Cheurfa Nadir, Dubois-Laforgue Danièle, Ferrarezi Daniela A F, Reis André F, Brenner Guilherme M, Bouché Clara, Le Feuvre Claude, Fumeron Frédéric, Timsit José, Marre Michel, Velho Gilberto
Institut National de la Santé et de la Recherche Médicale, Research Unit 695, Paris, France.
Diabetes. 2008 Apr;57(4):1063-8. doi: 10.2337/db07-1292. Epub 2008 Jan 11.
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.
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.
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).
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.
解偶联蛋白2（UCP2）是活性氧生成的生理性下调因子，在血管壁中发挥抗动脉粥样硬化作用。UCP2启动子中的一个常见变异（-866G>A）可调节mRNA表达，A等位基因与表达增加相关。我们在两组2型糖尿病患者中研究了该变异与冠状动脉疾病（CAD）的关联。
我们对来自为期6年的前瞻性非胰岛素依赖型糖尿病、高血压、微量白蛋白尿、心血管事件和雷米普利（DIABHYCAR）研究中的3122名受试者进行了研究（随访期间CAD发病率为14.9%）。还对一个以医院为基础的独立队列中的335名男性进行了研究，其中52%患有CAD。
在显性模型中，我们观察到A等位基因与CAD发病病例呈负相关（风险比0.88[95%CI 0.80 - 0.96]；P = 0.006）。对于CAD基线病例也观察到类似结果。按性别分层证实男性中该等位基因与CAD相关，而女性中未观察到关联。所有考虑的CAD表型——心肌梗死、心绞痛、冠状动脉搭桥术（CABG）和猝死——均对该关联有显著贡献。在一个独立队列的横断面研究中重复了该结果（隐性模型的比值比为0.47[95%CI 0.25 - 0.89]；P = 0.02）。
在一项为期6年的前瞻性研究中，UCP2的-866G>A变异的A等位基因与2型糖尿病男性患CAD的风险降低相关。心肌梗死、心绞痛、CABG和猝死风险的降低分别且显著地导致了CAD风险的降低。这种关联独立于其他常见的CAD危险因素。
