Abstract 2175: Pharmacogenomic Targeting of ACE Inhibitors: Interaction of the Beta-1 Adrenergic Arg389Gly and G-Protein Beta-3 Subunit 825 T/C Polymorphisms
Background: Subjects genetically predisposed to greater plasma renin activity may receive more benefit from higher ACE inhibitor (ACE-I) dose. The β1-adrenoceptor regulates renin release and contains an Arg389 gene variant associated with increased plasma renin activity. We hypothesized that the Arg389Arg genotype would be linked to a greater impact of ACE-I dose, and that its effects would be magnified by co-inheritance of the G-protein β3-subunit 825C (GNB3C) allele previously linked to ACE-I effect.
Methods: 459 patients with LV dysfunction were evaluated. Subjects were grouped into treatment groups based on ACE-I dose: >50% target classified as “high dose” and ≤50% target dose as “low dose”. Patients on ARBs (n=49) were excluded. Subjects were followed up to five years to an endpoint of cardiac transplantation or death. The impact of ACE-I dose on event free survival (EFS) was analyzed by Kaplan-Meier curves for the overall cohort and then separately by Arg389Gly genotype subsets (Group A: ArgArg, n=197; group B: GlyGly + Arg/Gly, n=213). Given the potential synergy of the Arg389 allele with the GNB3 825T/C polymorphism, the ACE-I dose effect was re-examined in subjects co-inheriting the Arg389Arg and GNB3CC genotypes (n=90, Group C).
Results: The entire cohort was 29% female, 48.7% ischemic, and 91.5% Caucasian. The mean age was 55±12 years, mean LVEF was 24.7%± 8.3%, and % NYHA class I/II/III/IV was 3/44/48/5. In group A, subjects on high dose ACE-I had a trend toward better EFS compared to those on low dose though this failed to reach significance (% EFS at 1-, 3-, and 5-years, low dose: 71/52/47 ; high dose: 89/59/42, p=0.22). In contrast a profound impact was evident with co-inheritance of GNB3CC and Arg389Arg genotypes. In group C, ACE-I high dose was found to significantly improve EFS (% EFS at 1-, 3-, and 5-years, low dose: 78/60/37 and high dose: 94/73/43, p=0.005). No effect of ACE-I dose was evident in group B regardless of GNB3 genotype.
Conclusion: In a cohort with heart failure, co-inheritance of the Arg389 and GNB3C alleles was associated with significantly greater impact of ACE-I dose on event free survival. Polygenic analysis of synergistic alleles may be required to accomplish pharmacogenetic targeting of heart failure therapeutics.