Title: Association of the angiotensin type 1 receptor gene A1166C polymorphisms with myocardial infarction: a meta‐analysis
Abstract: Angiotensin II plays an important role in the regulation of blood pressure and vascular homeostasis. However, over‐production of angiotensin II leads to multiple and diverse effects, including hypertension and atherosclerosis. All the above effects are mostly mediated by the angiotensin type 1 receptor (AT1R) [1Mehta P.K. Griendling K.K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.Am J Physiol Cell Physiol. 2007; 292: C82-97Crossref PubMed Scopus (1490) Google Scholar]. The AT1R gene A1166C polymorphism has been considered an important factor in the risk of myocardial infarction (MI). In 1994, Tiret et al. [2Tiret L. Bonnardeaux A. Poirier O. Ricard S. Marques‐Vidal P. Evans A. Arveiler D. Luc G. Kee F. Ducimetiere P. Soubrier F. Cambien F. Synergistic effects of angiotensin‐converting enzyme and angiotensin‐II type 1 receptor gene polymorphisms on risk of myocardial infarction.Lancet. 1994; 344: 910-3Abstract PubMed Scopus (438) Google Scholar] first reported the C‐allele distribution in both MI cases and controls. Since then, studies both supporting and questioning this association have been published [3Berge K.E. Bakken A. Bohn M. Erikssen J. Berg K. A DNA polymorphism at the angiotensin II type 1 receptor (AT1R) locus and myocardial infarction.Clin Genet. 1997; 52: 71-6Crossref PubMed Scopus (67) Google Scholar, 4Gardemann A. Nguyen Q.D. Humme J. Stricker J. Katz N. Tillmanns H. Hehrlein F.W. Rau M. Haberbosch W. Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin‐converting enzyme gene polymorphism on the risk of these diseases.Eur Heart J. 1998; 19: 1657-65Crossref PubMed Scopus (55) Google Scholar, 5Poirier O. Georges J.L. Ricard S. Arveiler D. Ruidavets J.B. Luc G. Evans A. Cambien F. Tiret L. New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas‐Temoin de l’Infarctus du Myocarde.J Hypertens. 1998; 16: 1443-7Crossref PubMed Scopus (79) Google Scholar, 6Fernandez‐Arcas N. Dieguez‐Lucena J.L. Munoz‐Moran E. Ruiz‐Galdon M. Espinosa‐Caliani S. Aranda‐Lara P. Martinez‐Espigares S. Banderas‐Donaire M.J. De Teresa‐Galvan E. Reyes‐Engel A. The genotype interactions of methylenetetrahydrofolate reductase and renin‐angiotensin system genes are associated with myocardial infarction.Atherosclerosis. 1999; 145: 293-300Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 7Canavy I. Henry M. Morange P.E. Tiret L. Poirier O. Ebagosti A. Bory M. Juhan‐Vague I. Genetic polymorphisms and coronary artery disease in the south of France.Thromb Haemost. 2000; 83: 212-6Crossref PubMed Scopus (94) Google Scholar, 8Kee F. Morrison C. Poirier O. McCrum E. Mallet C. Nicaud V. McMaster D. Dallongeville J. Fruchart J.C. Evans A.E. Angiotensin II type‐I receptor and ACE polymorphisms and risk of myocardial infarction in men and women.Eur J Clin Invest. 2000; 30: 1076-82Crossref PubMed Scopus (28) Google Scholar, 9Brscic E. Bergerone S. Gagnor A. Colajanni E. Matullo G. Scaglione L. Cassader M. Gaschino G. Di Leo M. Brusca A. Pagano G.F. Piazza A. Trevi G.P. Acute myocardial infarction in young adults: prognostic role of angiotensin‐converting enzyme, angiotensin II type I receptor, apolipoprotein E, endothelial constitutive nitric oxide synthase, and glycoprotein IIIa genetic polymorphisms at medium‐term follow‐up.Am Heart J. 2000; 139: 979-84Crossref PubMed Scopus (74) Google Scholar, 10Steeds R.P. Wardle A. Smith P.D. Martin D. Channer K.S. Samani N.J. Analysis of the postulated interaction between the angiotensin II sub‐type 1 receptor gene A1166C polymorphism and the insertion/deletion polymorphism of the angiotensin converting enzyme gene on risk of myocardial infarction.Atherosclerosis. 2001; 154: 123-8Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 11Hooper W.C. Dowling N.F. Wenger N.K. Dilley A. Ellingsen D. Evatt B.L. Relationship of venous thromboembolism and myocardial infarction with the renin‐angiotensin system in African‐Americans.Am J Hematol. 2002; 70: 1-8Crossref PubMed Scopus (46) Google Scholar, 12Araujo M.A. Menezes B.S. Lourenco C. Cordeiro E.R. Gatti R.R. Goulart L.R. The A1166C polymorphism of the angiotensin II type‐1 receptor in acute myocardial infarction.Arq Bras Cardiol. 2004; 83: 409-13Crossref PubMed Google Scholar, 13Su S. Chen J. Zhao J. Huang J. Wang X. Chen R. Gu D. Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.Pharmacogenetics. 2004; 14: 673-81Crossref PubMed Scopus (17) Google Scholar, 14Andrikopoulos G.K. Richter D.J. Needham E.W. Tzeis S.E. Zairis M.N. Gialafos E.J. Vogiatzi P.G. Papasteriadis E.G. Kardaras F.G. Foussas S.G. Gialafos J.E. Stefanadis C.I. Toutouzas P.K. Mattu R.K. The paradoxical association of common polymorphisms of the renin‐angiotensin system genes with risk of myocardial infarction.Eur J Cardiovasc Prev Rehabil. 2004; 11: 477-83PubMed Google Scholar, 15Ranjith N. Pegoraro R.J. Rom L. Lanning P.A. Naidoo D.P. Renin‐angiotensin system and associated gene polymorphisms in myocardial infarction in young South African Indians.Cardiovasc J S Afr. 2004; 15: 22-6PubMed Google Scholar, 16Araujo M.A. Goulart L.R. Cordeiro E.R. Gatti R.R. Menezes B.S. Lourenco C. Silva H.D. Genotypic interactions of renin‐angiotensin system genes in myocardial infarction.Int J Cardiol. 2005; 103: 27-32Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Pullareddy B.R. Babu B.M.V.S. Karunakar K.V. Yasovanthi J. Kumar P.S. Sharath A. Jyothy A. Angiotensin II type 1 receptor gene polymorphism in myocardial infarction patients.J Renin Angiotensin Aldosterone Syst. 2009; 10: 174-8Crossref PubMed Scopus (7) Google Scholar], leading to uncertainty about the importance of this polymorphism. The aim of this study was to assess the association of the AT1R gene A1166C polymorphism and MI by performing a meta‐analysis. We searched studies published in English using Medline (from 1966 to March 2011) and the following keywords: ‘angiotensin type 1 receptor’ or ‘AT1R’ or ‘AGT1R’, ‘polymorphism’ or ‘single nucleotide polymorphism’ or ‘SNP’, and ‘myocardial infarction’. References in retrieved articles were also searched. The inclusion criteria were as follows: (i) based on a case‐control design; (ii) evaluation of the association of MI and A1166C polymorphism; and (iii) available genotype frequency. For studies with overlapping subjects, those with larger sample size were included. Two reviewers (H. Zhang and M. L. Sun) independently searched the articles and extracted information. Discrepancies were resolved, through discussion, by a third reviewer (J. Peng). The analyses were performed with the reviewer manager 5.0.25 package (The Cochrane Collaboration, Oxford, UK). A total of 95 abstracts were identified. Of those, 19 studies were retrieved for more detailed evaluation. Three articles were excluded due to duplication of data [2Tiret L. Bonnardeaux A. Poirier O. Ricard S. Marques‐Vidal P. Evans A. Arveiler D. Luc G. Kee F. Ducimetiere P. Soubrier F. Cambien F. Synergistic effects of angiotensin‐converting enzyme and angiotensin‐II type 1 receptor gene polymorphisms on risk of myocardial infarction.Lancet. 1994; 344: 910-3Abstract PubMed Scopus (438) Google Scholar, 5Poirier O. Georges J.L. Ricard S. Arveiler D. Ruidavets J.B. Luc G. Evans A. Cambien F. Tiret L. New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas‐Temoin de l’Infarctus du Myocarde.J Hypertens. 1998; 16: 1443-7Crossref PubMed Scopus (79) Google Scholar, 12Araujo M.A. Menezes B.S. Lourenco C. Cordeiro E.R. Gatti R.R. Goulart L.R. The A1166C polymorphism of the angiotensin II type‐1 receptor in acute myocardial infarction.Arq Bras Cardiol. 2004; 83: 409-13Crossref PubMed Google Scholar]. Sixteen studies fulfilled the inclusion criteria and were selected for further data analysis [3Berge K.E. Bakken A. Bohn M. Erikssen J. Berg K. A DNA polymorphism at the angiotensin II type 1 receptor (AT1R) locus and myocardial infarction.Clin Genet. 1997; 52: 71-6Crossref PubMed Scopus (67) Google Scholar, 4Gardemann A. Nguyen Q.D. Humme J. Stricker J. Katz N. Tillmanns H. Hehrlein F.W. Rau M. Haberbosch W. Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin‐converting enzyme gene polymorphism on the risk of these diseases.Eur Heart J. 1998; 19: 1657-65Crossref PubMed Scopus (55) Google Scholar, 6Fernandez‐Arcas N. Dieguez‐Lucena J.L. Munoz‐Moran E. Ruiz‐Galdon M. Espinosa‐Caliani S. Aranda‐Lara P. Martinez‐Espigares S. Banderas‐Donaire M.J. De Teresa‐Galvan E. Reyes‐Engel A. The genotype interactions of methylenetetrahydrofolate reductase and renin‐angiotensin system genes are associated with myocardial infarction.Atherosclerosis. 1999; 145: 293-300Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 7Canavy I. Henry M. Morange P.E. Tiret L. Poirier O. Ebagosti A. Bory M. Juhan‐Vague I. Genetic polymorphisms and coronary artery disease in the south of France.Thromb Haemost. 2000; 83: 212-6Crossref PubMed Scopus (94) Google Scholar, 8Kee F. Morrison C. Poirier O. McCrum E. Mallet C. Nicaud V. McMaster D. Dallongeville J. Fruchart J.C. Evans A.E. Angiotensin II type‐I receptor and ACE polymorphisms and risk of myocardial infarction in men and women.Eur J Clin Invest. 2000; 30: 1076-82Crossref PubMed Scopus (28) Google Scholar, 9Brscic E. Bergerone S. Gagnor A. Colajanni E. Matullo G. Scaglione L. Cassader M. Gaschino G. Di Leo M. Brusca A. Pagano G.F. Piazza A. Trevi G.P. Acute myocardial infarction in young adults: prognostic role of angiotensin‐converting enzyme, angiotensin II type I receptor, apolipoprotein E, endothelial constitutive nitric oxide synthase, and glycoprotein IIIa genetic polymorphisms at medium‐term follow‐up.Am Heart J. 2000; 139: 979-84Crossref PubMed Scopus (74) Google Scholar, 10Steeds R.P. Wardle A. Smith P.D. Martin D. Channer K.S. Samani N.J. Analysis of the postulated interaction between the angiotensin II sub‐type 1 receptor gene A1166C polymorphism and the insertion/deletion polymorphism of the angiotensin converting enzyme gene on risk of myocardial infarction.Atherosclerosis. 2001; 154: 123-8Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 11Hooper W.C. Dowling N.F. Wenger N.K. Dilley A. Ellingsen D. Evatt B.L. Relationship of venous thromboembolism and myocardial infarction with the renin‐angiotensin system in African‐Americans.Am J Hematol. 2002; 70: 1-8Crossref PubMed Scopus (46) Google Scholar, 13Su S. Chen J. Zhao J. Huang J. Wang X. Chen R. Gu D. Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.Pharmacogenetics. 2004; 14: 673-81Crossref PubMed Scopus (17) Google Scholar, 14Andrikopoulos G.K. Richter D.J. Needham E.W. Tzeis S.E. Zairis M.N. Gialafos E.J. Vogiatzi P.G. Papasteriadis E.G. Kardaras F.G. Foussas S.G. Gialafos J.E. Stefanadis C.I. Toutouzas P.K. Mattu R.K. The paradoxical association of common polymorphisms of the renin‐angiotensin system genes with risk of myocardial infarction.Eur J Cardiovasc Prev Rehabil. 2004; 11: 477-83PubMed Google Scholar, 15Ranjith N. Pegoraro R.J. Rom L. Lanning P.A. Naidoo D.P. Renin‐angiotensin system and associated gene polymorphisms in myocardial infarction in young South African Indians.Cardiovasc J S Afr. 2004; 15: 22-6PubMed Google Scholar, 16Araujo M.A. Goulart L.R. Cordeiro E.R. Gatti R.R. Menezes B.S. Lourenco C. Silva H.D. Genotypic interactions of renin‐angiotensin system genes in myocardial infarction.Int J Cardiol. 2005; 103: 27-32Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Pullareddy B.R. Babu B.M.V.S. Karunakar K.V. Yasovanthi J. Kumar P.S. Sharath A. Jyothy A. Angiotensin II type 1 receptor gene polymorphism in myocardial infarction patients.J Renin Angiotensin Aldosterone Syst. 2009; 10: 174-8Crossref PubMed Scopus (7) Google Scholar, 18Franco E. Palumbo L. Crobu F. Anselmino M. Frea S. Matullo G. Piazza A. Trevi G.P. Bergerone S. Renin‐angiotensin‐aldosterone system polymorphisms: a role or a hole in occurrence and long‐term prognosis of acute myocardial infarction at young age.BMC Med Genet. 2007; 8: 27Crossref PubMed Scopus (26) Google Scholar, 19Morales‐Suarez‐Varela M.M. Riera‐Fortuny C. Mansego M.L. Martinez‐Triguero M.L. Chaves F.J. Martin‐Moreno J.M. Banuls C. Hernandez‐Mijares A. Association between AT C573T polymorphism and cardiovascular risk factors in myocardial infarction.Cardiovasc Pathol. 2011; 20: 156-61Crossref PubMed Scopus (5) Google Scholar, 20Mehri S. Mahjoub S. Finsterer J. Zaroui A. Mechmeche R. Baudin B. Hammami M. The CC genotype of the angiotensin II type I receptor gene independently associates with acute myocardial infarction in a Tunisian population.J Renin Angiotensin Aldosterone Syst. 2011; Crossref Scopus (6) Google Scholar]. In total, 6194 cases and 5716 controls were included from 16 studies. The overall distribution of genotypes in the controls was 57.3% AA, 35.9% AC and 6.8% CC, respectively. Compared with the AT1R AA genotype, subjects with the CC genotype showed a significantly higher risk of MI (odds ratio (OR) = 1.35; 95% confidence interval (CI), 1.05–1.73; P = 0.02) (Fig. 1A). Due to the low frequency of the CC genotype, we further compared the C allele carriers (AC/CC) with the AA genotype, which also revealed that individuals with the AC or CC genotype were more susceptible to MI (OR = 1.17; 95% CI, 1.04–1.31; P = 0.008) (Fig. 1B). Considering the deviation from Hardy–Weinberg equilibrium, we removed the study by Su et al. [13Su S. Chen J. Zhao J. Huang J. Wang X. Chen R. Gu D. Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.Pharmacogenetics. 2004; 14: 673-81Crossref PubMed Scopus (17) Google Scholar]. However, the pooled OR was not appreciably altered (CC vs. AA: OR = 1.38; 95% CI, 1.08–1.76; P = 0.01; AC/CC vs. AA: OR = 1.18; 95% CI, 1.05–1.33; P = 0.007) (Fig. 1C,D). The results of this meta‐analysis suggest that the C allele of the AT1R gene A1166C polymorphism is associated with an increased risk of MI. However, we cannot infer a causal relationship between the AT1R genotype and the risk of MI by this cross‐sectional analysis, and we cannot clarify the inner mechanisms by which the AT1R genotype increases MI risk. Further larger, muticentre, prospective studies are necessary to establish a causal link between the AT1R genotype and MI. In addition, systematic evaluation of the interaction of AT1R and other related genes might further interpret the internal mechanisms of vascular pathophysiological processes. In conclusion, our study indicates an association of the C allele of AT1R gene A1166C polymorphisms and MI. Further investigations are needed to illuminate the possible mechanisms involved in this phenomenon. The authors state that they have no conflict of interest.