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

Amber L. Beitelshees, Brian N. Finck, Teresa C. Leone, Sharon Cresci, Jun Wu, Michael A. Province, Elisa Fabbrini, Erik Kirk, Issam Zineh, Samuel Klein, John A. Spertus, Daniel R. Kelly

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Objective UCP2 -866G>A (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for ß-blocker response, particularly among patients with diabetes. We assessed the function of -8660>A and Its role as a modifier of ß-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 -8660>A on ß-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 β-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 ß-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 ß-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 ß-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 ß-blockers in those with diabetes.

Original languageEnglish
Pages (from-to)231-238
Number of pages8
JournalPharmacogenetics and Genomics
Volume20
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Acute coronary syndromes
  • Gene-environment interaction
  • Pharmacogenetics
  • Type 2 diabetes

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