Association between uncoupling protein 3 gene and obesity-related phenotypes in the Quebec Family Study

Background: UCP3 is a mitochondrial membrane transporter that is postulated to uncouple oxidative phosphorylation from ATP synthesis producing heat in stead of ATP. Human UCP3 is mainly expressed in skeletal muscle, which play s an important role in energy homeostasis and substrate oxidation. Therefor e, UCP3 is a good candidate gene for obesity. Materials and Methods: We analyzed, among 734 subjects from the Quebec Fami ly Study, a new GA repeat microsatellite located in intervening sequence (I VS) 6 (GAIVS6) in UCP3 gene, and two already described restriction fragment length polymorphisms (RFLP) Y210Y(C -->T) and V102I G -->A). Covariance an alysis across genotypes for different adiposity, resting energy expenditure , and glucose metabolism variables was undertaken with age and sex, plus bo dy fat and body mass for nonadiposity phenotypes, as covariates. Results: We found strong associations between GAIVS6 and body mass index (p = 0.0001), fat mass (p = 0.0005), percentage body fat (p = 0.0004), the su m of six skinfold thickness (p = 0.0001), and leptin level (p = 0.0001). Ho mozygote for the GAIVS6 240 bp alleles (15% frequency in QFS) showed higher adiposity than subjects with the GAIVS6 238 bp allele (70% in QFS). The ex ons, the 5 ' untranslated region (UTR), and the exon-intron junctions of UC P3 gene from subjects homozygote for either GAIVS6 238 bp or 240 bp alleles were sequenced in search for mutations. Variants 5 ' UTR-55C -->T and Y210 Y(C -->T) were detected, whereas IVS4-36C -->T was uncovered, but no new ex onic or splice junction mutation was observed. RFLP Y210Y(C -->T) was not a ssociated to adiposity in QFS; V102I(G -->A) showed no variation. Conclusion: Our results suggest that some alleles of UCP3 are involved in t he etiology of human obesity.