Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2

Eur Heart J. 2004 Mar;25(6):468-75. doi: 10.1016/j.ehj.2004.01.007.


Background: Oxidative stress reduces total antioxidant status (TAOS) and is implicated in atherogenesis. Mitochondrial uncoupling protein 2 (UCP2) negatively regulates reactive oxygen species generation. The UCP2 gene demonstrates a common functional promoter variant (-866G>A).

Methods and results: Amongst 465 diabetic men (age 61.7 +/- 13.3 years), an association of the UCP2-866A allele with significantly lower TAOS in those without CHD was even more pronounced in those with CHD (TAOS 30.1 +/- 16.1% vs. 41.6 +/- 12.4% for AA vs. GG; P=0.016). In a sample of 20 diabetic men selected for homozygosity for the UCP2-866G>A variant, matched for baseline characteristics, plasma markers of oxidative stress in those with CHD were significantly higher in AA genotype men (TAOS 31.7 +/- 7.3% vs. 52.6 +/- 6.3%; P=0.001 and F2-isoprostanes 220.6 +/- 37.2 pg ml(-1) vs. 109.9 +/- 51.1 pg ml(-1); P=0.005 for AA vs. GG). Amongst 2695 healthy men (age 56.1 +/- 3.5 years) prospectively studied for a median 10.2 years, AA homozygotes had a highly significant doubling in CHD risk after adjustment for established risk factors (HR 1.99 [1.37-2.90]; P=0.002). Risk associated with this genotype was substantially increased by the presence of other risk factors (obesity, hypertension and diabetes).

Conclusions: This study provides the first in vivo evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antioxidants / metabolism*
  • Biomarkers / blood
  • Coronary Disease / blood
  • Coronary Disease / genetics*
  • Diabetic Angiopathies / blood
  • Diabetic Angiopathies / genetics*
  • Genotype
  • Homozygote
  • Humans
  • Ion Channels
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Oxidative Stress / genetics*
  • Risk Factors
  • Uncoupling Protein 2


  • Antioxidants
  • Biomarkers
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • UCP2 protein, human
  • Uncoupling Protein 2