【摘要】：第一部分：中國(guó)成人空腹血糖水平與動(dòng)脈粥樣硬化性心血管疾病發(fā)病的關(guān)系背景與目的：糖尿病能夠顯著增加心血管疾病的發(fā)病風(fēng)險(xiǎn),但是正常范圍內(nèi)空腹血糖水平與心血管疾病發(fā)病的關(guān)系尚未得到一致的結(jié)論,來自于中國(guó)人群的證據(jù)也十分缺乏。另外,中國(guó)的衛(wèi)生資源有限,確定高危人群、合理利用有限的衛(wèi)生資源,才能更有效地開展心血管疾病防治工作。本研究旨在通過探討空腹血糖水平和糖尿病與動(dòng)脈粥樣硬化性心血管疾病的關(guān)系,為中國(guó)心血管疾病的高危人群預(yù)防提供證據(jù)。材料與方法：本研究采用前瞻性隊(duì)列研究設(shè)計(jì),以19687名中國(guó)35-74歲成人為研究對(duì)象�；�調(diào)查分別于1998年和2000-2001年開展,采用標(biāo)準(zhǔn)化問卷、體格檢查收集人口統(tǒng)計(jì)學(xué)特征、行為生活方式、心血管疾病危險(xiǎn)因素等信息,并進(jìn)行生化指標(biāo)的測(cè)定。隨訪調(diào)查于2007-2008年開展,收集研究對(duì)象疾病發(fā)病狀況等信息。本研究采用Cox比例風(fēng)險(xiǎn)模型,以空腹血糖水平85-99 mg/dL的研究對(duì)象為參照,估計(jì)不同空腹血糖水平以及糖尿病對(duì)動(dòng)脈粥樣硬化性心血管疾病發(fā)病的影響,并進(jìn)一步探討血壓、血脂、體力活動(dòng)等與血糖的聯(lián)合作用對(duì)動(dòng)脈粥樣硬化性心血管疾病發(fā)病的影響。結(jié)果：本研究平均隨訪7.9年(154520人年),共發(fā)生動(dòng)脈粥樣硬化性心血管疾病534例,其中冠心病事件129例,腦卒中事件405例�？�?cè)巳�、男性、女性年齡調(diào)整的動(dòng)脈粥樣硬化性心血管疾病的發(fā)病率分別為5.61/1000人年、6.63/1000人年和4.59/1000人年。在調(diào)整年齡、性別、體質(zhì)指數(shù)、吸煙狀況、飲酒狀況、工作相關(guān)體力活動(dòng)、教育水平、動(dòng)脈粥樣硬化性心血管疾病家族史以及其他傳統(tǒng)心血管病危險(xiǎn)因素后,與空腹血糖水平85-99 mg/dL組相比,總?cè)巳褐兄挥刑悄虿〗M的HR(95%CI)具有統(tǒng)計(jì)學(xué)意義,為1.58(1.18,2.11),男性人群中糖尿病組的HR(95%CI)為1.17(0.78,1.77),女性人群中糖尿病組的HR(95%CI)為2.19(1.43,3.33),存在性別差異。糖尿病與動(dòng)脈粥樣硬化性心血管疾病的關(guān)系還存在地域差異和城鄉(xiāng)差異,即北方人群和城市居民中的糖尿病患者發(fā)病風(fēng)險(xiǎn)更高,HR(95%CI)分別為1.62(1.14,2.30)和1.89(1.26,2.83)。另外,空腹血糖水平與動(dòng)脈粥樣硬化性心血管疾病的關(guān)系可能存在J型關(guān)系,但是沒有達(dá)到統(tǒng)計(jì)學(xué)顯著性。高血壓、血脂異常、工作相關(guān)體力活動(dòng)不足會(huì)增加糖尿病人群動(dòng)脈粥樣硬化性心血管疾病的發(fā)病風(fēng)險(xiǎn)。結(jié)論：空腹血糖水平與動(dòng)脈粥樣硬化性心血管疾病的發(fā)病風(fēng)險(xiǎn)可能存在J型關(guān)系,但是,只有糖尿病能夠增加動(dòng)脈粥樣硬化性心血管疾病的發(fā)病風(fēng)險(xiǎn),并且獨(dú)立于其他危險(xiǎn)因素。在動(dòng)脈粥樣硬化性心血管疾病的一級(jí)預(yù)防中,需要加強(qiáng)糖尿病患者血壓、血脂以及體力活動(dòng)的干預(yù)與管理。另外,糖尿病與動(dòng)脈粥樣硬化性心血管病的關(guān)系存在性別差異、地域差異以及城鄉(xiāng)差異,因此,需要在不同性別、地域以及城鄉(xiāng)人群中,實(shí)施針對(duì)性的干預(yù)措施來預(yù)防糖尿病高危人群的動(dòng)脈粥樣硬化性心血管疾病的發(fā)生。第二部分：中國(guó)漢族人群內(nèi)皮系統(tǒng)相關(guān)基因?qū)ρ獕洪L(zhǎng)期變化的影響背景與目的：研究發(fā)現(xiàn),內(nèi)皮細(xì)胞在血管平滑肌以及血管緊張度的調(diào)節(jié)方面具有十分重要的作用,內(nèi)皮功能紊亂可能是高血壓的潛在病理機(jī)制。既往橫斷面調(diào)查的結(jié)果發(fā)現(xiàn)內(nèi)皮系統(tǒng)相關(guān)基因與血壓水平或者高血壓相關(guān),然而,內(nèi)皮系統(tǒng)相關(guān)基因遺傳變異是否會(huì)影響血壓水平的長(zhǎng)期變化及高血壓發(fā)病等證據(jù)尚不充足。本研究旨在通過單核苷酸多態(tài)性(Single Nucleotide Polymorphism, SNP)的單個(gè)位點(diǎn)關(guān)聯(lián)分析和基于基因(Gene-based)的多個(gè)位點(diǎn)的聯(lián)合作用分析,探討內(nèi)皮系統(tǒng)相關(guān)基因與血壓的長(zhǎng)期變化和高血壓發(fā)病之間的關(guān)系。材料與方法：本研究利用“鹽敏感性研究遺傳流行病學(xué)協(xié)作網(wǎng)絡(luò)(Genetic Epidemiology Network of Salt Sensitivity, GenSalt) "研究以及GenSalt隨訪研究的資料,共納入來自于633個(gè)家庭的1768名研究對(duì)象進(jìn)行分析。所有研究對(duì)象在基線調(diào)查以及2次隨訪調(diào)查中均接受血壓測(cè)量,每天測(cè)量3次,每次測(cè)量間隔至少30秒,連續(xù)3天,根據(jù)3天共9次收縮壓和舒張壓的讀數(shù)計(jì)算各階段的平均收縮壓和舒張壓。本研究通過MEDLINE數(shù)據(jù)庫(kù)進(jìn)行文獻(xiàn)檢索,共查找出16個(gè)內(nèi)皮系統(tǒng)相關(guān)的候選基因,在進(jìn)行質(zhì)量控制之后,共15個(gè)基因的206個(gè)SNPs納入分析。本研究采用混合效應(yīng)模型分別探討遺傳加性模型下單個(gè)SNP與血壓長(zhǎng)期變化和高血壓發(fā)病的關(guān)系,采用截點(diǎn)乘積法進(jìn)行基于基因的分析,采用Bonferroni法對(duì)多重檢驗(yàn)進(jìn)行校正。統(tǒng)計(jì)分析采用Haploview, PLINK, SAS及R軟件完成。結(jié)果：本研究中1768名研究對(duì)象的平均年齡為39.0歲,平均體質(zhì)指數(shù)為23.4kg/m2,基線階段平均收縮壓為116.9mmHg,平均舒張壓為73.8mmHg�；�高血壓患者173名,占總?cè)巳旱?.8%。經(jīng)過平均7.2年的隨訪,收縮壓和舒張壓的水平隨著隨訪年限的延長(zhǎng)而升高,其中收縮壓平均每年升高1.8mmHg,舒張壓平均每年升高1.2mmHg。另外,在所有基線未患有高血壓的研究對(duì)象中,共有512例新發(fā)高血壓患者,占32.1%。在單個(gè)SNP分析中發(fā)現(xiàn),SELF.基因上的位點(diǎn)rs4656704、rs6427212和rs5368的變異與高血壓發(fā)病顯著相關(guān),隨著少見等位基因個(gè)數(shù)的增加,發(fā)病率升高(P趨勢(shì)分別為1.48×104、6.69×104和7.64×104)。另外,隨著SELF.基因上的位點(diǎn)rs3917436少見等位基因個(gè)數(shù)的增加,舒張壓增加幅度降低(P=7.22×104)。基于基因的分析發(fā)現(xiàn),SELF.基因與舒張壓的長(zhǎng)期變化和高血壓發(fā)病都顯著相關(guān)(P值均為1.00x10-6)。另外,DDAH1和COL18A1基因與收縮壓的長(zhǎng)期變化相關(guān)(P值分別為1.00×10-6和4.00×10-6),EDNRA基因與高血壓的發(fā)病相關(guān)(P值為2.39×10-4)。結(jié)論：本研究結(jié)果表明內(nèi)皮系統(tǒng)基因與血壓的長(zhǎng)期變化和高血壓的發(fā)病相關(guān),為闡明高血壓的發(fā)病機(jī)制提供了有力的證據(jù)。
[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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R543.5;R587.1

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