¹University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK

²Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, UK

³Section of Endocrinology, Imperial College School of Medicine, London, UK

⁴International Diabetes Institute, Caulfield, Victoria, Australia

Correspondence to: DJ Halsall, Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, CB2 2QR, UK. E-mail: djh44@hermes.cam.ac.uk

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity.

SUBJECTS: Ninety-one obese children (BMI>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 identified 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 post-glucose challenge plasma triglycerides, non-esterified 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 significantly (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.

International Journal of Obesity (2001) 25, 472-477

uncoupling proteins; UCP3; obesity; BMI