Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population

Abstract

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity. SUBJECTS: Ninety-one obese children (BMI b 4 standard deviations from age related mean) and 419 Caucasian adults from the Isle of Ely Study. DESIGN: Single strand conformation polymorphism (SSCP) analysis was used to scan the coding region of the UCP3 gene in 91 severely obese children. A common polymorphism identi®ed in this gene (c-55t) has been shown to associate with lower UCP3 mRNA expression. Polymerase chain reaction-based forced restriction digestion was used to detect this allele in Caucasian adults. Multiple regression analysis was used to determine associations between the c-55t genotype and anthropometric, energetic and biochemical indices relevant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of variants were carried out. For the Isle of Ely Study, c-55t genotype and anthropometric (body mass index, waist ± hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maximum oxygen consumption) and biochemical indices (pre-and postglucose challenge plasma triglycerides, non-esteri®ed fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V102I) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of Ely study carried the c-55t promoter variant. Age-adjusted body mass index (BMI) was signi®cantly (P 0.0037) lower in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a common monogenic cause of severe human obesity. In a Caucasian population the UCP3 c-55t polymorphism is negatively associated with BMI.

Interactions between physical activity and variants of the genes encoding uncoupling proteins −2 and −3 in relation to body weight changes during a 10-y follow-up

“…13,16,17 Some investigators have suggested a functional role of the insertion variant, because it decreases UCP2 mRNA expression, 17 while others failed to show an altered function of the variant. 14 Associations between a À55 c/t polymorphism in the UCP3 promoter and BMI have been reported, 18,19 while other studies find no association. 14,15,[20][21][22] A functional role of the variant has been suggested, because skeletal muscle UCP3 mRNA expression has been reported higher in males, who are hetero-and homozygous for the t-allele compared to males who are homozygous for the c-allele.…”

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

“…The T allele was associated with higher BMI or waist-to-hip ratio, consistent with decreased function, in French and German Caucasians, South Asian Indian parentoffspring trios, South Asian Indians, and the British Diabetic Association Warren 2 trios collection (29,31,33,48). However, one study showed a lower BMI in TT subjects in a U.K. sample (31), and increased function is also suggested with the association of protection from diabetic neuropathy (22). In these studies association with type 2 diabetes was examined only once, and a relationship was not found.…”

“…This variant has been associated with changes in fat distribution (waist-to-hip ratio) and BMI (29). In one study the Ϫ55T allele was associated with reduced risk of type 2 diabetes (30), but this was not replicated in other studies (29,31). This variant has also been associated with lower rates of neuropathy in a small study of type 1 diabetes (22).…”

Functional Polymorphisms of UCP2 and UCP3 Are Associated With a Reduced Prevalence of Diabetic Neuropathy in Patients With Type 1 Diabetes

“…In the first reports of this polymorphism, an influence on body weight was described (24,25), whereas in several following studies, this finding was not confirmed (35)(36)(37)(38). For the C-55T polymorphism in the promoter of the UCP3 gene, several reports described a significant lower BMI for carriers of the TT genotype (29,39). However, other studies did not find an association, suggesting that the influence on BMI might depend on the ethnic background of the study population (26,40).…”