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


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 = 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 = 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 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.
Cheurfa
Nadir
N
Institut National de la Santé et de la Recherche Médicale, Research Unit 695, Paris, France.
Dubois-Laforgue
Danièle
D
Ferrarezi
Daniela A F
DA
Reis
André F
AF
Brenner
Guilherme M
GM
Bouché
Clara
C
Le Feuvre
Claude
C
Fumeron
Frédéric
F
Timsit
José
J
Marre
Michel
M
Velho
Gilberto
G
D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D005500:Follow-Up Studies; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D017257:Ramipril / Q000627:therapeutic use; D012307:Risk Factors; D000071246:Uncoupling Protein 2
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D017257:Ramipril