FT 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 LICP2 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 F-2-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 doubting 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 LICP2 in modifying oxidative stress, and CHD risk in humans. (C) 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.