Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction

doi:10.1016/S0140-6736(94)92268-3

The Lancet

Volume 344, Issue 8927, 1 October 1994, Pages 910-913

https://doi.org/10.1016/S0140-6736(94)92268-3 Get rights and content

Abstract

Summary

We reported from our previous multicentre case-control study that the deletion (D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) was associated with increased risk of myocardial infarction. The main function of ACE is to convert angiotensin I into angiotensin II, which exerts its known cellular actions through the angiotensin II AT₁ receptor subtype (AGT₁R). We have now investigated the role of a common polymorphism of the AT₁ receptor gene (an A→C transversion at position 1166 of AGT₁R) and looked for an interaction between ACE and AGT₁R gene polymorphisms on the risk of myocardial infarction.

We analysed DNA from 613 patients with myocardial infarction and 723 age-matched population controls. We found a significant interaction between ACE and AGT₁R gene polymorphisms; the odds ratio for myocardial infarction associated with the ACE DD genotype was 1·05 (95% Cl 0·75-1·49) for subjects without the AGT₁R C allele, 1·52 (1·06-2·18) in AC heterozygotes, and 3·95 (1·26-12·4) in CC homozygotes (test for trend, p<0·02). Among patients defined as low risk by traditional risk factors (serum apolipoprotein B <1·25 g/L, body-mass index<26 kg/m²) the interaction was even stronger (odds ratios 1·64 [0·68-3·92], 7·03 [2·61-19·0], and 13·3 [p=0·05], respectively).

These findings, if confirmed, could have clinical implications for the prevention and treatment of coronary heart disease.

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Cited by (442)

Role of Angiotensin-Converting Enzyme (ACE) gene polymorphism and ACE activity in predicting outcome after acute myocardial infarction
2021, IJC Heart and Vasculature
Citation Excerpt :
A human angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, due to I/D of a 287-base pair element in intron 16 of this gene, is associated with the development of AMI by modifying ACE activity and contributing to enhanced plaque vulnerability, ulceration and thrombosis [6,7]. The Ace polymorphism shown association with ACE activity [8–14], Premature atherosclerosis [15], myocardial infarction [6,7,12,16–29], LV dysfunction [30], LV remodelling [31–36], severity and extent of CAD [37] and mortality after MI [32,38,39,40]. Though ACE I/D polymorphism has been reported to be associated with various cardiovascular diseases it remained a controversial risk factor and studies have presented conflicting results [16,41].
The Ace polymorphism had shown association with ACE activity, premature atherosclerosis, myocardial infarction, LV dysfunction, LV remodelling, severity and extent of CAD and mortality after MI. Though ACE I/D polymorphism has been reported to be associated with various cardiovascular diseases it remained a controversial risk factor and studies have presented conflicting results. This study was designed to determine the association between ACE) gene insertion/deletion (I/D) polymorphism, ACE activity and acute STEMI in Indian population and to determine its influence on outcome after acute MI.
We investigated 934 patients diagnosed with acute STEMI who underwent thrombolysis. ACE I/D polymorphism was detected by polymerase chain reaction and ACE activity was measured in 615 patients.
The prevalence of DD, ID, and II genotypes in our study group were 41.97%, 34.36%, and 23.66% respectively. The ACE polymorphism was not significantly associated with the type of myocardial infarction, the LV ejection fraction, the number of vessels diseased and patency of the vessel after thrombolysis. The polymorphism had no influence on in hospital mortality (P = 0.453). The ACE activity also showed no influence on in hospital mortality (P = 0.482). The age > 60 years, Male gender, occluded artery and severe LV dysfunction (LVEF < 35%) were predictors of in-hospital mortality on multivariate regression analysis.
There was no differences among ACE (I/D) polymorphism observed in STEMI population. Neither ACE I/D polymorphism nor ACE activity predicted in-hospital mortality inpatients admitted with acute STEMI.
Probiotic lactobacillus strains for enhanced health benefits (genetic engineering and microencapsulation)
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Genetically, engineered probiotic organisms are envisioned as the next new age functional products. The concerted ability of the engineered probiotic strains designed to recognize the target, synthesize, and deliver biomolecules at a specific site has made them popular biotherapeutics. Several evidences discussed in this chapter confirm the potential application of genetically modified probiotic strains in numerous conditions ranging from irritable bowel syndrome to hypertension to phenylketonurea to tumor therapy to antiinfectives. In the future, the tools of Clustered Regularly Interspaced Short Palindromic Repeats can be further modified to develop a diverse range of designer probiotic strains by swapping the promoter and therapeutics genes to target several other disease biomarkers and treatments, respectively. Considering the growing application of probiotics as biotherapeutics, the chapter also discusses some of the emerging techniques for microencapsulation of probiotic strains.
Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases
2015, European Journal of Pharmacology
G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases.
Role of angiotensin II type i (AT1 A1166C) receptor polymorphism in susceptibility of left ventricular dysfunction
2015, Indian Heart Journal
Left ventricular dysfunction (LVD) with subsequent congestive heart failure (CHF) constitutes the final common pathway for a host of cardiac disorders. The impaired LV function develops in response to an ischemic insult followed by a fall in cardiac output that leads to activation of renin-angiotensin-system (RAS). Angiotensin II type I receptor (AT1), which mediate the vasoconstrictive and salt-conserving actions of the RAS, represent interesting candidate genes for cardiovascular diseases. Therefore, we conducted an association study between single nucleotide polymorphism (SNP) in AT1 gene and LVD in CAD patients.
The present study recruited a total of 950 subjects including 720 angiography confirmed CAD patients and 230 healthy controls. Among 720 CAD patients, 229 with reduced left ventricle ejection fraction (LVEF ≤ 45%) were categorized as LVD. The AT1 (A1166C, rs5186) polymorphism was determined by ARMS-PCR. Our results showed that the frequency of AT1 1166AC and CC genotypes were significantly higher in LVD patients in comparison to non-LVD (LVEF >45%) patients (p value = 0.003; OR = 1.81 and p value <0.001; OR = 4.33). Further analysis showed that AT1 A1166C polymorphism was significantly associated with LV end diastole (p-value = 0.031), end systole (p-value = 0.038) dimensions, and mean LVEF (p-value = 0.035). Moreover, on comparing the AT1 A1166C polymorphism in CAD patients with healthy controls, we did not find any association both at genotypic and allelic level (p value = 0.927; OR = 1.04 and p value = 0.219; OR = 0.83) respectively.
Our study suggests that AT1 A1166C polymorphism may play significant role in conferring genetic susceptibility of LVD.
Genetic predisposition to left ventricular dysfunction: A multigenic and multi-analytical approach
2014, Gene
Left ventricular dysfunction (LVD) is a complex, multifactorial condition, caused by mechanical, neurohormonal, and genetic factors. We have previously observed association of renin–angiotensin–aldosterone system (RAAS), matrix metalloproteinases (MMPs) and inflammatory pathway genes with LVD. Therefore the present study was undertaken to identify the combination of genetic variants and their possible interactions contributing towards genetic susceptibility to LVD in the background of coronary artery disease (CAD).
The study included 230 healthy controls and 510 consecutive patients with angiographically confirmed CAD. Among them, 162 with reduced left ventricle ejection fraction (LVEF ≤ 45%) were categorized as having LVD. We analyzed 11 polymorphisms of RAAS, MMPs and inflammatory pathways. Single locus analysis showed that AT1 A1166C (p value < 0.001; OR = 3.67), MMP9 R668Q (p value = 0.007; OR = 3.48) and NFKB1-94 ATTG ins/del (p value = 0.013; OR = 2.01) polymorphisms were independently associated with LVD when compared with both non-LVD patients and healthy controls. High-order gene–gene interaction analysis, using classification and regression tree (CART) and multifactor dimensionality reduction (MDR) revealed that AT1 A1166C and NFKB1-94 ATTG ins/del polymorphisms jointly increased the risk of LVD to great extent (p-value = 0.001; OR = 8.55) and best four-factor interaction model consisted of AT1 A1166C, MMP7 A-181G, MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms with testing accuracy of 0.566 and cross validation consistency (CVC) = 9/10 (permutation p < 0.001) showed increased risk for LVD respectively.
AT1 A1166C independently and in combination with MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms plays important role in conferring genetic susceptibility to LVD in CAD patients.
The AGTR1 gene A1166C polymorphism as a risk factor and outcome predictor of primary intracerebral and aneurysmal subarachnoid hemorrhages
2014, Neurologia i Neurochirurgia Polska
Associations between the angiotensin II type 1 receptor (AGTR1) gene A1166C polymorphism and hypertension, aortic abdominal aneurysms (as a risk factor) as well as cardiovascular disorders (as a risk factor and an outcome predictor) have been demonstrated. We aimed to investigate the role of this polymorphism as risk factors and outcome predictors in primary intracerebral hemorrhage (PICH) and aneurysmal subarachnoid hemorrhage (aSAH).
We have prospectively recruited 1078 Polish participants to the study: 261 PICH patients, 392 aSAH patients, and 425 unrelated control subjects. The A1166C AGTR1 gene polymorphism was studied using the tetra-primer ARMS-PCR method. Allele and genotype frequencies were compared with other ethnically different populations.
The A1166C polymorphism was not associated with the risk of PICH or aSAH. Among the aSAH patients the AA genotype was associated with a good outcome, defined by a Glasgow Outcome Scale of 4 or 5 (p < 0.02). The distribution of A1166C genotypes in our cohort did not differ from other white or other populations of European descent.
In conclusion, we found an association between the A1166C AGTR1 polymorphism and outcome of aSAH patients, but not with the risk of PICH or aSAH.

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ArticlesSynergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction

Abstract

Lancet

Lancet

Lancet

Biochem Biophys Res Commun

Biochem Biophys Res Commun

TIBS

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

Nature

Distribution of the angiotensin-converting enzyme gene polymorphism in subjects who die of coronary heart disease

QJ Med

A potent genetic risk factor for restenosis

Nature Genet

The ACE insertion/deletion polymorphism is independently associated with myocardial infarction and body mass index but not with stenosis

Circulation

Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus

Proc Natl Acad Sci USA

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

Clin Genet

Significance of the deletion polymorphism of the angiotensin-converting enzyme gene as a risk factor for myocardial infarction in Japanese

Hypertens Res

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

Clin Gent

Angiotensin-converting enzyme genotype and risk for coronary heart disease

Circulation

Articles
Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction