Key result
In ACS patients with diabetes, beta-blocker use was associated with reduced cardiac rehospitalization in UCP2 -866 G/G individuals (HR 0.20) but an 11-fold increase in A-carriers (HR 11.75).
Why the study?
Does the UCP2 -866G>A genotype modify the effect of beta-blocker therapy on cardiac rehospitalizations or death in patients with ACS and diabetes?
Cohort (n=468)
Does the UCP2 -866G>A genotype modify the effect of beta-blocker therapy on cardiac rehospitalizations or death in patients with ACS and diabetes?
Hazard Ratio: 0.2 (95% CI 0.04–1.02)
p-value: p=0.002
The UCP2 -866G>A polymorphism significantly modifies the clinical response to beta-blockers in ACS patients with diabetes, suggesting a pharmacogenetic interaction that could influence treatment efficacy and safety.
UCP2 -866G>A should not yet guide beta-blocker use in diabetic ACS; leaves open pharmacogenetic confirmation in trials.
OBJECTIVE: UCP2 -866G>A (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 -866G>A and its role as a modifier of beta-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort. METHODS: ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n=468) were assessed. The influence of -866G>A on beta-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of -866G>A, 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. RESULTS: An interaction between -866G>A 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. CONCLUSION: We identified a significant interaction between -866G>A 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.
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Beitelshees et al. (2010) conducted a cohort in Acute coronary syndromes (ACS) (n=468). Beta-blocker therapy vs. No beta-blocker therapy was evaluated on Cardiac rehospitalizations or death (HR 0.20, 95% CI 0.04-1.02, p=0.002). In ACS patients with diabetes, beta-blocker use was associated with reduced cardiac rehospitalization in UCP2 -866 G/G individuals (HR 0.20) but an 11-fold increase in A-carriers (HR 11.75).
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