Genetics of uncoupling proteins in humans

Genetic studies in humans provide a method to test hypotheses about the bio logical roles of specific genes. So far, ten published papers have chosen t o examine the hypothesis that uncoupling protein-2 (UCP2) and/or UCP3 influ ence energy expenditure and/or body fat accumulation. These genes were chos en because they are candidate energy expenditure genes, based on their homo logy to UCP1. Studies of UCP2 and UCP3 are intrinsically intertwined becaus e the two genes are separated by only 6000 base pairs on human chromosome 1 1. Linkage studies in families have suggested that UCP2 and/or UCP3, or a c losely linked gene, may influence resting metabolic rate (RMR) Some associa tion studies using a 3' untranslated region insertion/deletion variant of U CP2 have produced statistically positive evidence For association with body mass index (BMI) and RMR. In contrast, association studies of UCP2 using a n Ala to Val variant at amino acid 55 have produced negative results. Posit ive results have also been reported for association of a UCP3 splice varian t with respiratory quotient in African Americans. In addition, no studies h ave reported linkage or association of UCP2 or UCP3 with diabetes. Overall, the results suggest that some variants of UCP2 and UCP3 may be associated with obesity traits in some populations. The UCPs, to date, show positive r esults in associations with obesity traits but not with diabetes traits. Fu rther work will be needed to settle the role of UCP2 and UCP3 alleles in hu man body weight regulation.