Associations between hypertension and genes in the renin-angiotensin system

The genes of the renin-angiotensin system have been subjected to intense molecular scrutiny in cardiovascular disease studies, but their contribution to risk is still uncertain. In this study, we sampled 192 African American and 153 European American families (602 and 608 individuals, respectively) to evaluate the contribution of variations in genes that encode renin-angiotensin system components of susceptibility to hypertension. We genotyped 25 single-nucleotide polymorphisms in the renin-angiotensin system genes ACE, AGT, AGTR1, and REN. The family-based transmission/disequilibrium test was performed with each single-nucleotide polymorphism and with the multilocus haplotypes. Two individual single-nucleotide polymorphisms were significantly associated with hypertension among African Americans, and this result persisted when both groups were combined. The associations were confirmed in haplotype analysis for REN, AGTR1, and ACE in African Americans. Consistent but less significant evidence was found in European Americans. We also randomly sampled unrelated individuals across families to obtain 84 cases and 108 controls among the African Americans and 41 cases and 113 controls in the European Americans. Single-nucleotide polymorphism and haplotype analyses again showed consistent, albeit weaker, results. Thus, in this biracial population sample, we find evidence that interindividual variation in the renin-angiotensin system genes contributes to hypertension risk.     

Gene polymorphisms of the renin-angiotensin system and early development of hypertension

BACKGROUND: A case-control association study was conducted to investigate a possible involvement of polymorphisms of three renin-angiotensin system genes: ACE (I/D and T-3892C), AGT (M235T and T174M), and AT1R (A1166C) in the early development of hypertension. METHODS: One hundred nineteen hypertensive and 125 normotensive participants aged 18 to 40 years were selected from a broader sample representative of the general population of Croatia. The selection criteria for hypertensive cases were systolic blood pressure (BP) higher than 140 mm Hg or diastolic BP higher than 90 mm Hg and a history of hypertension according to patient interview. RESULTS: Among the polymorphisms investigated, only those located on the ACE gene were associated with hypertension. For ACE I/D, the odds ratio for hypertension of DD versus II homozygote individuals was 2.50 (95% confidence interval [CI] 1.19-5.25) and for ACE T-3892C, the odds ratio of CC versus TT individuals was 2.32 (95% CI 1.05-5.10). Both polymorphisms of the ACE gene were in tight linkage disequilibrium. Of the investigated risk factors for hypertension, only body mass index (BMI) showed an influence on the early development of hypertension, acting independently of the ACE polymorphism. Their additive effect gives rise to 86% of hypertensives in subjects having both the DD genotype and BMI >or=30 kg/m(2). CONCLUSIONS: The present study provides evidence of the association of the ACE gene polymorphisms and premature hypertension. In addition, BMI proved to be another important predictor of the disorder acting independently of the ACE gene.     

Combination of renin-angiotensin system polymorphisms is associated with altered renal sodium handling and hypertension

Genes of the renin-angiotensin-aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (ACE), M235T of angiotensinogen (AGT), A1166C of angiotensin II type-1 receptor (AT1R), and C-344T of aldosterone synthase (CYP11B2). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M (AGT), A (AT1R), and C (CYP11B2) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0%+/-5.9% versus 25.0%+/-7.5%; P=0.004; mean+/-sD), FE-UA (6.3%+/-2.0% versus 8.2%+/-2.7%; P=0.001), and FE-Na (0.96%+/-0.41% versus 1.22%+/-0.61%; P=0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.     

Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study

OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.     

The paradoxical association of common polymorphisms of the renin-angiotensin system genes with risk of myocardial infarction.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) and the A1166C polymorphism of the angiotensin-II AT1 receptor (AT1R) have been extensively investigated as possible risk factors for myocardial infarction (MI). DESIGN AND METHODS: Genetic association, case-control study, specifically designed to investigate the association of the above-mentioned polymorphisms with risk of MI in a homogeneous, low coronary risk, Caucasian population. The study population consisted of 1603 consecutive patients with acute MI who were recruited from nine clinics, located in three cities, and 699 unrelated adults who were randomly selected from the city catalogues. RESULTS: In univariate analysis, the DD genotype was found to be more prevalent among controls (40.8 vs. 35.2%, P=0.011). In multivariate analysis adjusted for age, gender, smoking status, diabetes mellitus, hypercholesterolaemia, hypertension and family history of coronary artery disease, the presence of the DD genotype was independently and negatively associated with risk of AMI (RR=0.743, 95% CI=0.595-0.927, P=0.008). The CC genotype was not found to be significantly associated with risk of MI, either in univariate (6.2 vs. 6.4%, P=0.856), or in multivariate analysis adjusted for the same confounders (RR=0.743, 95% CI=0.473-1.167, P=0.197). CONCLUSIONS: Contrary to previous reports, in this study the DD genotype of the ACE gene, but not the CC genotype of the AT1R gene, was associated with a lower risk of MI. Our results emphasize the complexity of genotype-phenotype interactions in the pathogenesis of ischaemic heart disease and question the previously hypothesized role of the DD genotype on risk of acute myocardial infarction.     

肾素-血管紧张素系统基因多态性与高血压病患者伊贝沙坦降压幅度关系的研究

目的：对原发性高血压患者采用血管紧张素Ⅱ受体拮抗剂（伊贝沙坦）单药治疗，在观察降压疗效的同时测定RAS基因多态性靶位点：ACEI／D、ACTM235T、AT1R 1166A／C、573T／C、1062A／G、-521C／T的基因型，旨在发现与血管紧张素Ⅱ受体拮抗剂降压疗效相关的基因多态性位点。方法：符合WHO／ISH高血压诊断标准轻、中度高血压患者117例，服用伊贝沙坦单药治疗8周，在临床观察疗效的同时，应用RFLP及PCR的方法对患者血白细胞基因组DNA进行RAS基因多态性位点ACEI／D、AGT M235T、AT1R 1166A／C、573T／C、1062A／G、-521C／T基因型的分析。结果：含ACED等位基因、的患者服用伊贝沙坦后SBP下降幅度明显大于Ⅱ型基因型患者，两者之间有统计学差异（P〈0．05）；含AT1R 573T等位基因的患者服用伊贝沙坦后收缩压下降幅度明显大于CC纯合基因型患者，两者之间有统计学差异（P〈0．05）；AGT M235T、AT1R 1166A／C、-521C／T各基因型之间BP下降幅度均无显著差异。所有入选患者未发现AT1R 1062A→G的变异。结论：肾素-血管紧张素系统基因多态性位点ACEI／D及AT1R 573T／C与ARB类药物的药物敏感性有一定相关性。     

Population-based study of the relationship among muscle morphology, insulin action, and hypertension

To examine whether changes in muscle morphology are linked to the metabolic abnormalities associated with the insulin resistance syndrome, muscle morphology and the metabolic profile were examined in 52 individuals with untreated hypertension (mean arterial pressure [MAP] = 117 ± 7 mm Hg) and 38 carefully matched controls (MAP = 89 ± 5 mm Hg). Oral glucose tolerance tests and hyperglycemic clamps were performed for measurements of insulin action on glucose disposal and suppression of nonesterified fatty acids (NEFA). Fully automated, computer-aided techniques were used for morphometric measurements of muscle biopsies from m. vastus lateralis. The hypertensive and normotensive groups did not differ in insulin sensitivity to glucose disposal (0.18 ± 0.16 v 0.19 ± 0.13 μmol/kg/min/pmol/L; P = .20) and NEFA suppression (87.5 ± 7.3 v 87.2 ± 9.4%, P > 0.30) during a hyperglycemic clamp. The groups were similar in the proportion of types 1, 2a, and 2b muscle fibers, fiber size, and capillary density. Fiber roundness (ratio of fiber perimeter squared to fiber area) differed in the hypertensive (1.51 ± 0.07) and normotensive (1.58 ± 0.12, P = .004) groups, showing that the muscle fibers in the hypertensive group were more rounded in shape, a nonspecific change often seen after minimal ischemic lesions. The quotient expressing fiber roundness was associated with systolic (r = −0.29, P = .01) and diastolic (r = −0.32, P = .005) blood pressure.

We conclude that persons with mild and moderate hypertension do not have abnormalities in muscle morphology that could explain the impairment of insulin action often observed in this condition. However, hypertensive individuals have increased muscle fiber roundness. It is wondered whether hypertension may be a condition with defects in the regulation of the transmembranous ion transport, leading to raised intracellular sodium concentration, swelling of the cytoplasma, and roundening of the fibers.     

Lack of association between common polymorphisms in genes of the renin-angiotensin system and mortality after myocardial infarction

The insertion/deletion (I/D) polymorphism in the ACE gene and the A1166C polymorphism in the AT1R gene have been associated with left ventricular remodelling and prognosis after acute myocardial infarction (AMI). We investigated whether these genetic variants associate with impaired left ventricular ejection fraction (LVEF) and increased risk for in-hospital mortality after AMI. Consecutive AMI patients were recruited on admission and were genotyped for the above-mentioned polymorphisms. The frequency of the studied genotypes did not differ significantly between deceased patients and those who survived. The LVEF did not differ among patients with or without the DD genotype (45 +/- 10 vs. 45 +/- 10%, p = 0.892) or the CC genotype (45 +/- 10 vs. 46 +/- 10%, p = 0.859). These data question the role of the studied genotypes in the pathogenesis of AMI and do not support the previously supported hypothesis that these genotypes influence prognosis after AMI.     

The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

肾素-血管紧张素系统基因多态性与冠心病合并慢性心力衰竭严重程度的关系

目的检测部分中国南方汉族人群冠心病合并慢性心力衰竭患者的ACE及AGT基因多态性分布情况,以探讨肾素-血管紧张素系统（1／AS）基因多态性对冠心病合并慢性心力衰竭严重程度的影响。方法应用聚合酶链反应及限制性片断长度多态性技术,对210例冠心病合并慢性心力衰竭患者的ACE基因插入／缺失（I/D）及AGT基因M235T多态性进行检测,采用彩色多普勒检测患者的左室舒张末内径（LVDD）及左室射血分数（LVEF）。结果不同ACE基因型患者其LVDD及LVEF均存在差异,LVDD（DD）〉LVDD（ID）〉LVDD（II）（P〈0．05）,LVEF（DD）〈IXEF（ID）〈LVEF（II）（P〈0．05）,不同AGT基因型亚组间LVDD及LVEF差别均无统计学意义（P〉0．05）。结论ACE基因I／D多态性与中国南方部分汉族人群冠心病合并慢性心力衰竭的严重程度相关,DD型ACE基因的冠心病患者发生心力衰竭后病情较其他基因型者更加严重。AGT基因M235T多态性似与冠心病合并慢性心力衰竭的严重程度无关。     

Gene polymorphisms of the renin-angiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension

BACKGROUND: Few studies have examined to what extent genes might modulate the changes of systolic and diastolic blood pressure (BP) with age although, in older populations, systolic BP and diastolic BP vary with age in opposite directions. METHODS: This study involved 205 men and 99 women with either systolic-diastolic or isolated systolic hypertension. Age was > 50 years. Using polymerase chain reaction, four gene polymorphisms related to the renin-angiotensin system were independently investigated in men and women. Adjustments to cardiovascular and renal risk factors as well to the sodium/potassium extracellular space ratio were performed. RESULTS: Regarding the angiotensin-converting enzyme (ACE) gene polymorphism, in men > 50 years of age, the slope (mm Hg per unit of age) of the age-diastolic BP (and not age-systolic BP) relationships significantly (P = .0092) differed between genotypes: - 0.79 +/- 0.15 (P < .0001) for the DD genotype, -0.53 +/- 0.10 for the ID genotype (P < .0001), and -0.23 +/- 0.11 for II genotypes (P = NS). Such findings were not observed in the female population in which the age-diastolic BP curves were substantially flatter than in men. No comparable results were observed for gene polymorphisms related either to angiotensinogen or to angiotensin II type 1 receptor. CONCLUSIONS: In men > 50 years of age, the ACE gene polymorphism modulates the physiologic age-induced reduction of diastolic BP. The D allele might contribute to enhance this reduction, a finding that needs confirmation using prospective studies.     

The renin-angiotensin system genetic polymorphisms and rheumatic mitral valve disease

BACKGROUND AND AIM OF THE STUDY: Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) gene polymorphism and angiotensin II type 1 receptor (AT1R) polymorphism in relation to rheumatic mitral valve disease were examined in a case-control study to investigate possible relationships between these gene polymorphisms and rheumatic mitral valve disease in patients undergoing mitral valve replacement (MVR). METHODS: A total of 50 patients with rheumatic mitral valve disease and undergoing MVR was compared with 50 normal, and age- and sex-matched control subjects. ACE I/D, AGT gene M235T and AT1R-adenine/cytosine 1166 (A1166C) genotype polymorphisms were identified by polymerase chain reaction (PCR) -based restriction analysis. RESULTS: ACE I/D polymorphism differed significantly between the groups. The control group mostly represented the heterozygote ID allele (74%), while the MVR group showed frequencies of 60% for the homozygote DD and II alleles. MM homozygote frequency was significantly greater in controls, but TT homozygote frequency was significantly greater in the MVR group. AT1R-A1166C genotype polymorphism also differed significantly between groups; the MVR group had 73.7% of the AC heterozygote allele, while controls had 64.4% of the AA and 66.7% of the CC homozygote alleles. CONCLUSION: These results provided evidence of an association between ACE I/D polymorphism, M235T polymorphism and AT1R-A1166C genotype polymorphism and rheumatic mitral valve disease.     

Linkage disequilibrium analysis of the renin-angiotensin system genes

The genes of the renin-angiotensin system (RAS) are important candidates to confer susceptibility to cardiovascular diseases. A large number of association studies between cardiovascular traits and the polymorphisms in RAS have been conducted, although inconsistent results are often reported. The patterns of linkage disequilibrium in RAS genes have also been reported in different populations. However, our understanding of the genetic architecture underlying the RAS is still limited despite rapid progress in empiric studies regarding the patterns of the human genome as a whole. In this review, the linkage disequilibrium among the polymorphisms within the four RAS genes and current association analyses involving the RAS are discussed, as well as some of the gaps of knowledge and possible solutions.