The Common 866G>A Variant in the Promoter of UCP2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men Nadir Cheurfa, 1 Danie ` le Dubois-Laforgue, 2 Daniela A.F. Ferrarezi, 1,3 Andre ´ F. Reis, 4 Guilherme M. Brenner, 1,5 Clara Bouche ´, 2 Claude Le Feuvre, 6 Fre ´de ´ ric Fumeron, 1,7 Jose ´ Timsit, 2,8 Michel Marre, 1,7 and Gilberto Velho 1 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 (-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 3,122 subjects from the 6-year prospective Non–Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD inci- dence 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 = 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—myocar- dial 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 = 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 type 2 diabetes in a 6-year prospective study. Decreased risk of myo- cardial 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. Diabetes 57:1063–1068, 2008 C ardiovascular disease accounts for up to 80% of the deaths of type 2 diabetic patients (1). Dia- betic patients have a threefold higher risk than nondiabetic individuals of developing athero- sclerosis and its clinical complications, such as stroke, myocardial infarction, and peripheral vascular disease (2). Arterial hypertension and dyslipidemia frequently coexist with diabetes and contribute to the increased prevalence of cardiovascular disease in diabetic patients. However, type 2 diabetes is an independent risk factor for cardio- vascular disease (3). The molecular mechanisms linking type 2 diabetes and atherosclerosis remain unclear (4). Several metabolic dysfunctions associated with type 2 diabetes have been proposed to play a role in the acceler- ation of atherosclerosis, including hyperinsulinemia, hy- perglycemia, increased formation of advanced glycation end products, platelet hyperaggregability, coagulation ab- normalities, endothelial dysfunction, and increased oxida- tive stress (4). Particularly, increased oxidative stress in vascular cells plays a key role in the formation of ather- oma (5) and in the instability of the atherosclerotic plaque, a crucial step in the occurrence of acute coronary events (6). Uncoupling protein 2 (UCP2) functions as a physiolog- ical downregulator of reactive oxygen species (ROS) gen- eration in endothelial and smooth muscle cells of the vascular wall and in macrophages (7–11). Several studies have shown that UCP2 plays an antiatherogenic role in the vascular wall (8,9,11) and may improve tolerance to car- diac ischemia (12). A series of clinical investigations have shown associations of the -866GA (rs659366) functional single nucleotide polymorphism (SNP) in the promoter region of UCP2 with phenotypes related to obesity (13), glucose homeostasis (14 –16), and dyslipidemia (17). In the present study, we investigated the association of this variant with coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Prospective study. The Non-Insulin-Dependent Diabetes, Hypertension, Mi- croalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study was a 6-year double-blind multicenter multinational clinical trial conducted in 4,912 men and women with type 2 diabetes aged 50 years or older at baseline and selected on the basis of a persistent micro- or macroalbuminuria (urinary albumin concentration [UAC] 20 mg/l) without renal failure (serum creati- From the 1 Institut National de la Sante ´ et de la Recherche Me ´ dicale, Research Unit 695, Paris, France; the 2 Department of Immunology and Diabetology, AP-HP Cochin Hospital, Paris, France; the 3 Laboratory of Cellular and Molecular Endocrinology, Sa ˜ o Paulo University, Sa ˜ o Paulo, Brazil; the 4 Lab- oratory of Molecular Endocrinology, Federal University of Sa ˜o Paulo, Sa ˜o Paulo, Brazil; the 5 Post-Graduation Program in Medical Sciences, Federal Faculty Foundation of Medical Sciences of Porto Alegre, Porto Alegre, Brazil; the 6 Department of Cardiology, Assistance Publique–Ho ˆ pitaux de Paris, La Pitie ´ Hospital, Paris, France; the 7 Universite ´ Denis Diderot Paris 7, Paris, France; and the 8 Universite ´ Rene ´ Descartes Paris 5, Paris, France. Address correspondence and reprint requests to Dr. Gilberto Velho, Institut National de la Sante ´ et de la Recherche Me ´ dicale U-695, Faculte ´ de Me ´ decine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. E-mail: velho@bichat.inserm.fr. Received for publication 11 September 2007 and accepted in revised form 7 January 2008. Published ahead of print at http://diabetes.diabetesjournals.org on 11 Jan- uary 2008. DOI: 10.2337/db07-1292. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1292. CABG, coronary artery bypass graft; CAD, coronary artery disease; DIAB- HYCAR Study, Non-Insulin-Dependent Diabetes, Hypertension, Microalbumin- uria, Cardiovascular Events, and Ramipril Study; NCH, Necker and Cochin Hospitals; ROS, reactive oxygen species; SNP, single nucleotide polymor- phism; UAC, urinary albumin concentration; UCP2, uncoupling protein 2. © 2008 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ORIGINAL ARTICLE DIABETES, VOL. 57, APRIL 2008 1063