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

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% CI 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.