Interaction between the UCP2 -866 G>A polymorphism, diabetes, and β-blocker use among patients with acute coronary syndromes

UCP2 -866GA (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for beta-blocker response, particularly among patients with diabetes. We assessed the function of -866GA and its role as a modifier of beta-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort.ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n=468) were assessed. The influence of -866GA on beta-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of -866GA, we compared uncoupling protein 2 (UCP2) expression in the skeletal muscle of obese participants by genotype and compared the activity of UCP2 luciferase promoters with -866G and -866A alleles.An interaction between -866GA and beta-blocker treatment was found in individuals with diabetes (P=0.002) but not those without (P=0.79). Among G/G individuals with diabetes, discharge beta-blocker use was associated with an 80% reduction in cardiac rehospitalization (adjusted hazard ratio: 0.20; 95% confidence interval: 0.04-1.02). In contrast, among A-carrier patients with diabetes, there was an 11-fold increase in cardiac rehospitalizations with discharge beta-blocker therapy (adjusted hazard ratio: 11.75; 95% confidence interval: 1.28-108.2). Promoter activity assays showed that -866G had greater cyclic AMP response element binding protein-responsiveness compared with -866A, and compared with -866A carriers G/G individuals exhibited increased UCP2 expression in the skeletal muscle.We identified a significant interaction between -866GA and beta-blocker response among ACS patients with diabetes. Furthermore, -866G conferred greater gene transcriptional activity than -866A in cell lines and in obese patients. These findings may help us gain insight into the mechanisms underlying the beneficial and detrimental effects of beta-blockers in those with diabetes.