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

Abstract

The rising prevalence of Type II (non-insulin-dependent) diabetes and obesity worldwide poses a serious challenge to human health and incomplete understanding of the aetiological basis of these closely related metabolic conditions is a major impediment to improved management. There is considerable evidence to suggest that primary abnormalities in energy balance contribute to the pathogenesis of diabetes and obesity [1]. Reduced energy expenditure is correlated with subsequent weight gain [2] and normoglycaemic women at increased risk of future diabetes have defective post-prandial thermogenesis [3,4]. Diabetologia (2000) Abstract Aims/hypothesis. Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (±55 c®t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. Methods. The ±55 c®t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. Results. In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the ±55 c®t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers 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 population-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. [Diabetologia (2000)

UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan

“…12,13 The following will be investigated in this study: (1) two UCP2 gene polymorphisms, including the G-866A polymorphism in the promoter region, 14 A55V (Ala55Val) polymorphism in exon 4; 15,16 and (2) two UCP3 gene polymorphisms, including the C-55T polymorphism of the promoter [17][18][19] and V102I (Val102Ile) in exon 3. 9 These variants have been reported to be associated with body mass index (BMI), 3,[18][19][20] sleeping metabolic rate, energy expenditure, 12 waist-to-hip ratio 17 and diabetes. 21 But results of several studies have shown no significant association with non-insulin-dependent diabetes mellitus, 17,22,23 RMR 24 and BMI.…”

“…9 These variants have been reported to be associated with body mass index (BMI), 3,[18][19][20] sleeping metabolic rate, energy expenditure, 12 waist-to-hip ratio 17 and diabetes. 21 But results of several studies have shown no significant association with non-insulin-dependent diabetes mellitus, 17,22,23 RMR 24 and BMI. 9,[25][26][27] These relationships between polymorphisms in UCP2/UCP3 genes, BMI and obesity-related phenotypes are still controversial.…”

Genetic Variants in the UCP2-UCP3 Gene Cluster and Risk of Diabetes in the Women's Health Initiative Observational Study

“…Despite strong functional evidence for the UCP2 Ϫ866 G/A and UCP3 Ϫ55 C/T polymorphisms, previous association studies of both UCP2 and UCP3 gene variants have not been consistent. Several studies found that these functional variants exhibited significantly increased (8,9,13) or decreased (14 -16) type 2 diabetes risk, but others did not report any significant associations (10,17). Such discrepancies may be attributable to differences in study design (population based vs. hospital based), selection and ascertainment schemes, sample sizes, or statistical analysis strategies.…”

Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy

“…The T allele in UCP3 C ! T ( À 55) polymorphism was associated with increased waist to hip ratio in women (Cassell et al, 2000), and the T/T genotype with higher BMI . The À 55 T/T genotype was also found to be associated with an atherogenic lipid profile in French Caucasians, and the T/T genotype conferred decreased risk of Type 2 diabetes in French but not in Danish subjects Data are number of subjects (percent).…”