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

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contr ibutes to human obesity. SUBJECTS: Ninety-one obese children (BMI > 4 standard deviations from age r elated mean) and 419 Caucasian adults from the Isle of Fly 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 c ommon polymorphism identified in this gene (c-55t) has been shown to associ ate 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 relev ant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of varia nts were carried out. For the Isle of fly Study, c-55t genotype and anthrop ometric (body mass index, waist-hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maxi mum oxygen consumption) and biochemical indices (pre- and postglucose chall enge plasma triglycerides, non-esterified fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V1021) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of fly study carried the c-55t promoter vari ant. Age-adjusted body mass index (BMI) was significantly (P = 0.0037) lowe r in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a c ommon monogenic cause of severe human obesity. In a Caucasian population th e UCP3 c-55t polymorphism is negatively associated with BMI.