中国汉族人群ADAMTS7、MRAS、ALDH2基因与心血管病遗传易感性的研究
发布时间：2018-08-13 18:51
【摘要】：心血管疾病是西方国家发病率和死亡率的主要原因。在美国估计从2010到2030所有心血管疾病增加约10%,心力衰竭增加约25%。在多项随机安慰剂对照临床试验中已经评估减少已知的心血管疾病危险因素如高脂血症、高血压,吸烟是关联30%到40%少的临床事件如死亡和心肌梗死。流行病学和家庭研究已经多次表明遗传易感性占40%至60%冠心病风险。CAD的全基因组关联研究(genome-wide association studies,GWAS)已发现多个易感基因位点,常见变异与CAD的发病风险相关。但是这些研究大多是针对欧洲人群。由于欧洲和亚洲人群的遗传背景具有本质区别,这些关联需要进一步的重复性研究,尤其是在其他种族进行确认。ADAMTS(a disintegrin and metalloprotease with thrombospondin motif,7[MIM 605009])是一种属于解聚素及金属蛋白酶与血小板1型重复序列(ADAMTS)家族的金属蛋白酶。ADAMTS7的单核苷酸多态性(single nucleotide polymorphisms,SNP)与多个白种人研究人群的CAD的发病风险相关。研究已在动物模型中证明,ADAMTS7通过降解细胞外基质蛋白血小板-5(thrombospondin-5,TSP5)促进血管平滑肌细胞(vascular smooth muscle cell,VSMC)的迁移,从而促进了新内膜形成和接下来的血管机械损伤。鉴于VSMC迁移是动脉粥样硬化的重要过程,很可能ADAMTS7在动脉粥样硬化和再狭窄的发生过程中发挥重要作用,而上述的病理生理过程参与大多数的CAD发生。肌肉的Ras(MRAS)基因驻留在3q22.3染色体和编码膜结合的Ras小GTP酶蛋白,其用作在多个进程信号转导,包括细胞生长和分化.曾有报道,MRAS基因内四个单核苷酸多态性(SNP)(rs9818870,rs2306374,rs1720819和rs1199337)名义上与在欧洲人群的CAD遗传易感性,并导致部分已在沙特人群复制.但是,不同于欧洲血统的人群,rs9818870的T等位基因和rs2306374 C-等位基因的频率比较低(1%)在Hap Map计划中国汉族北京(CHB)数据库。提出一个问题是否这些变体是中国人群CAD的主要贡献者的问题。此外,一直缺乏MRAS周围的基因多态性与中国人群冠心病的关联研究。乙醛脱氢酶2(ALDH2)是ALDH基因家族中19名成员的一员7。在酒精代谢中,它是催化乙醛氧化形成乙酸的第二大关键的酶8。ALDH2同时还参与其它的脱醛反应,比如4-羟基-2-壬烯醛(4-HNE)。GWASs已经发现在ALDH2基因上12q24位置上的基因变异参与冠心病的发生发展。然而,由于潜在的遗传异质性,在不同的祖先群体中,关联研究得到相当多不同的结果,特别是白种人和亚洲人之间。人体肝脏的醛脱氢酶主要有胞质和线粒体里两个主要的同种型。大多数白种人有两个主要的同功酶,而将近50%的亚洲人不具有线粒体的同工型12。体内无催化活性的酶的个体乙醛暴露越多越易罹患各种疾病。第一部分基因ADAMTS7变异位点跨种族影响冠状动脉粥样斑块的形成目的:冠状动脉疾病(coronary artery disease,CAD)具有相当大的遗传成分是不完全表征。最近的CAD的全基因组关联研究(genome-wide association studies,GWAS)在欧洲人群发现一个新的易感位点ADAMTS7。本项研究旨在评估位于蛋白酶ADAMTS7功能前区的非同义替换变异位点rs3825807对中国人群CAD的发病风险和动脉粥样硬化的严重程度的影响。方法:本研究纳入两个独立的研究人群,分别来自石家庄和武汉,其中第一组包括1536例冠心病患者和1609正常对照人群,参与者为2012年9月和2013年9月间从河北医科大学第二医院连续招募的就医者。第二组来源于武汉同济医院的5009例人群中进行了独立的重复研究,该人群包括2466例CAD患者和2543正常对照参与者。本组患者为2004年5月至2012年12月在同济医院连续招募的就诊者,为了匹配种族及地区差异,正常对照组为同期来自武汉市社区收集的正常人群。总计8154例参与者,进行遗传关联分析;此外,我们评估了ADAMTS7 rs3825807基因型在3支血管病变的CAD患者和1支血管病变的患者之间的分布。结果:我们发现,ADAMTS7 rs3825807与中国人群对CAD的易感性相关(危险比=1.15,95%可信区间=1.05-1.26,P=0.002)。在调整了临床协变量后,该关联仍然显著(调整后危险比=1.12,95%可信区间=1.02-1.24,P=0.02)。其中3741例参与者经冠状动脉血管造影证实为冠心病患者,rs3825807的风险等位基因表现出与疾病的严重程度具有显著相关性(P=0.04,趋势P=0.02)。此外,3支血管病变患者表现出了很强的、直接的与ADAMTS7 rs3825807的基因剂量关联(P=0.02)。结论:ADAMTS7是CAD的一个重要的易感位点,不仅跨种族影响CAD的发病风险,也预示冠状动脉粥样硬化病变的严重程度。第二部分MRAS在冠心病风险中的遗传学作用目的:研究发现,在欧洲白种人,肌肉Ras基因(muscle Ras,MRAS)与冠心病相关。本研究的目的是确定MRAS基因多态性在冠心病患病风险中的作用,并探讨对中国人冠心病严重程度的影响。方法:在5009例中国样本中(其中2466例冠心病患者和2543例正常对照个体),检测MRAS基因周围的8个单核苷酸多态性(single nucleotide polymorphisms,SNPs),采用逻辑回归方法分析SNPs是否与冠心病发病有关,并采用逻辑回归和线性回归研究SNPs与冠心病严重程度的关系。结果:研究结果显示,内含子SNP(RS 1199337)与CAD之间的关联与先前在白种人中的报导一致(标准化的P=0.01,OR 1.10,95%CI1.01-1.20)。但是,在进行Bonferroni校正后(校正P=0.08),该关联就不存在了。在多因素分析,没有找到与CAD相关的SNP位点(P0.05)。此外,我们还进行了显性和隐性模型的遗传分析。然而,在显性或隐性遗传模式下,仍没有找到与CAD相关联的SNP(所有的P值0.05)。我们进一步对SNPs与CAD之间的关联进行单倍体型分析。但仍没有哪一种单倍体与CAD相关联,而且我们未发现SNPs与冠心病严重度有关联(所有的P0.05)。结论:在中国人群,MRAS基因多态性可能对冠心病的患病风险影响微乎其微。第三部分ALDH2基因变异对冠心病患者的影响目的:乙醛脱氢酶2基因变异对动脉粥样硬化的影响之前已有报道,而在CVD患者中,这种常见变异对心血管事件的影响尚未被广泛的研究。方法:在这项研究中,我们随访了两个队列,最初的队列包括1920例冠心病患者和1920例种族和地理上配对的对照组。所有病例均来自武汉同济医院,健康受试者来自武汉的两个社区。为了证实我们的结果的可信度,我们也对第二个人群进行了验证,包括1573 CAD患者和1920的健康人群。这个病例和对照组均来自于河北医科大学第二医院。随访的中位时间是41.44±19.71个月,研究乙醛脱氢酶2基因变异对心血管结局事件的影响。结果:在同济队列中只有rs671与CAD显著相关(OR=1.26,95%CI:1.13-1.40,P0.001)。校正传统的危险因素(包括年龄,性别,体重指数(BMI),腰臀比(WHR),高血压,高血脂,糖尿病,吸烟和饮酒状况),结果不变(OR=1.26,95%CI:1.07-1.48,P=0.004)。在隐性模式下,结果类似(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,这种关联没有在石家庄的队列中发现。我们把终点事件定义为心肌梗死,卒中,心脏衰竭和再住院。在41.44±19.71个月随访期间,410人发生了事件。校正性别,年龄,性别,体重指数,腰臀比,吸烟和饮酒状态,在我们随访研究中,GG和GA+AA基因型(HR=1.11,95%CI之间:0.892-1.38,P=0.346)之间无统计学差异。GG和GA+AA在心肌梗死,中风,心脏衰竭和再住院的终点事件的发生率同样也无显著的统计学差异。我们的研究结果并没有证据证明ALDH2基因型可能会影响CAD患者的事件发生(HR=1.11,95%CI:0.892-1.38,P=0.346)。结论:ALDH2上的常见变异rs671与中国武汉地区患CAD的风险增加有关,而在中国石家庄地区没有相关性。RS671基因型可能不会影响CVD患者的结局事件。
[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.
【学位授予单位】：河北医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R54
本文编号：2181869
[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.
【学位授予单位】：河北医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R54
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1 尤玲;中国汉族人群ADAMTS7、MRAS、ALDH2基因与心血管病遗传易感性的研究[D];河北医科大学;2016年
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