胆固醇酯转运蛋白基因常见变异在冠状动脉粥样硬化进展中的作用。回归生长评估他汀类药物研究组。

The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group.

作者信息

Kuivenhoven J A, Jukema J W, Zwinderman A H, de Knijff P, McPherson R, Bruschke A V, Lie K I, Kastelein J J

机构信息

Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

出版信息

N Engl J Med. 1998 Jan 8;338(2):86-93. doi: 10.1056/NEJM199801083380203.

DOI:10.1056/NEJM199801083380203

PMID:9420339

Abstract

BACKGROUND

The high-density lipoprotein (HDL) cholesterol concentration is inversely related to the risk of coronary artery disease. The cholesteryl ester transfer protein (CETP) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis.

METHODS

The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP. The presence of this DNA variation was referred to as B1, and its absence as B2. All patients participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for two years.

RESULTS

The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [+/-SD], 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34+/-8 vs. 39+/-10 mg per deciliter). In addition, we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group (decrease in mean luminal diameter: 0.14+/-0.21 mm for the B1B1 genotype, 0.10+/-0.20 mm for the B1B2 genotype, and 0.05+/-0.22 mm for the B2B2 genotype). This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers (representing 16 percent of the patients taking pravastatin).

CONCLUSIONS

There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes. This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis.

摘要

背景

高密度脂蛋白（HDL）胆固醇浓度与冠状动脉疾病风险呈负相关。胆固醇酯转运蛋白（CETP）在这种脂蛋白的代谢中起核心作用，因此可能改变动脉粥样硬化的易感性。

方法

对807名经血管造影证实患有冠状动脉粥样硬化的男性的DNA进行分析，以检测编码CETP的基因中是否存在多态性。这种DNA变异的存在被称为B1，不存在则称为B2。所有患者都参与了一项旨在促使冠状动脉粥样硬化消退的降胆固醇试验，并被随机分配接受普伐他汀或安慰剂治疗两年。

结果

CETP基因的B1变异与较高的血浆CETP浓度（B1B1基因型的平均值[±标准差]为2.29±0.62微克/毫升，B2B2基因型为1.76±0.51微克/毫升）以及较低的HDL胆固醇浓度（分别为34±8与39±10毫克/分升）相关。此外，我们在安慰剂组中观察到该标志物与冠状动脉粥样硬化进展之间存在显著的剂量依赖性关联（平均管腔直径减小：B1B1基因型为0.14±0.21毫米，B1B2基因型为0.10±0.20毫米，B2B2基因型为0.05±0.22毫米）。普伐他汀消除了这种关联。普伐他汀治疗减缓了B1B1携带者冠状动脉粥样硬化的进展，但对B2B2携带者无效（B2B2携带者占服用普伐他汀患者的16%）。