The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity: A study of obesity and related metabolic traits among 17,636 Danes

Context: Uncoupling protein 2 (UCP2) is involved in regulating ATP-synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus.
Objective: To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes, and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes.
Design: We genotyped UCP2 rs659366 in a total of 17,636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analyzed within separate study populations.
Results: We found no consistent associations between the UCP2 -866 G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12,984 subjects showed an association with obesity (GA vs. GG OR(95% CI): 0.894(0.826-0.968) P=0.00562, and AA vs. GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15,107 individuals showed no association. The -866 G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test (IVGTT) in young Caucasian subjects (n=377) was decreased in carriers of the GG-genotype (P=0.05). Conclusions: The UCP2 -866 G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.