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, hypercholesterolemia, 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.