Abstract
BackgroundA variant in the promoter of the human uncoupling protein 2 (UCP2) gene, the G-866A polymorphism, has been associated with future risk of coronary heart disease events, in those devoid of traditional risk factors and in those suffering from diabetes. We thus examined the impact of the G-866A polymorphism on 5-year survival in a cohort of 901 post-myocardial infarction patients, and the impact of type-2 diabetes on this relationship. The association of UCP2 with baseline biochemical and hormonal measurements, including levels of the inflammatory marker myeloperoxidase, was also examined.MethodsUCP2 G-866A genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Myeloperoxidase levels were measured in plasma samples taken from 419 cohort patients 24–96 hours after admission.ResultsGenotypes were obtained for 901 patients with genotype frequencies AA 15.5%, GA 45.5%, and GG 39.0%. Genotype was not associated with survival in the overall cohort (mortality: AA 15.6%, GA 16.8%, GG 19.4%, p = 0.541). However, amongst diabetics, AA and GA genotype groups had significantly worse survival than GG diabetic patients (p < 0.05) with an attributable risk of 23.3% and 18.7% for those of AA and GA genotype respectively. Multivariate analysis using a Cox proportional hazards model confirmed that the interaction of diabetes with genotype was significantly predictive of survival (p = 0.031). In the cohort's diabetic subgroup AA/GA patients had higher myeloperoxidase levels than their GG counterparts (GA/AA, n = 51, 63.9 ± 5.23; GG, n = 34, 49.1 ± 3.72 ng/ml, p = 0.041). Further analysis showed that this phenomenon was confined to male patients (GA/AA, n = 36, 64.3 ± 6.23; GG, n = 29, 44.9 ± 3.72 ng/ml, p = 0.015).ConclusionDiabetic patients in this post-myocardial infarction cohort with UCP2 -866 AA/GA genotype have poorer survival and higher myeloperoxidase levels than their GG counterparts.
Highlights
A variant in the promoter of the human uncoupling protein 2 (UCP2) gene, the G-866A polymorphism, has been associated with future risk of coronary heart disease events, in those devoid of traditional risk factors and in those suffering from diabetes
Baseline Characteristics and UCP2 Genotyping Of an available cohort of 982, genotypes were obtained for 901 patients with genotype frequencies AA 15.5%, GA 45.5%, and GG 39.0% which did not deviate from the Hardy-Weinberg equilibrium (p = 0.999)
Baseline characteristics stratified by UCP2 G-866A genotype group are shown in Table 1, and did not differ from those in whom genotyping was not possible
Summary
A variant in the promoter of the human uncoupling protein 2 (UCP2) gene, the G-866A polymorphism, has been associated with future risk of coronary heart disease events, in those devoid of traditional risk factors and in those suffering from diabetes. While UCP1 may play a role in thermogenesis [3], UCP2 may regulate inflammation and apoptosis, and inhibition of the mitochondrial production of reactive oxygen species (ROS) [4] These functions have important implications for brain and heart disease. In a prospective study of 2695 men, those with -866AA genotype exhibited a greater prevalence of obesity and hypertension, and a shorter time to first coronary heart disease (CHD) event This risk was amplified fourfold in diabetic -866AA men [15]
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