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.
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.
Dhamrait
Sukhbir S
SS
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
Stephens
Jeffrey W
JW
Cooper
Jacqueline A
JA
Acharya
Jayshree
J
Mani
Ali R
AR
Moore
Kevin
K
Miller
George J
GJ
Humphries
Steve E
SE
Hurel
Steven J
SJ
Montgomery
Hugh E
HE
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
D000975:Antioxidants; D015415:Biomarkers; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2