Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Aims/hypothesisUncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians.MethodsThe coding and untranslated regions of UCP2, and approximately 1 kb of the 5′ upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives.ResultsFive variants were identified: (1) a −866G/A in the 5′ upstream region; (2) a G/A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3′ untranslated region. Among the 83 subjects whose DNA was sequenced, the −866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the −866G/A variant (as a representative of Ala55Val and the 3-bp ins/del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the −866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass).Conclusions/interpretationOur data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.

[1]  C. Bogardus,et al.  A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. , 2000, The Journal of clinical investigation.

[2]  Young-Bum Kim,et al.  Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes , 2001, Cell.

[3]  H. Esterbauer,et al.  A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. , 2002, Diabetes.

[4]  S. Le Fur,et al.  The common -866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity. , 2004, Diabetes.

[5]  C. Chan,et al.  Uncoupling protein-2: evidence for its function as a metabolic regulator , 2002, Diabetologia.

[6]  B. Paulweber,et al.  A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans , 2001, Nature Genetics.

[7]  T. Hansen,et al.  Mutational analysis of the UCP2 core promoter and relationships of variants with obesity. , 2003, Obesity research.

[8]  B. Lowell,et al.  Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. , 2001, Cell.

[9]  P. Marchetti,et al.  A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. , 2003, Diabetes.

[10]  P. Kern,et al.  Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. , 2004, American journal of physiology. Endocrinology and metabolism.

[11]  R. A. Norman,et al.  Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. , 1998, Human molecular genetics.