Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease

doi:10.1016/0021-9150(96)05866-2

Atherosclerosis

Volume 125, Issue 2, 6 September 1996, Pages 161-169

https://doi.org/10.1016/0021-9150(96)05866-2 Get rights and content

Abstract

The D allele of an insertion/deletion ( $I D$ ) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with a risk of myocardial infarction, and the relative risk associated with the ACE D allele is increased by the C allele of an angiotensin II type 1 receptor (AT₁R) gene polymorphism (an A → C transversion at nucleotide position 1166) [28]. The relation of the ACE and AT₁R gene polymorphisms to coronary heart disease and the severity of coronary artery stenosis has now been investigated in 133 patients with myocardial infarction (MI) or angina pectoris who underwent coronary angiography and in 258 control subjects. The frequency of the ACE DD genotype as compared with non-DD was significantly higher in the patients who experienced an MI and in the low-risk patients than that in the controls (P < 0.05). The DD genotype showed a significantly increased risk of MI (odds ratio 1.85). The frequency of the AT₁R $A C$ genotypes did not differ between the patients and the controls. The severity of coronary stenosis in the patients was estimated by the number of affected vessels (> 75% stenosis) and the coronary score of Gensini. Neither the number of affected vessels nor the coronary score differed among the ACE $I D$ genotypes. However, the number of affected vessels was significantly greater in patients with the AT₁R AC genotype than in those with the AA genotype (1.93 ± 0.27 vs. 1.27 ± 0.99; P < 0.05) (CC genotype was not found in the patients). After excluding patients with diabetes mellitus, the coronary score of those with the AC genotype was also significantly higher than in those with the AA genotype (51.7 ± 34.4 vs. 18.2 ± 23.3; P < 0.01). These results suggest that the ACE D allele is associated with the occurrence of myocardial infarction, while the AT₁R C allele is involved in the development of the coronary artery stenosis.

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This finding supports our hypothesis that the AT1R (A1166C) polymorphism is associated with an increased risk of hypotension when undergoing spinal anaesthesia for caesarean delivery. The AT1R (A1166C) polymorphism has been associated with hypertensive disease, including drug-resistant essential hypertension,12,15,16 hypertensive disease of pregnancy,14 cardiovascular remodelling,17,18 and increased arterial stiffness.19 As the polymorphism is located in the 3′ untranslated region of the AT1R gene, it does not directly alter the protein structure of AT1R, but may exert its effect by increasing AT1R gene transcription and upregulating its expression.20,42,43
Unless prevented, hypotension occurs in up to 80% of normotensive women undergoing spinal anaesthesia for caesarean delivery. Renin-angiotensin-aldosterone system genetic polymorphisms have been associated with hypertensive disease, but few studies investigated effects on blood pressure regulation under spinal anaesthesia. We postulated that these polymorphisms increased vasodilation and maternal hypotension during spinal anaesthesia.
A retrospective secondary analysis of data from four prospective trials with similar inclusion/exclusion criteria evaluating phenylephrine/ephedrine delivery systems during spinal anaesthesia for elective caesarean delivery. Angiotensin type-1 receptor (AT1R) (A1166C), angiotensin-converting enzyme (ACE) (I/D), and aldosterone synthase CYP11B2 (C344T) polymorphisms were identified from stored specimens. The associations between the polymorphisms and hypotension (systolic blood pressure <80% of baseline), and vasopressor use, were determined by univariable and multivariable regression.
Of 556 patients, 378 (68.0%) had hypotension. The AC/CC genotypes of AT1R (A1166C) were associated with hypotension by univariable analysis (OR 2.70, 95% CI 1.38 to 5.28, P=0.004]) and multivariable analysis (OR 3.65, [95% CI 1.68 to 7.94, P=0.004]) after adjustment for age, race, intravenous fluid volume, and block height. No difference in vasopressor use or adverse maternal or fetal outcomes were noted. Baseline characteristics were similar, with the exception of higher baseline blood pressure, block height, and intravenous fluid volume in the hypotensive group. There was no significant association between ACE and CYP11B2 polymorphisms and hypotension.
AC/CC genotypes of AT1R (A1166C) polymorphism were associated with maternal hypotension under spinal anaesthesia for caesarean delivery. An association with cardiovascular indices and high-risk parturients should be examined.
Sonographic evaluation of atherosclerosis burden in carotid arteries of ischemic stroke patients and its relation to paraoxonase 1 and 2, MTHFR and AT1R genetic variants
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The rs662 and rs854560 polymorphisms on the PON1 gene and the rs7493 polymorphism on the PON2 gene were genotyped as described [26,27]. The rs5186 (A1166C) and the rs1801133 (C677T, Ala222Val, and A222V) variants at the AGT1R and MTHFR genes were genotyped as described [15,28]. Generalized Multifactor Dimensionality Reduction (GMDR) version 0.9, obtained from http://www.ssg.uab.edu/gmdr/ was applied to analyze high order interaction of gene-gene.
Common variants of the Paraoxonase (PON), 5-Methyl-Tetrahydrofolate-Reductase (MTHFR) and Angiotensin-II receptor 1 (AT1R) genes have been associated with ischemic stroke (IS) risk. Moreover, carotid atherosclerosis is a common cause of IS. The aim of this study is to explore whether variants in these genes associate with the severity of ultrasonographic determined atherosclerosis assessed in carotid arteries.
Etiologic subtype of cerebral ischemia was determined according to the TOAST classification. Genotypes were detected by PCR and restriction analysis. An ultrasonographic supra-aortic trunks study was performed to all patients to assess their atherosclerotic involvement based on predefined criteria.
In IS patients, none of the analyzed gene distributions differed concerning the stenosis degree. Nevertheless, a trend was observed for the rs662 and rs7493 variants of the PON1 and PON2 genes respectively. When evaluated the results based on different inheritance models, a significant contribution of rs7493 variant according to a dominant (OR = 2.397, 95% CI (1.001–5.376); p = 0.045) and log-additive inheritance forms (OR = 1.85, 95% CI (1.07–3.2); p = 0.03) was observed. Only rs7493 reached statistical significance (p = 0.013), when genotype distribution was analyzed according to carotid intima-media thickness (cIMT) and remain significant in multivariate logistic regression analysis (OR = 2.66, 95% CI (1.1 to 6.4); p = 0.03).
In IS patients of the north area of the Gran Canaria island the PON2 (rs7493) gene variant associates with a worse ultrasonographic profile. Conversely, the Cys311Cys homozygosis of the rs7493 variant was also related to a better ultrasonographic profile in our study.
Association of four CpG-SNPs in the vascular-related genes with coronary heart disease
2015, Biomedicine and Pharmacotherapy
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Candidate gene association tests [4,5] as well as genome-wide association studies (GWAS) [6] have revealed a handful of genetic variants to the CHD pathogenesis, however, the function of the variants remained to be investigated. Clinical manifestations of CHD include vascular anomalies, the formation of coronary intravascular platelet thrombosis and paroxysmal chest pain [7]. Many vascular-related genes were found to be associated with CHD susceptibility, including genes encoding angiotensin converting enzyme [8,9], endothelin [10], cytokines [11] and coagulation system [12,13].
Vascular-related gene polymorphism can affect the susceptibility of coronary heart disease. In current study, we aimed to evaluate the contribution of four vascular-related gene CpG-SNPs to coronary heart disease (CHD). A total of 784 angiography-proven CHD patients and 746 non-CHD controls were included in the current association study. The four CpG-SNPs (including VEGFA rs1005230, ACE rs4316, CST3 rs3827143 and AGTR1 rs275653) were genotyped using the Sequenom MassARRAY platform. All genotype distribution of four SNPs met HWE. Among the four CpG-SNPs, none was found to be associated with CHD on both genotype and allele levels. Further subgroup tests by age or gender were unable to observe any significant associations of them with CHD. Our case-control study showed that none of four CpG-SNPs in the vascular-related genes was associated with the risk of CHD in Han Chinese, although we could not exclude other genetic variants of these vascular-related genes with contribution to CHD.
Polymorphisms of angiotensin II type 1 receptor gene and those of angiotensinogen point at culprit artery in ST-segment elevation myocardial infarction
2012, Gene
Citation Excerpt :
Nakauchi et al. found that the number of affected vessels was significantly greater in patients with the AC genotype for AGTR1 1166A/C gene polymorphism than in those with the AA genotype (1.93 vs 1.27, p < 0.05) (Nakauchi et al., 1996). In patients without diabetes mellitus, the coronary score of Gensini of those with AC genotype was also significantly higher than in those with AA genotype (51.7 vs 18.2, p < 0.01) (Nakauchi et al., 1996). Lanz et al. in a univariate analysis revealed that the presence of 235Thr variant allele for AGT Met235Thr gene was associated with higher angiographic extension scores in patients with clinically suspected CAD (Lanz et al., 2005).
The aim of the study was to determine whether the presence of angiotensin II type 1 receptor 1166A/C gene polymorphism and two polymorphisms of angiotensinogen, namely Met235Thr and Thr174Met, pointed at the culprit artery in patients with ST-segment elevation myocardial infarction (STEMI).
The AGTR1 1166A/C polymorphism and two AGT gene polymorphisms, Met235Thr and Thr174Met, were assessed in 100 patients with STEMI.
The odds ratio (OR) of circumflex artery (CRX) responsible for STEMI was 3.49 (95% CI: 1.1–10.8, p < 0.05) for MetThr genotype for AGT Met235Thr gene and 4.54 (95% CI: 1.5–14.2, p < 0.01) for ThrMet genotype for AGT Thr174Met gene. Homozygous ThrThr genotype for AGT Thr174Met gene reduced OR of CRX as culprit artery in STEMI (OR = 0.29, 95% CI: 0.1–0.9, p < 0.05). However, the highest OR that increased up to 13.71 (95% CI: 1.58–119.3) was shown in case of right coronary artery and C/C genotype for AGTR1 1166A/C gene.
Polymorphism of AGTR1 1166A/C gene can point at the right coronary artery as infarct-related artery in STEMI. Polymorphisms of AGT Met235Thr and AGT Thr174Met genes are able to mark increased or reduced odds ratio of circumflex artery as culprit artery in STEMI.
Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease
2012, Gene
Citation Excerpt :
In Italian subjects, Fatini et al. (2000) reported a significant association between ATR1 CC genotype and the presence of CAD. In addition, the C allele of the ATR1 gene was reported to be associated with the severity of CAD in Japanese patients (Nakauchi et al., 1996) and development of CAD in Chinese patients (Qiu et al., 2008). Xu et al. (2010) found weak association between A1166C polymorphism and CAD in a meta-analysis study.
Genetics polymorphism of the renin–angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.
A1166C genetic variation of the angiotensin II type I receptor gene and susceptibility to coronary heart disease: Collaborative of 53 studies with 20,435 cases and 23,674 controls
2010, Atherosclerosis
Citation Excerpt :
Since then, considerable effort has been poured on exploring the relationships between the AGTR1 polymorphisms and CHD. However, a number of studies yielded apparently conflicting and inconsistent results [6–60]. These disparate findings may partly due to improper study design and insufficient power in most of such studies (which have not involved more than a few hundred disease cases), and are too few to assess reliably any genetic effects that might be realistically expected (such as per-allele odds ratio (OR) increases of about 10–20%).
Angiotensin II induces vasoconstriction and vascular smooth muscle growth via stimulation of the angiotensin II type I receptor (AGTR1). Some studies have reported an association between a genetic variant (A1166C) in the 3′ un-translated region of AGTR1 and increased risk of coronary heart disease (CHD), but other have yielded apparently conflicting results.
Literature-based meta-analyses were performed on 48 papers including 53 studies published before June 2008 in relation to the A1166C polymorphism (NCBI, dbSNP: rs5186) of the AGTR1, involving a total of 20,435 CHD cases and 23,674 controls. We also explored potential sources of heterogeneity and conducted appropriate stratified analyses.
In a combined analysis, the per-allele odds ratio (OR) for CHD of the A1166C polymorphism was 1.11 (95% confidence interval: 1.03–1.19), but there is an indication of publication bias and heterogeneity among the 53 studies. Sample size and study quality were significant sources of heterogeneity among studies of the A1166C polymorphism with possibly overestimates in studies of smaller sample-size and poor-quality. When the analyses were restricted to 11 larger studies (≥500 cases), and to 8 high-quality studies (quality score: ≥11 points), the summary per-allele odds ratios were 0.992 (95% confidence interval, 0.944–1.042) and 0.990 (95% confidence interval, 0.915–1.072), respectively.
An overall weak association between the A1166C polymorphism and CHD is observed but this is likely to be due to publication bias and heterogeneity between studies. There were no significant associations among the larger sample-size and high-quality studies which are less prone to selective publication and have greater power to detect a true association.

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Research paperSignificance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease

Abstract

Lancet

Lancet

Atherosclerosis

Lancet

Lancet

Am J Cardiol

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension

N Engl J Med

Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall

Circ Res

Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells

Circ Res

Immunohistochemical localization of rat angiotensin II AT1 receptor

Am J Physiol

Chronic angiotensin II type 1 receptor antagonism in genetic hypertension: effects on vascular structure and reactivity

J Hypertens

Increase of angiotensin converting enzyme gene expression in the hypertensive aorta

Hypertension

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

J Clin Invest

Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels

Am J Hum Genet

Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction

Nature

Insertion/deletion (ID) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction

Clin Genet

Research paper
Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease

Immunohistochemical localization of rat angiotensin II AT₁ receptor

Insertion/deletion ( $I D$ ) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction