Genetic Epidemiological Studies On Central Blood Pressure In Jingning Population Of Zhejiang Province

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.