三种血脂基因多态性与冠心病和缺血性卒中的关系研究

发布时间：2018-05-10 06:48

本文选题：MAFB基因 + 单核苷酸多态性　；参考：《广西医科大学》2016年博士论文

【摘要】：第一部分MAFB基因多态性与冠心病及缺背景:冠心病与卒中是目前世界上死亡率和致残率最高的一种复杂的多因素疾病,遗传及环境因素在其发病中发挥着一定的作用。近年来全基因组关联研究发现和筛选出的一系列与脂代谢及动脉粥样硬化相关A易感基因或突变,但多为欧美人群的研究或者后期的重复验证结果,缺乏中国人群的资料,部分易感位点在中国人群中尚未涉及。MAFB基因多态脂代谢有关,但其与冠心病及缺血动脉粥样硬化相关A易感 ,在中国人群中亦缺少研究资料。目的:观察MAFB基因多态-rs2902940、rs6102059在广西汉族人群中的等位基因频率与基因型分布,探讨其与血脂水平的影响,以及与冠心病及缺血方法:本研究是基于广西地区汉族群体的病例-对照研究,共收集1604例样本,其中冠心病组525例,缺血 540例,对照组539例。以问卷调查形式收集研究对象的一般信息及临床资料,提取全血基因组DNA。采用SNa Pshot SNP分型技术对两个MAFB基因SNPs位点rs2902940和rs6102059进行基因分型。比较病例组与对照组之间等位基因及基因型频率分布的差异,计算基因型与冠心病及缺血 ,并分析基因型与血脂水平的关系。结果:CAD及IS组MAFB rs2902940 SNP基因型频率与对照组比较有显著差异(P0.05),而该位点的等位基因频率差异仅在CAD与对照组有统计学意义(P0.05)。MAFB rs2902940 SNP AA基因型或携带A等位基因增加CAD的发病风险(AA基因型:OR=1.63,95%CI=1.07-2.48,P=0.023;A等位基因:OR=1.22,95%CI=1.01-1.48,P=0.036)。GA、AA基因型增加IS的发病风险相关(GA基因型:OR=1.76,95%CI=1.14-2.71,P=0.011;AA基因型:OR=1.69,95%CI=1.09-2.61,P=0.017)。GA/AA基因型亦与增加CAD及IS风险相关(CAD:OR=1.56,95%CI=1.04-2.32,P=0.030 for GA/AA vs.GG;IS:OR=1.72,95%CI=1.14-2.60,P=0.010for GA/AA vs.GG)。分层分析显示,男 ≤60岁、高BMI、以及饮酒、伴有高血压、糖尿病的个体中,携带rs2902940 GA/AA基因型的个体较之GG基因型者有更高的CAD及IS罹患风险;该位点与高BMI、高血压和糖尿病这些危险因素之间存在交互作用。对照组人群的MAFB rs2902940 SNP各基因型间血清Apo AI水平的比较差异具有统计学意义(P=0.018),GA/AA基因型比GG基因型者有着更低的Apo AI水平(P=0.024)。结论:MAFB rs2902940 SNP GA/AA基因型比GG基因型者有着更低的Apo AI水平,携带rs2902940 GA/AA基因型的个体较之GG基因型者有更高的CAD及IS罹患风险。MAFB基因多态粒相关联,与冠心病和缺血有关。第二部分FADS1/FADS2基因簇与冠心病及缺背景:长链多不饱和脂肪酸(LC-PUFAs)对心脑血管有一定程度的保护作用,FADS1、FADS2基因分别编码合成LC-PUFA的限速酶△-5去饱和酶和△-6去饱和酶。FADS1/FADS2基因簇多态 CAD和IS易感多以及血浆脂质水平亦有相关全一致。目的:FADS1 rs174546 SNP和FADS2 rs174601 SNP在广西汉族人群中的等位基因频率与基因型分布,探讨其与冠心病及缺血关系,且与脂代谢的相关方法:本研究以广西地区汉族群体的病例-对照的研究方式,入选研究对象1669例,对照组582例,病例组1087例(CAD:534例,IS:553例)。选择FADS1 rs174546 SNP和FADS2 rs174601 SNP两个位点采用SNa Pshot SNP分型技术进行基因分型,比较病例组与对照组之间等位基因及基因型频率分布的差异,计算基因型与冠心病及缺血相关粒结果:广西地区汉族群体中FADS1 rs174546 SNP和FADS2 rs174601SNP T等位基因及TT基因型频率分布所占的比率高。CAD及IS组FADS1 rs174546 SNP和FADS2 rs174601 SNP等位基因及基因型频率与对照组比较有显著差异(P0.05)。FADS1 rs174546 SNP和FADS2rs174601 SNP T等位基因与增加CAD及IS的发病风险相关(rs174546SNP:OR=1.30,95%CI=1.06-1.59 for CAD,OR=1.29,95%CI=1.06-1.57 for IS;rs174601 SNP:OR=1.38,95%CI=1.13-1.69 for CAD,OR=1.42,95%CI=1.16-1.73 for IS)。相应的,两个SNPs C等位基因携带与减少CAD及IS的发病风险相关(rs174546 SNP:OR=0.57,95%CI=0.44-0.75for CAD,OR=0.62,95%CI=0.48-0.80 for IS;for rs174601 SNP:OR=0.54,95%CI=0.41-0.70 for CAD,OR=0.61,95%CI=0.48-0.79 for IS)。单体型分析示单体型T-T(rs174546-rs174601)与增加IS的发病风险相关(OR=1.32,95%CI=1.10-1.59),而单体型C-C(rs174546-rs174601)与减少CAD及IS的发病风险相关(OR=0.72,95%CI=0.60-0.87 for CAD,OR=0.76,95%CI=0.63-0.91 for IS)。CAD组rs174601 TT基因型比CC/TC基因型有着较低血清TC、HDL-C和Apo AI水平(P0.025)。而在IS组,rs174546和rs174601 TT/TC基因型较CC基因型者有着较低的血清HDL-C和Apo AI水平(P0.025)。结论:FADS1 rs174546 SNP和FADS2 rs174601 SNP T等位基因及单体型T-T(rs174546-rs174601)与增加CAD及IS的发病风险相关。相对应的,C等位基因及与单体型C-C(rs174546-rs174601)减少CAD及IS的发病风险。FADS1/FADS2基因簇多态 FADS1 rs174546 SNP和FADS2 rs174601 SNP TT/TC基因型和FADS2rs174601 SNP TT基因型有着较低的血清HDL-C和Apo AI水平,可能是增加CAD和IS的发病风险的原因。第三部分ANGPTL4基因多态性与冠心病及缺背景:血管生成素样蛋白4(ANGPTL4)为血管生成素样蛋白家族成员。与脂代谢有着非常密切的关系,在动脉粥样硬化相关A过程中起着重要的作用。目前ANGPTL4与血脂水平、动脉粥样硬化相关A ANGPTL4基因多态不尽一致,尤其缺乏中国人群的相关资料。开展ANGPTL4基因多态血脂及人类动脉粥样硬化相关疾病的关系的研究有助于了解ANGPTL4在动脉粥样硬化中的作用,将为脂代谢、动脉粥样硬化相关疾病的靶向治疗提供更多新思路。目的:本文旨在探讨ANGPTL4 SNPs rs2967605、rs4076317、rs7255436和rs1044250对血脂水平的影响,以及与动脉粥样硬化相关疾病即CAD和IS发病风险的关系。方法:基于广西地区汉族群体的病例-对照研究,共收集1654例样本,其中冠心病组568例,缺血 537例,对照组549例。采用SNa Pshot SNP分型技术对rs2967605、rs4076317、rs7255436和rs1044250 4个ANGPTL4SNPs进行基因分型。比较病例组与对照组之间等位基因及基因型频率分布的差异,计算基因型与冠心病及缺血 ,并分析基因型与血脂水平的关系。结果:4个ANGPTL4 SNPs中,只有rs2967605 SNP的对照组与病例组基因型频率分布有显著差异(P0.05)。rs2967605 SNP CT/TT基因型与减少CAD及IS的发病风险相关(CAD:OR=0.68,95%CI=0.47-0.99 for CT/TT vs.CC;IS:OR=0.55,95%CI=0.38-0.80 for CT/TT vs.CC)。分层分析显示该位点的保护效应主要体现在年龄≤60岁(CAD:OR=0.50,95%CI=0.27-0.95,P=0.035;IS:OR=0.37,95%CI=0.20-0.68,P=0.002),高BMI(CAD:OR=0.53,95%CI=0.28-0.99,P=0.049;IS:OR=0.52,95%CI=0.27-0.99,P=0.048),高血压人群(CAD:OR=0.37,95%CI=0.18-0.76,P=0.007;IS:OR=0.42,95%CI=0.21-0.84,P=0.015)和高脂血症人群(CAD:OR=0.37,95%CI=0.18-0.75,P=0.006;IS:OR=0.32,95%CI=0.16-0.65,P=0.001)。该位点与女 BMI、饮酒和糖尿病这些因素存在交互作用。ANGPTL4 SNPs的各种遗传模式分析与CAD冠状动脉病变严重程度无相关 logistic回归分析显示高BMI、高血压、高脂血症和糖尿病为CAD的危险因素(P0.05),而女 P0.05)。在对照组人群中,ANGPTL4 rs4076317 SNP CG/CC基因型比GG基因型者具有较高的血清TC和LDL-C水平(P0.001)及较低的血清HDL-C水平(P=0.008)。未发现rs7255436、rs1044250、rs2967605基因型与血脂水平存在相关结论:ANGPTL4 rs4076317 SNP与脂代谢相关,ANGPTL4 rs4076317SNP rs4076317 CG/CC基因型比GG基因型有着较低的血清HDL-C水平和较高的血清TC、LDL-C水平。ANGPTL4 rs2967605 SNP与血脂水平无相关 CAD和IS相关,ANGPTL4 rs2967605 SNP CT/TT基因型较CC基因型对CAD及IS更具有保护效应。ANGPTL4基因与CAD及IS的关系是复杂的,并不一定由血脂水平介导,可能还有其它因素的参与。进一步明确其功能具有重要意义。
[Abstract]:The first part of the MAFB gene polymorphism and coronary heart disease and the absence of background: coronary heart disease and stroke are a complex multifactor disease with the highest mortality and disability in the world. Genetic and environmental factors play a role in its pathogenesis. In recent years, a series of total genome association studies have been developed and screened with lipid metabolism and arteries. Atherosclerosis related A susceptibility gene or mutation, but most of the European and American population research or later repeated validation results, the lack of Chinese population data, some susceptible loci have not been involved in the.MAFB gene polymorphism of lipid metabolism in Chinese population, but its susceptibility to coronary heart disease and ischemic atherosclerotic A is also susceptible to the Chinese population. Objective: To observe the allele frequency and genotype distribution of MAFB gene polymorphism -rs2902940 and rs6102059 in Guangxi Han population, to explore the effects of the allele and the blood lipid level, as well as the methods of coronary heart disease and ischemia: This study was based on a case-control study of Han population in Guangxi region. A total of 1604 samples were collected, among them, crowns were collected. 525 cases of heart disease, 540 cases of ischemia and 539 cases in the control group. The general information and clinical data of the subjects were collected by questionnaire survey. The genomic DNA. of whole blood was extracted by SNa Pshot SNP typing technique, and the SNPs loci rs2902940 and rs6102059 were genotyping of the SNPs loci of the MAFB gene. The alleles and genotypes between the cases of the disease cases and the control group were compared. The difference in frequency distribution, the calculation of genotype and coronary heart disease and ischemia, and the relationship between genotypes and blood lipid levels. Results: the genotype frequencies of MAFB rs2902940 SNP in CAD and IS groups were significantly different from those of the control group (P0.05), but the difference in allele frequency of the loci was statistically significant (P0.05).MAFB rs2902940 SNP in CAD and the control group (P0.05). The AA genotype or A allele increases the risk of CAD (AA genotype: OR=1.63,95%CI=1.07-2.48, P=0.023; A alleles: OR=1.22,95%CI=1.01-1.48, P=0.036).GA, and AA genotype increases the risk associated with IS. It is also related to increasing the risk of CAD and IS (CAD:OR=1.56,95%CI=1.04-2.32, P=0.030 for GA/AA vs.GG; IS:OR=1.72,95%CI=1.14-2.60, P=0.010for GA/AA vs.GG). The risk of D and IS was associated with the risk factors of high BMI, hypertension and diabetes. The comparison of the serum Apo AI levels between the MAFB rs2902940 SNP genotypes of the control group was statistically significant (P=0.018), and the GA/AA genotypes had lower Apo levels than those of the GG genotype. The 2902940 SNP GA/AA genotype has a lower Apo AI level than that of the GG genotype. The individuals carrying the rs2902940 GA/AA genotype have higher CAD and IS associated with the risk.MAFB gene polymorphisms of the GG genotypes, which are associated with coronary heart disease and ischemia. The second part of the FADS1/FADS2 gene cluster is associated with coronary heart disease and the absence of background: long chain polyunsaturated Fatty acids (LC-PUFAs) have a certain protective effect on the cardiovascular and cerebral vessels. FADS1, FADS2 genes encode the speed limiting enzyme Delta -5 desaturase and delta -6 desaturase.FADS1/FADS2 gene cluster polymorphism CAD, IS susceptibility and plasma lipid levels, respectively. The allele frequency and genotype distribution of the Han population in Guangxi, and the relationship with coronary heart disease and ischemia, and the related methods of lipid metabolism: in this study, 1669 cases were selected, 582 cases in the control group, 1087 cases in the control group (CAD:534 cases, IS:553 cases), and the choice of FADS1 rs17454 in the case control study of Han population in the region of Guangxi. 6 SNP and FADS2 rs174601 SNP loci were genotyping by SNa Pshot SNP typing. The difference of allele and genotype frequency distribution between the case group and the control group was compared. The results of the genotype and coronary heart disease and ischemia related particles were calculated: the FADS1 rs174546 SNP and FADS2 rs174601SNP alleles in the Han population in Guangxi region The frequencies of the frequency distribution of TT genotype and.CAD and the FADS1 rs174546 SNP and FADS2 rs174601 SNP alleles and genotype frequencies of the IS group were significantly different from those of the control group (P0.05) CAD, OR=1.29,95%CI=1.06-1.57 for IS; rs174601 SNP:OR=1.38,95%CI=1.13-1.69 for CAD, OR=1.42,95%CI=1.16-1.73 for IS). .41-0.70 for CAD, OR=0.61,95%CI=0.48-0.79 for IS). The haplotype analysis shows that the somatotype T-T (rs174546-rs174601) is associated with the risk of increasing IS (OR=1.32,95%CI=1.10-1.59), while the somatotype C-C (rs174546-rs174601) is associated with the risk of reducing the onset of the disease. The rs174601 TT genotype has lower serum TC, HDL-C and Apo AI levels (P0.025). In the IS group, rs174546 and rs174601 TT/TC genotypes are lower than those of the genotype. The risk of increasing the risk of CAD and IS. Corresponding, C allele and C-C (rs174546-rs174601) decrease the risk of CAD and IS The causes of the risk of CAD and IS. Third part ANGPTL4 gene polymorphism and coronary heart disease and lack of background: angiopoietin like protein 4 (ANGPTL4) is a member of the angiopoietin like protein family. It has a very close relationship with lipid metabolism and plays an important role in the process of atherosclerosis related A. At present, ANGPTL4 and blood lipid level, movement The polymorphism of the A ANGPTL4 gene associated with atherosclerosis is not consistent, especially in the Chinese population. The study of the relationship between ANGPTL4 gene polymorphisms and human atherosclerosis related diseases will help to understand the role of ANGPTL4 in atherosclerosis, and will be the target of lipid metabolism and atherosclerosis related diseases. Treatment provides more new ideas. Objective: This article aims to explore the effects of ANGPTL4 SNPs rs2967605, rs4076317, rs7255436 and rs1044250 on blood lipid levels, and the relationship with the risk of atherosclerotic disease, CAD and IS. Methods: a total of 1654 samples were collected from the Han population in Guangxi, including coronary heart disease. There were 568 cases, 537 cases of ischemia and 549 cases of control group. SNa Pshot SNP typing was used to genotyping rs2967605, rs4076317, rs7255436 and rs1044250, and the difference of allele and genotype frequency distribution between the case group and the control group was compared, the genotype and coronary heart disease and ischemia were calculated, and the genotype and blood lipid water were analyzed. Results: in 4 ANGPTL4 SNPs, there was a significant difference in the genotype frequency distribution between the control group of the rs2967605 SNP and the case group (P0.05) the.Rs2967605 SNP CT/TT genotype was related to the risk of decreasing CAD and IS. The protective effects of the loci were mainly reflected in the age less than 60 years (CAD:OR=0.50,95%CI=0.27-0.95, P=0.035; IS:OR=0.37,95%CI=0.20-0.68, P=0.002), high BMI (CAD:OR=0.53,95%CI=0.28-0.99, P=0.049; IS:OR=0.52,95%CI=0.27-0.99, P=0.048), and high blood pressure population (CAD: OR=0.37,95%CI=0.18-0.76, P=0.007; P=0.002) and Hyperlipidemia (CAD:OR=0.37,95%CI=0.18-0.75, P=0.006; IS:OR=0.32,95%CI=0.16-0.65, P=0.001). The loci and women BMI, drinking, and diabetes have the interaction of the various genetic patterns of.ANGPTL4 SNPs analysis and the severity of coronary artery disease without a correlation of logistic regression analysis showing high BMI, high blood pressure, high fat blood. In the control group, the ANGPTL4 rs4076317 SNP CG/CC genotype had higher serum TC and LDL-C levels than those of the GG genotype (P0.001) and the lower serum HDL-C level in the control group. ANGPTL4 rs4076317 SNP is associated with lipid metabolism, and ANGPTL4 rs4076317SNP rs4076317 CG/CC genotype has a lower serum HDL-C level and a higher serum TC than GG genotype. The relationship between the protective effect of.ANGPTL4 gene and CAD and IS is complex, and it is not necessarily mediated by blood lipid levels, and may be involved in other factors. Further clarifying its function is of great significance.

【学位授予单位】：广西医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R743.3;R541.4

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