Endocrinology, Diabetes and Nutrition Division, University of Maryland School of Medicine, Baltimore, MD, USA.
Pharmacogenet Genomics. 2010 Apr;20(4):231-8. doi: 10.1097/FPC.0b013e3283377abc.
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.
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.
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.
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.
UCP2-866G>A(rs659366) 与代谢性心血管疾病有关，是β受体阻滞剂反应的新候选基因，尤其是在糖尿病患者中。我们评估了 UCP2-866G>A 在急性冠脉综合征（ACS）患者中的功能及其作为糖尿病状态下β受体阻滞剂治疗结果修饰因子的作用。
评估了具有遗传样本和 12 个月心脏再住院或死亡随访的 ACS 患者（n=468）。在有糖尿病和无糖尿病的患者中评估了-866G>A 对β受体阻滞剂治疗结果的影响。为了评估-866G>A 的功能相关性，我们比较了基因型肥胖参与者骨骼肌中的解偶联蛋白 2（UCP2）表达，并比较了 UCP2 荧光素酶启动子与-866G 和-866A 等位基因的活性。
在糖尿病患者中发现-866G>A 与β受体阻滞剂治疗之间存在相互作用（P=0.002），但在无糖尿病患者中无相互作用（P=0.79）。在糖尿病 G/G 个体中，出院时使用β受体阻滞剂与心脏再住院率降低 80%相关（调整后的危险比：0.20；95%置信区间：0.04-1.02）。相比之下，在糖尿病 A 携带者患者中，出院时β受体阻滞剂治疗与心脏再住院率增加 11 倍相关（调整后的危险比：11.75；95%置信区间：1.28-108.2）。启动子活性测定表明，与-866A 相比，-866G 具有更大的环磷酸腺苷反应元件结合蛋白反应性，与-866A 携带者相比，G/G 个体的骨骼肌中 UCP2 表达增加。
我们发现，在糖尿病 ACS 患者中，-866G>A 与β受体阻滞剂反应之间存在显著的相互作用。此外，-866G 在细胞系和肥胖患者中的基因转录活性大于-866A。这些发现可能有助于我们深入了解β受体阻滞剂在糖尿病患者中产生有益和有害影响的机制。
