The Common −866G>A Variant in the Promoter of UCP2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men

Abstract

OBJECTIVE-Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (Ϫ866GϾA) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects.RESEARCH DESIGN AND METHODS-We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied. RESULTS-We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80 -0.96]; P ϭ 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered-myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death-contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P ϭ 0.02 for a recessive model). CONCLUSIONS-TheA allele of the Ϫ866GϾA variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors.

Nutritional and hormonal regulation of uncoupling protein 2

“…Among the type 2 diabetes patients, 2866A-allele carriers have been shown to have significantly lower insulin secretion during intravenous glucose tolerance test than G-allele carriers (26)(27)(28). Same genotype also were associated with reduced risk of diabetic neuropathy in Germany Caucasians (29), reduced risk of coronary artery disease in French Caucasian (30), and a higher waist-to-hip ratio and increased risk of metabolic syndrome in Chinese, Malay, and Indian populations (31). Although 2866G-allele variant was associated with reduction of Ucp2 expression and transcriptional activity, high BMI, and fat mass changes in adipose tissue in female Korean (32), the Austrian Caucasian patients possessing the 2866G-allele have lower blood triacylglycerol levels and higher insulin sensitivity (33).…”

Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano

“…Al respecto, en un estudio de cohortes de una población de hombres caucásicos, se analizó la asociación de diabetes mellitus tipo 2 y dos de las variantes incluidas en este estudio (-866G/A de UCP2 y -55C/T de UCP3), con resultados positivos (12); en el trabajo de Cheurfa y colaboradores se encontró que el alelo -866A de UCP2 tiene una relación inversa con el riesgo de desarrollar enfermedad arterial coronaria en personas caucásicas con diabetes mellitus tipo 2 (55). Estos resultados positivos en análisis prospectivos confirman la asociación de los UCP con diabetes mellitus tipo 2, al menos para algunas poblaciones.…”

Association of Genetic Variants with Chronic Kidney Disease in Japanese Individuals

“…The A allele of the Ϫ866G3 A variant was also associated with reduced risk of coronary heart disease in men with type 2 diabetes mellitus in a 6-yr prospective study (18). The deletion allele of the insertion/deletion polymorphism in the 3Ј region of UCP2 was related to ESRD in Indian subjects (19).…”