A genetic variation in the 5 ' flanking region of the UCP3 gene is associated with body mass index in humans in interaction with physical activity

Aims/hypothesis. In obese French Caucasian subjects we previously described a silent UCP3 Tyr99Tyr mutation, associated with body mass index. We hypot hesised that an unknown polymorphism in the vicinity of the gene could cont ribute to obesity. Methods. Morbidly obese subjects were screened for mutations in 1 kb upstre am from the UCP3 gene. Association studies were done between a variant and obesity in 401 morbidly obese and 231 control subjects. Results. We detected three rare genetic variants and one polymorphism: a+5 G-->A in exon 1, a -155 C-->T, a -439 A insertion and a -55 C-->T located 6 bp from the putative TATA box. This variant was in linkage disequilibrium with the Tyr99Tyr polymorphism. Frequencies of the variant allele at the -5 5 locus were similar in the obese and control groups (0.23 vs 0.21). The -5 5 polymorphism was associated with BMI in the obese group (p = 0.0031): BMI was higher in TT than in CC or CT patients. Likewise control subjects with a TT genotype had a higher BMI (p = 0.03). In the obese group, homozygocit y for this variant is a risk factor for high BMI (odds ratio: 1:75, p = 0.0 2). Obese patients were divided into tertiles according to physical activit y. In the group with a wild C/C genotype, BMI was negatively associated wit h physical activity (p = 0.015). Conclusion/interpretation. The C-->T polymorphism in the 5' sequences of th e UCP3 gene might contribute to the corpulence in obese and normal weight s ubjects and alter the benefit of physical activity. The UCP3 gene can be co nsidered as a gene modifying corpulence.