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

Louise Torp Dalgaard, Gitte Andersen, Johanne Marie Justesen, Stine Anthonsen, Trine Nielsen, Lise Wegner Thørner, Daniel Witte, Torben Jørgensen, Jesper Clausen, Torsten Lauritzen, Johan Holmkvist, Torben Hansen, Oluf Pedersen

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    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.
    TidsskriftInternational Journal of Obesity
    Udgave nummer2
    Sider (fra-til)1775-181
    StatusUdgivet - 21 feb. 2013

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