Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin

Aims/hypothesis. Uncoupling proteins are mitochondrial transmembrane carrie rs implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expe cted to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mel litus. A variant in the putative promoter region of UCP3 (-55 c-->t) has re cently been identified, and an association with obesity reported in French subjects. Our aim tvas to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic p opulations. Methods. The -55 c-->t variant was genotyped in 85 South Indian and 150 Eur opean parent-offspring tries ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey int o the prevalence of diabetes. Results. In South Indian and European parent-offspring trios there was no p referential transmission of either allele at the -55 c-->t polymorphism to diabetic offspring (South Indians, p=0.60; Europeans, p = 0.15). When famil y members were analysed for intermediate traits, the t-allele was associate d with increased waist-to-hip ratio but only in females (South Indian mothe rs p = 0.036, daughters p =0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the pop ulation-based survey (P = 0.039). Conclusion/interpretation. The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.