title: 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.
abstract: 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).
  
  
  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.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, Rayne Building, 5 University Street, London WC1E 6JF, UK. s.dhamrait@ucl.ac.uk
authors.forename: Sukhbir S
authors.initials: SS
authors.lastname: Dhamrait
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Stephens
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Jayshree
authors.initials: J
authors.lastname: Acharya
authors.forename: Ali R
authors.initials: AR
authors.lastname: Mani
authors.forename: Kevin
authors.initials: K
authors.lastname: Moore
authors.forename: George J
authors.initials: GJ
authors.lastname: Miller
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hurel
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000097:blood / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D012307:Risk Factors; D000071246:Uncoupling Protein 2
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2