A common polymorphism in the promoter of UCP2 is associated with decreasedrisk of obesity in middle-aged humans

Obesity is the most common nutritional disorder in Western society. Uncoupl ing protein-2 (UCP2) is a recently identified member of the mitochondrial t ransporter superfamily that is expressed in many tissues, including adipose tissue(1,2). Like its close relatives UCP1 and UCP3. UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis(1,3) and is therefore a candidate gene for obesity(4-6). We show here that a common G/A polymorp hism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a report er gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant red uction in obesity prevalence associated with the less-common allele. We con firmed this association in a population-based sample of 791 middle-aged sub jects from the same geographic area. Despite its modest effect, but because of its high frequency (similar to 63%). the more-common risk allele confer red a relatively large population-attributable risk accounting for 15% of t he obesity in the population studied.