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

Diabetologia. 2000 Feb;43(2):245-9. doi: 10.1007/s001250050037.


Aims/hypothesis: In obese French Caucasian subjects we previously described a silent UCP3 Tyr99Tyr mutation, associated with body mass index. We hypothesised that an unknown polymorphism in the vicinity of the gene could contribute to obesity.

Methods: Morbidly obese subjects were screened for mutations in 1 kb upstream 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 -55 locus were similar in the obese and control groups (0.23 vs 0.21). The -55 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, homozygosity for this variant is a risk factor for high BMI (odds ratio: 1:75, p = 0.02). Obese patients were divided into tertiles according to physical activity. In the group with a wild C/C genotype, BMI was negatively associated with physical activity (p = 0.015).

Conclusion/interpretation: The C-->T polymorphism in the 5' sequences of the UCP3 gene might contribute to the corpulence in obese and normal weight subjects and alter the benefit of physical activity. The UCP3 gene can be considered as a gene modifying corpulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Mass Index
  • Carrier Proteins / genetics*
  • DNA Transposable Elements
  • European Continental Ancestry Group / genetics
  • Exercise*
  • Exons
  • Female
  • France
  • Genetic Variation*
  • Humans
  • Ion Channels
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondrial Proteins
  • Mutation*
  • Obesity, Morbid / genetics*
  • Polymorphism, Genetic
  • Reference Values
  • Uncoupling Protein 3


  • Carrier Proteins
  • DNA Transposable Elements
  • Ion Channels
  • Mitochondrial Proteins
  • UCP3 protein, human
  • Uncoupling Protein 3