Abstract 3465: The Pharmacogenomic Interaction Between Inhibition of Renin-Angiotensin-Aldosterone System and beta1 Adrenoreceptor Gly389Arg Polymorphism
Background. Neurohormonal activation plays an important role in occurrence of cardiovascular events after myocardial infarction (MI). Beta-adrenergic receptor blockade and inhibition of renin-angiotensin-aldosterone system (RAAS) are both established treatment for secondary prevention of MI. As previous studies have shown that the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with the effects of beta-blocker therapy, there seems to be some interaction between the control of neurohormonal system and some gene polymorphisms. In this study, we genotyped the polymorphisms in the genes associated to beta receptors and RAAS, and evaluated the effect of ACE inhibitors on the survival rate after MI.
Patients and Methods. Among consecutive Japanese patients with acute myocardial infarction who were registered in the Osaka Acute Coronary Insufficiency Study (OACIS) from April 1998, 2430 survivors who gave written informed consent were included in this study. We genotyped 4 polymorphisms in the RAAS-related genes and 5 polymorphisms in the genes of beta-adrenergic receptors. Patients were divided into two groups according to presence or absence of ACE inhibitors or angiotensin receptor blockers (ACEI/ARB). Cumulative survival curve of each group is constructed using Kaplan-Meier method and the difference was compared by log-rank test Results. In overall, patients with ACEI/ARB revealed lower mortality than patients without (95.3% vs. 91.6%, p=0.0006). In the subgroup analysis, there are no significant differences of the effect of ACEI/ARB among 8 of 9 gene polymorphisms. However, there was a pharmacogenetic interaction between ACEI/ARB and beta1-adrenergic receptor (B1AR) Gly389Arg polymorphism. The favorable effect of ACEI/ARB was only significant in the patients with CC genotype (p<0.00001) in this gene. On the other hand, there were no difference in patients with and without ACEI/ARB in the subgroup of G allele carriers (p=0.7981).
Conclusion. Our data suggested a potential pharmacogenomic interaction between the effect of ACEI/ARB and B1AR Gly389Arg polymorphism. Further studies in vitro will be needed to clarify this issue.