最初的隊(duì)列包括1920例冠心病患者和1920例種族和地理上配對的對照組。所有病例均來自武漢同濟(jì)醫(yī)院,健康受試者來自武漢的兩個社區(qū)。為了證實(shí)我們的結(jié)果的可信度,我們也對第二個人群進(jìn)行了驗(yàn)證,包括1573 CAD患者和1920的健康人群。這個病例和對照組均來自于河北醫(yī)科大學(xué)第二醫(yī)院。隨訪的中位時間是41.44±19.71個月,研究乙醛脫氫酶2基因變異對心血管結(jié)局事件的影響。結(jié)果:在同濟(jì)隊(duì)列中只有rs671與CAD顯著相關(guān)(OR=1.26,95%CI:1.13-1.40,P0.001)。校正傳統(tǒng)的危險因素(包括年齡,性別,體重指數(shù)(BMI),腰臀比(WHR),高血壓,高血脂,糖尿病,吸煙和飲酒狀況),結(jié)果不變(OR=1.26,95%CI:1.07-1.48,P=0.004)。在隱性模式下,結(jié)果類似(校正前OR=1.37,95%CI:1.21-1.56,P0.001,校正后的OR=1.34,95%CI:1.10-1.64,P=0.004)。然而,這種關(guān)聯(lián)沒有在石家莊的隊(duì)列中發(fā)現(xiàn)。我們把終點(diǎn)事件定義為心肌梗死,卒中,心臟衰竭和再住院。在41.44±19.71個月隨訪期間,410人發(fā)生了事件。校正性別,年齡,性別,體重指數(shù),腰臀比,吸煙和飲酒狀態(tài),在我們隨訪研究中,GG和GA+AA基因型(HR=1.11,95%CI之間:0.892-1.38,P=0.346)之間無統(tǒng)計學(xué)差異。GG和GA+AA在心肌梗死,中風(fēng),心臟衰竭和再住院的終點(diǎn)事件的發(fā)生率同樣也無顯著的統(tǒng)計學(xué)差異。我們的研究結(jié)果并沒有證據(jù)證明ALDH2基因型可能會影響CAD患者的事件發(fā)生(HR=1.11,95%CI:0.892-1.38,P=0.346)。結(jié)論:ALDH2上的常見變異rs671與中國武漢地區(qū)患CAD的風(fēng)險增加有關(guān),而在中國石家莊地區(qū)沒有相關(guān)性。RS671基因型可能不會影響CVD患者的結(jié)局事件。
[Abstract]:Cardiovascular disease is the leading cause of morbidity and mortality in Western countries. It is estimated in the United States that all cardiovascular diseases will increase by about 10% and heart failure by about 25% from 2010 to 2030. Epidemiological and family studies have repeatedly shown that genetic susceptibility accounts for 40% to 60% of the risk of coronary heart disease. The genome-wide association studies (GWAS) of CAD have identified multiple susceptibility loci, common variations associated with the risk of CAD. These associations require further repetitive studies, especially in other races, because of the essential differences in genetic backgrounds between European and Asian populations. ADAMTS (a disintegrin and metalloprotease with thrombospondin motif, 7 [MIM 605009]) is a class of depolymers and metalloproteinases and metalloproteinases. Single nucleotide polymorphisms (SNPs) of platelet type 1 repeats (ADAMTS) family metalloproteinases. ADAMTS7 is associated with the risk of developing CAD in multiple white study populations. Studies have shown that ADAMTS7 promotes the progression of CAD by degrading extracellular matrix protein platelet-5 (TSP5) in animal models. Vascular smooth muscle cell (VSMC) migration promotes neointima formation and subsequent vascular mechanical injury. Given that VSMC migration is an important process of atherosclerosis, it is likely that ADAMTS7 plays an important role in the pathogenesis of atherosclerosis and restenosis, and the pathophysiological process described above Muscle RAS (MRAS) genes reside on chromosome 3q22.3 and encode membrane-bound Ras small GTP proteins, which are used for signal transduction in multiple processes, including cell growth and differentiation. It has been reported that four single nucleotide polymorphisms (SNPs) within the MRAS gene (rs9818870, rs2306374, rs1720819, and rs1199337) are nominally associated with However, unlike people of European origin, the frequencies of the T allele and the rs2306374 C-allele of rs9818870 are relatively low (1%) in the Hap Map Chinese Han Beijing (CHB) database. A question is raised whether these variants are the main CAD variants in the Chinese population. Aldehyde dehydrogenase 2 (ALDH2) is one of the 19 members of the ALDH family. It is the second key enzyme in alcohol metabolism that catalyzes the oxidation of acetaldehyde to acetic acid. ALDH2 is also involved in other aldehyde removal reactions. For example, 4-hydroxy-2-nonenoaldehyde (4-HNE). GWASs has been found to be involved in the development of coronary heart disease (CHD) by mutations in the 12q24 locus of the ALDH2 gene. However, due to potential genetic heterogeneity, association studies have yielded quite different results in different ancestral populations, especially between Caucasians and Asians. Most Caucasians have two major isoenzymes, while nearly 50% of Asians do not have mitochondrial isoenzymes. Individuals without catalytic enzymes are more susceptible to various diseases when exposed to acetaldehyde. Objectives of atherosclerotic plaque formation: Coronary artery disease (CAD) is incompletely characterized by a considerable genetic component. Recent CAD genome-wide association studies (GWAS) have identified a new susceptibility site, ADAMTS7, in European populations. METHODS: This study included two independent study groups from Shijiazhuang and Wuhan. The first group consisted of 1536 patients with coronary heart disease and 1609 normal controls. Participants were 201. A second cohort of 5 009 people from Wuhan Tongji Hospital, including 2 466 CAD patients and 2 543 normal controls, were recruited from the Second Hospital of Hebei Medical University from May 2004 to December 2012. In addition, we assessed the distribution of ADAMTS7 rs3825807 genotype between CAD patients with three vessel lesions and patients with one vessel lesion. ADAMTS7 rs3825807 was found to be associated with susceptibility to CAD in the Chinese population (risk ratio = 1.15, 95% confidence interval = 1.05-1.26, P = 0.002). After adjusting for clinical covariates, the association remained significant (adjusted risk ratio = 1.12, 95% confidence interval = 1.02-1.24, P = 0.02). Of these, 3741 participants were confirmed as having coronary artery disease by coronary angiography. The risk allele of rs3825807 was significantly correlated with the severity of the disease (P = 0.04, trend P = 0.02). In addition, patients with three vascular lesions showed a strong association with the gene dose of ADAMTS7 rs3825807 (P = 0.02). Conclusion: ADAMTS7 is an important susceptible site of CAD, and not only affects the incidence of CAD across races. The second part is the genetic role of MRAS in the risk of coronary heart disease. Objective: The study found that muscle Ras (MRAS) gene is associated with coronary heart disease in European Caucasians. Methods: Eight single nucleotide polymorphisms (SNPs) around the MRAS gene were detected in 5 009 Chinese samples (2 466 patients with coronary heart disease and 2 543 normal controls). Logistic regression analysis was used to determine whether SNPs were associated with coronary heart disease. Results: The association between intron SNP (RS 1199337) and CAD was consistent with previous reports in Caucasians (standardized P = 0.01, OR 1.10, 95% CI1.01-1.20). However, the association did not exist after Bonferroni correction (corrected P = 0.08). In multivariate analysis, no SNP loci associated with CAD were found (P 0.05). In addition, genetic analysis of dominant and recessive models was carried out. However, no SNP associated with CAD was found in dominant or recessive models (all P values were 0.05). We further analyzed the association between SNPs and CAD by haplotype analysis. No haploid was associated with CAD, and we did not find SNPs associated with the severity of coronary heart disease (all P 0.05). Conclusion: In Chinese population, MRAS gene polymorphisms may have little effect on the risk of coronary heart disease. Part III Aldehyde dehydrogenase 2 gene mutations in patients with coronary heart disease Objective: Aldehyde dehydrogenase 2 gene mutations The effect of heterotransplantation on atherosclerosis has been previously reported, but the effect of this common variant on cardiovascular events has not been extensively studied in CVD patients. METHODS: In this study, we followed up two cohorts of 1920 patients with coronary artery disease and 1920 ethnically and geographically matched controls. Both cases were from Wuhan Tongji Hospital and healthy subjects were from two communities in Wuhan. To confirm the reliability of our results, we also validated the second population, including 1573 CAD patients and 1920 healthy people. Results: Only rs671 was significantly associated with CAD in the Tongji cohort (OR = 1.26, 95% CI: 1.13-1.40, P 0.001). Traditional risk factors (including age, sex, body mass index (BMI), waist-hip ratio (WHR), hypertension, hyperlipidemia, diabetes mellitus, smoking and alcohol consumption) were corrected. The results remained the same (OR = 1.26, 95% CI: 1.07-1.48, P = 0.004). In the implicit mode, the results were similar (OR = 1.37, 95% CI: 1.21-1.56, P 0.001 before correction, OR = 1.34, 95% CI: 1.10-1.64, P = 0.004 after correction). During the follow-up period of 19.71 months, 410 people had events. There was no significant difference between GG and GA + AA genotypes (HR = 1.11, 95% CI: 0.892-1.38, P = 0.346) in adjusted gender, age, sex, body mass index, waist-hip ratio, smoking and alcohol status. GG and GA + AA had no significant difference in the endpoints of myocardial infarction, stroke, heart failure and readmission. There is no evidence that the ALDH2 genotype may affect the incidence of CAD (HR = 1.11, 95% CI: 0.892-1.38, P = 0.346). Conclusion: The common variant rs671 on ALDH2 is associated with an increased risk of CAD in Wuhan, China, but not in Shijiazhuang, China. .RS671 genotype may not affect the outcome of CVD patients.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R54

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1 尤玲;中國漢族人群ADAMTS7、MRAS、ALDH2基因與心血管病遺傳易感性的研究[D];河北醫(yī)科大學(xué);2016年

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