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The common –866G>A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men

¹INSERM, Research Unit 695, Paris, France
²AP-HP Cochin Hospital, Department of Immunology and Diabetology
³São Paulo University, Laboratory of Celular and Molecular Endocrinology - LIM 25, São Paulo, Brazil
⁴Federal University of São Paulo, Laboratory of Molecular Endocrinology, São Paulo, Brazil
⁵Federal Faculty Foundation of Medical Sciences of Porto Alegre, Post-graduation Program in Medical Sciences, Porto Alegre, Brazil
⁶AP-HP La Pitié Hospital, Department of Cardiology, Paris, France
⁷Université Denis Diderot Paris 7, Paris, France
⁸Université René Descartes Paris 5, Paris, France

Objective: Uncoupling protein 2 (UCP2) is a physiological down-regulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (–866G>A) 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 3122 subjects from the 6-year prospective 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% C.I. 0.80-0.96, p=0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, while 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 (OR=0.47, 95% C.I. 0.25-0.89, p=0.02 for a recessive model).

Conclusions: The A-allele of the-866G>A variant of UCP2 was associated with reduced risk of CAD in men with T2DM 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 from other common CAD risk factors.

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