2004 25(6):468-475; doi:10.1016/j.ehj.2004.01.007
Copyright © 2004 by the European Society of Cardiology.
Clinical research
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
a 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
b Department of Diabetes and Endocrinology, UCL Hospitals, London W1T 3AA, UK
c Centre for Hepatology, RFUCL Medical School, London NW3 2PF, UK
d Medical Research Council, Cardiovascular Research Group, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK
Received January 13, 2004;
revised January 21, 2004;
accepted January 23, 2004
* Corresponding author. Tel.: +44-207-679-6965/6964; fax: +44-207-679-6212
E-mail address: s.dhamrait{at}ucl.ac.uk
E-mail address: rmhasud{at}ucl.ac.uk
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; 
). 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%; 
and F2-isoprostanes 220.6±37.2 pg ml–1 vs. 109.9±51.1 pg ml–1; 
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]; 
). 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.
Key Words: UCP2 • Genetics • Coronary heart disease • Diabetes mellitus • Inflammation • Oxidative stress
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