中国成人空腹血糖水平与动脉粥样硬化性心血管疾病发病的关系及内皮系统相关基因对血压长期变化的影响

发布时间：2018-07-31 05:29

【摘要】：第一部分：中国成人空腹血糖水平与动脉粥样硬化性心血管疾病发病的关系背景与目的：糖尿病能够显著增加心血管疾病的发病风险,但是正常范围内空腹血糖水平与心血管疾病发病的关系尚未得到一致的结论,来自于中国人群的证据也十分缺乏。另外,中国的卫生资源有限,确定高危人群、合理利用有限的卫生资源,才能更有效地开展心血管疾病防治工作。本研究旨在通过探讨空腹血糖水平和糖尿病与动脉粥样硬化性心血管疾病的关系,为中国心血管疾病的高危人群预防提供证据。材料与方法：本研究采用前瞻性队列研究设计,以19687名中国35-74岁成人为研究对象。基线调查分别于1998年和2000-2001年开展,采用标准化问卷、体格检查收集人口统计学特征、行为生活方式、心血管疾病危险因素等信息,并进行生化指标的测定。随访调查于2007-2008年开展,收集研究对象疾病发病状况等信息。本研究采用Cox比例风险模型,以空腹血糖水平85-99 mg/dL的研究对象为参照,估计不同空腹血糖水平以及糖尿病对动脉粥样硬化性心血管疾病发病的影响,并进一步探讨血压、血脂、体力活动等与血糖的联合作用对动脉粥样硬化性心血管疾病发病的影响。结果：本研究平均随访7.9年(154520人年),共发生动脉粥样硬化性心血管疾病534例,其中冠心病事件129例,脑卒中事件405例。总人群、男性、女性年龄调整的动脉粥样硬化性心血管疾病的发病率分别为5.61/1000人年、6.63/1000人年和4.59/1000人年。在调整年龄、性别、体质指数、吸烟状况、饮酒状况、工作相关体力活动、教育水平、动脉粥样硬化性心血管疾病家族史以及其他传统心血管病危险因素后,与空腹血糖水平85-99 mg/dL组相比,总人群中只有糖尿病组的HR(95%CI)具有统计学意义,为1.58(1.18,2.11),男性人群中糖尿病组的HR(95%CI)为1.17(0.78,1.77),女性人群中糖尿病组的HR(95%CI)为2.19(1.43,3.33),存在性别差异。糖尿病与动脉粥样硬化性心血管疾病的关系还存在地域差异和城乡差异,即北方人群和城市居民中的糖尿病患者发病风险更高,HR(95%CI)分别为1.62(1.14,2.30)和1.89(1.26,2.83)。另外,空腹血糖水平与动脉粥样硬化性心血管疾病的关系可能存在J型关系,但是没有达到统计学显著性。高血压、血脂异常、工作相关体力活动不足会增加糖尿病人群动脉粥样硬化性心血管疾病的发病风险。结论：空腹血糖水平与动脉粥样硬化性心血管疾病的发病风险可能存在J型关系,但是,只有糖尿病能够增加动脉粥样硬化性心血管疾病的发病风险,并且独立于其他危险因素。在动脉粥样硬化性心血管疾病的一级预防中,需要加强糖尿病患者血压、血脂以及体力活动的干预与管理。另外,糖尿病与动脉粥样硬化性心血管病的关系存在性别差异、地域差异以及城乡差异,因此,需要在不同性别、地域以及城乡人群中,实施针对性的干预措施来预防糖尿病高危人群的动脉粥样硬化性心血管疾病的发生。第二部分：中国汉族人群内皮系统相关基因对血压长期变化的影响背景与目的：研究发现,内皮细胞在血管平滑肌以及血管紧张度的调节方面具有十分重要的作用,内皮功能紊乱可能是高血压的潜在病理机制。既往横断面调查的结果发现内皮系统相关基因与血压水平或者高血压相关,然而,内皮系统相关基因遗传变异是否会影响血压水平的长期变化及高血压发病等证据尚不充足。本研究旨在通过单核苷酸多态性(Single Nucleotide Polymorphism, SNP)的单个位点关联分析和基于基因(Gene-based)的多个位点的联合作用分析,探讨内皮系统相关基因与血压的长期变化和高血压发病之间的关系。材料与方法：本研究利用“盐敏感性研究遗传流行病学协作网络(Genetic Epidemiology Network of Salt Sensitivity, GenSalt) "研究以及GenSalt随访研究的资料,共纳入来自于633个家庭的1768名研究对象进行分析。所有研究对象在基线调查以及2次随访调查中均接受血压测量,每天测量3次,每次测量间隔至少30秒,连续3天,根据3天共9次收缩压和舒张压的读数计算各阶段的平均收缩压和舒张压。本研究通过MEDLINE数据库进行文献检索,共查找出16个内皮系统相关的候选基因,在进行质量控制之后,共15个基因的206个SNPs纳入分析。本研究采用混合效应模型分别探讨遗传加性模型下单个SNP与血压长期变化和高血压发病的关系,采用截点乘积法进行基于基因的分析,采用Bonferroni法对多重检验进行校正。统计分析采用Haploview, PLINK, SAS及R软件完成。结果：本研究中1768名研究对象的平均年龄为39.0岁,平均体质指数为23.4kg/m2,基线阶段平均收缩压为116.9mmHg,平均舒张压为73.8mmHg。基线高血压患者173名,占总人群的9.8%。经过平均7.2年的随访,收缩压和舒张压的水平随着随访年限的延长而升高,其中收缩压平均每年升高1.8mmHg,舒张压平均每年升高1.2mmHg。另外,在所有基线未患有高血压的研究对象中,共有512例新发高血压患者,占32.1%。在单个SNP分析中发现,SELF.基因上的位点rs4656704、rs6427212和rs5368的变异与高血压发病显著相关,随着少见等位基因个数的增加,发病率升高(P趋势分别为1.48×104、6.69×104和7.64×104)。另外,随着SELF.基因上的位点rs3917436少见等位基因个数的增加,舒张压增加幅度降低(P=7.22×104)。基于基因的分析发现,SELF.基因与舒张压的长期变化和高血压发病都显著相关(P值均为1.00x10-6)。另外,DDAH1和COL18A1基因与收缩压的长期变化相关(P值分别为1.00×10-6和4.00×10-6),EDNRA基因与高血压的发病相关(P值为2.39×10-4)。结论：本研究结果表明内皮系统基因与血压的长期变化和高血压的发病相关,为阐明高血压的发病机制提供了有力的证据。
[Abstract]:The first part: the relationship between the level of fasting blood glucose in Chinese adults and the pathogenesis of atherosclerotic cardiovascular disease: diabetes can significantly increase the risk of cardiovascular disease, but the relationship between the normal range of fasting blood glucose and the incidence of cardiovascular disease is not consistent, from the Chinese population. There is also a lack of evidence. In addition, China's health resources are limited to determine the high risk population and the rational use of limited health resources to carry out the prevention and control of cardiovascular diseases more effectively. This study aims to explore the relationship between fasting blood glucose level and diabetes and atherosclerotic cardiovascular disease, and to improve the cardiovascular disease in China Evidence for the prevention of dangerous crowds. Materials and methods: a prospective cohort study was conducted in 19687 Chinese 35-74 year old adults. The baseline survey was conducted in 1998 and 2000-2001 years, using a standardized questionnaire and physical examination to collect demographic characteristics, behavioral lifestyles, and cardiovascular risk factors. Information, and the determination of biochemical indexes. The follow-up survey was conducted in 2007-2008 years to collect information about the condition of the disease. The Cox proportional hazard model was used to estimate the levels of fasting blood glucose and diabetes for atherosclerotic cardiovascular disease, with the reference of the research object of fasting blood glucose level 85-99 mg/dL. The influence of the disease and the effect of the combined effect of blood pressure, blood lipid, physical activity and blood glucose on the pathogenesis of atherosclerotic cardiovascular disease. Results: This study was followed up for 7.9 years (154520 years) and 534 cases of atherosclerotic cardiovascular disease, including 129 cases of coronary heart disease and 405 cases of stroke. The incidence of atherosclerotic cardiovascular disease in group, male and female age adjusted atherosclerotic cardiovascular disease was 5.61/1000 year, 6.63/1000 year and 4.59/1000 year. In adjusting age, sex, body mass index, smoking status, drinking status, work related physical activity, educational level, family history of atherosclerotic cardiovascular disease, and other transmission After the risk factors of cardiovascular disease, compared with the 85-99 mg/dL group, the only HR (95%CI) of the diabetes group was 1.58 (1.18,2.11), and the HR (95%CI) of the diabetic group in the male population was 1.17 (0.78,1.77), and the HR (95%CI) of the diabetic group in the female population was 2.19 (1.43,3.33), and there was a sex difference. The relationship between the disease and atherosclerotic cardiovascular disease has regional differences and urban and rural differences, that is, the risk of diabetes in the northern and urban residents is higher, HR (95%CI) is 1.62 (1.14,2.30) and 1.89 (1.26,2.83) respectively. In addition, the relationship between fasting blood glucose level and atherosclerotic cardiovascular disease may exist in the J type Relationship, but not statistically significant. Hypertension, dyslipidemia, and lack of work related physical activity may increase the risk of atherosclerotic cardiovascular disease in the diabetic population. Conclusion: the relationship between the level of fasting blood glucose and the risk of atherosclerotic cardiovascular disease may have a J type relationship, but only diabetes mellitus is associated with diabetes. It can increase the risk of atherosclerotic cardiovascular disease and be independent of other risk factors. In the primary prevention of atherosclerotic cardiovascular disease, it is necessary to strengthen the intervention and management of blood pressure, blood lipid, and physical activity in diabetic patients. In addition, the relationship between diabetes and atherosclerotic cardiovascular disease is stored. In gender, regional and urban and rural differences, it is necessary to implement targeted interventions in different sexes, regions and urban and rural populations to prevent the occurrence of atherosclerotic cardiovascular disease in high-risk groups of diabetes. The second part: the long-term changes in blood pressure of the endothelial related genes of the Chinese Han population Background and purpose: it is found that endothelial cells play a very important role in the regulation of vascular smooth muscle and vascular tension. Endothelial dysfunction may be a potential pathological mechanism of hypertension. Previous cross-sectional study found that endothelial related genes were associated with blood pressure or hypertension, however, endothelium The objective of this study is to explore the endothelial system by analysis of single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP) and the combination of multiple loci based on gene (Gene-based). The relationship between the related genes and the long-term changes in blood pressure and hypertension. Materials and methods: This study used the data of "Genetic Epidemiology Network of Salt Sensitivity, GenSalt", and the follow-up study of GenSalt, and included 1768 studies from 633 families. The subjects were analyzed. All subjects received blood pressure measurements in baseline and 2 follow-up surveys. 3 times per day were measured at least 30 seconds each time. The average systolic pressure and relaxation pressure at each stage were calculated on the basis of 9 systolic and diastolic pressure readings for 3 days. The study was conducted by the MEDLINE database. A total of 16 endothelial related candidate genes were found. After quality control, a total of 206 SNPs of 15 genes were analyzed. In this study, a mixed effect model was used to explore the relationship between single SNP and the long-term changes of blood pressure and hypertension. Multiple tests were corrected with the Bonferroni method. The statistical analysis was completed by Haploview, PLINK, SAS and R software. Results: the average age of 1768 subjects in this study was 39 years, the average body mass index was 23.4kg/m2, the average systolic blood pressure at baseline was 116.9mmHg, and the average diastolic blood pressure was 173 of the baseline of 73.8mmHg. baseline hypertension. The 9.8%. of the population was followed up for an average of 7.2 years. The level of systolic and diastolic pressure increased with the duration of follow-up. The systolic pressure increased by 1.8mmHg on average, and the diastolic pressure increased by 1.2mmHg. a year on average. In all the subjects with no baseline hypertension, there were 512 cases of new hypertensive patients, accounting for a single SNP. It was found that the mutations in the loci of the SELF. gene rs4656704, rs6427212 and rs5368 were significantly associated with hypertension. With the increase of the number of rare alleles, the incidence was increased (the trend of P was 1.48 * 104,6.69 * 104 and 7.64 * 104 respectively). In addition, with the increase of the number of rare alleles on the SELF. gene, the diastolic function of the allele was increased. The amplitude of pressure increased (P=7.22 x 104). The gene based analysis showed that the SELF. gene was associated with long term changes in diastolic pressure and the incidence of hypertension (P values were 1.00x10-6). In addition, the DDAH1 and COL18A1 genes were associated with long term changes in systolic blood pressure (P values were 1 x 10-6 and 4 x 10-6 respectively), and the EDNRA gene was associated with the pathogenesis of hypertension (P value) 2.39 * 10-4) conclusion: the results of this study suggest that the endothelial gene is related to the long-term changes in blood pressure and the incidence of hypertension, which provides strong evidence to clarify the pathogenesis of hypertension.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R543.5;R587.1

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