【作者】 陈歆；

【导师】 郑杨；

【作者基本信息】 吉林大学 ， 内科学， 2010， 博士

【摘要】 中心动脉的血流动力学变化与靶器官损害、心血管疾病独立相关,可能比外周血压更具预测价值。而肾素-血管紧张素-醛固酮系统基因(RAAS)的遗传变异在高血压大动脉结构和功能的改变中发挥了重要作用。由于中心动脉与外周动脉功能不同,基因变异对二者可能有不同影响。因此,我们在浙江景宁自然人群中,研究肾素-血管紧张素-醛固酮系统血管紧张素转换酶插入/缺失多态(ACE I/D)、醛固酮合成酶C-344T多态(ALD C-344T)、血管紧张素Ⅱ1型受体A1166C多态(AT1R A1166C)、血管紧张素Ⅱ2型受体G1675A多态(AT2R G1675A)、血管紧张素原C-532T多态(AGT C-532T)单基因、基因与基因、基因与环境之间的相互作用对中心动脉压、外周血压及高血压患病的影响,以及尿酸对中心动脉压、外周血压及高血压的影响,探讨基因变异和尿酸在特定的环境条件下与血压、高血压、动脉硬化之间的关系。我们在浙江景宁1293名畲族为主的居民中,进行问卷调查,血、尿标本采集,使用SphygmoCor大动脉功能仪测量中心动脉血压。采用聚合酶链式反应–限制性片段长度多态性(PCR–RFLP)方法和Taqman探针法进行候选基因单核苷酸多态(SNP)的基因分型。使用SAS 9.1软件进行统计分析。结果显示:1293名受检者,包括高血压患者308名(23.8%),其中106名(34.4%)正在接受降压治疗。与女性相比,男性的血清尿酸(P <0.0001)和高尿酸血症患病率(P<0.0001)较高。调整年龄前、后,男性尿酸与中心动脉收缩压相关(P=0.02)。分类变量分析,高尿酸血症组与正常尿酸组比较,男性中心动脉血压显著升高(P=0.006)。在调整年龄、性别、体重指数、饮酒、吸烟、心率、降压治疗前、后,ALD C-344T多态与肱动脉血压水平和高血压患病密切相关,与CC型相比,T等位基因携带者肱动脉血压水平显著升高(P≤0.01),TT型高血压患病风险增加78%。AGT C-532T多态CT+TT型与CC型比较,中心脉压降低(P=0.048),男性中心动脉收缩压(P=0.03)及中心脉压(P=0.02)降低尤为显著,每个T等位基因降低中心脉压2.5mmHg。AGT C-532T多态和AT2R G1675A多态相互作用影响中心动脉收缩压(Pint=0.05),G1675A多态A等位基因携带者中,AGT C-532T多态各基因型收缩压随T等位基因的增多而显著降低(P=0.05)。ACE I/D多态与年龄相互作用影响中心动脉血压(Pint≤0.02),随年龄增长,D等位基因携带者中心动脉血压显著升高。ACE I/D多态与24小时尿钠排泄量相互作用影响中心脉压(Pint=0.005),在低于尿钠排泄量中位数组,ID型的中心动脉脉压比II型(P=0.003)及DD型(P=0.02)增高明显。AT1R A1166C多态与24小时尿钠排泄量相互作用影响肱动脉舒张压(Pint=0.02),尿钠≥212.3mmol/day时,AC+CC型肱动脉舒张压明显低于AA型(P=0.04)。AGT C-532T多态与尿酸相互作用影响中心动脉血压(Pint≤0.01),尿酸在264μmol/l-319μmol/l之间时,CT+TT型中心动脉血压明显低于CC型(P≤0.04)。结果提示景宁人群ACE I/D多态D等位基因及ALD C-344T多态T等位基因可能是高血压危险因素;AT1R A1166C多态C等位基因可能与较低的高血压风险有关;AGT C-532T多态、AT2R G1675A多态、ACE I/D多态可能与中心动脉血压相关;尿酸和血压及动脉硬化相关,在男性中尤为显著。景宁人群RAAS基因变异与环境因素相互作用,与中心动脉血压、高血压患病及动脉硬化有关。更多还原

【Abstract】 Background and objective: Hemodynamic changes in central aorta were independently associated with target organ damage and cardiovascular diseases. Central blood pressure (BP) may be more predictive than brachial BP. Understanding the interaction between genetic and environmental factors contributing to BP is an important issue in view of the relation of hypertension with outcome. Genetic variation of renin-angiotensin-aldosterone system (RAAS) genes is closely related to the susceptibility in hypertension, and plays an important role in the changing of artery structure and function in hypertensives. Moreover, because the pathophysiological role of central aortic and brachial BP is different, genetic variations maybe have different effects on the regulation of central and brachial BP. Using the standardized genetic epidemiological methods in the general population, we studied the association of five single nucleotide polymorphisms (SNPs) in RAAS genes including angiotensin-converting enzyme (ACE, I/D polymorphism), aldosterone synthase (ALD, C-344T polymorphism), angiotensin II type 1 receptor (AT1R, A1166C polymorphism), angiotensin II type 2 receptor (AT2R, G1675A polymorphism), angiotensinogen (AGT, C-532T polymorphism) with central and brachial BP and hypertension. We also studied the interaction between genes and environmental factors, including serum uric acid, in relation to central BP, brachial BP and hypertension.Methods: In 1293 She residents of Jingning County, Zhejiang province, we conducted a questionnaire survey, collected blood and urine samples, estimated central blood pressure using the SphygmoCor device and genotyped five SNPs in candidate RAAS genes with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and Taqman probe method. SAS 9.1 software was used for statistical analysis.Results: The 1293 participants included 308 (23.8%) hypertensive patients, of whom 106 (34.4%) were taking antihypertensive medication. Men (n=617), compared with women (n=669), had significantly (P<0.0001) higher serum uric acid concentration (319±74 vs. 230±60μmol/l), and prevalence of hyperuricemia (10.2% vs. 2.8%,P<0.0001). Both before and after adjustment for age, serum uric acid was significantly (P=0.02) and positively associated with central systolic blood pressure (SBP) in men. Categorical analyses were confirmatory. In men, patients with hyperuricemia had significantly (P=0.006) higher central SBP (125.5 vs. 117.9mmHg) than those with normal serum uric acid. Both before and after adjustment for age, sex, body mass index, alcohol intake, current smoking, heart rate and use of antihypertensive drugs, the ALD C-344T polymorphism was significantly associated with brachial BP and hypertension. TT and TC compared with CC had significantly higher brachial BP (P≤0.01). TT subjects were more probably to be hypertensive than the CC subjects by 78%. For AGT C-532T polymorphism, CT and TT compared with CC had lower central pulse pressure (PP) (P=0.048) in all subjects and lower central SBP (P=0.03) and PP (P=0.02) in men. Each T allele was associated with a lower central PP by 2.5mmHg. We found a significant interaction between AGT C-532T polymorphism and AT2R G1675A polymorphism in relation to central SBP (Pint=0.05). With the increase of the AGT C-532T T allele, the A allele carriers of the AT2R G1675A polymorphism had a lower central SBP (P=0.05). The ACE I/D polymorphism interacted with age in relation to central BP (Pint≤0.02). Compared with ACE II genotype, the D allele carriers had a significant increase in central BP with age. We also found a significant interaction between the ACE I/D polymorphism and 24-hour urinary sodium excretion in relation to central PP (Pint=0.005). We also found a significant interaction between the AT1R A1166C polymorphism and 24 hour urinary sodium excretion in relation to brachial DBP (Pint=0.02). When 24-hour urinary sodium excretion was more than 212.3mmol/day, brachial DBP was significantly lower in A1166C C carriers than AA subjects (P=0.04). We also found a significant interaction between the AGT C-532T polymorphism and serum uric acid in relation to central BP (Pint≤0.03). Compared with AGT C-532T CC subjects,central BP was significantly lower in T allele carriers with a concentration of serum uric acid between 264μmol/l and 319μmol/l (P≤0.04).Conclusions: First, ACE I/D polymorphism interacts with age, as well as with 24-hour urinary sodium excretion in relation to brachial and central blood pressure, D allele may be a risk factor of hypertension and arterial stiffness in Jingning population. Second, the risk of hypertension in ALD -344TT subjects was 78% higher than the CC subjects, T allele may be a risk factor of hypertension in Jingning population. Third, the frequency of A allele in AT1R A1166C polymorphism in hypertensives was significantly higher than that in normotensives. There was an interaction between the AT1R A1166C polymorphism and 24-hour urinary sodium excretion on brachial diastolic blood pressure (DBP).The C allele carriers had lower brachial DBP, indicating that the AT1R 1166C was associated with lower risk of hypertension. Fourth, both in single gene analysis and analyses involving gene-gene, gene-environment interactions, the T allele carriers of AGT C-532T polymorphism (except women) showed a lower central SBP and PP. AGT C-532T polymorphism may be associated with hypertension and arterial stiffness in Jingning population. Fifth, the interaction between AGT C-532T polymorphism and AT2R G1675A polymorphism influenced central SBP. With the increase of the AGT C-532T T allele, the A allele carriers of the AT2R G1675A polymorphism had a lower central SBP compared with GG homozygotes. The AT2R G1675A polymorphism may be involved in the blood pressure regulation in Jingning population. Sixth, Serum uric acid was associated with central blood pressure in Jingning population, especially in men.Genetic variants of RAAS might interact with environmental factors in the regulation of central BP, pathogenesis of hypertension and arterial stiffness in Jingning population.更多还原