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


CONCLUSIONS
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.
Beitelshees
Amber L
AL
Endocrinology, Diabetes and Nutrition Division, University of Maryland School of Medicine, Baltimore, MD, USA. abeitels@medicine.umaryland.edu
Finck
Brian N
BN
Leone
Teresa C
TC
Cresci
Sharon
S
Wu
Jun
J
Province
Michael A
MA
Fabbrini
Elisa
E
Kirk
Erik
E
Zineh
Issam
I
Klein
Samuel
S
Spertus
John A
JA
Kelly
Daniel P
DP
D054058:Acute Coronary Syndrome / Q000209:etiology* / Q000235:genetics*; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000368:Aged; D002460:Cell Line; D015331:Cohort Studies; D048909:Diabetes Complications / Q000209:etiology / Q000235:genetics; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D000071246:Uncoupling Protein 2
D000319:Adrenergic beta-Antagonists; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2