Koeijvoets Kristel C M C, van der Net Jeroen B, van Rossum Elisabeth F C, Steyerberg Ewout W, Defesche Joep C, Kastelein John J P, Lamberts Steven W J, Sijbrands Eric J G
Department of Internal Medicine, D-435, Erasmus Medical Center, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2008 Dec;93(12):4902-8. doi: 10.1210/jc.2008-0813. Epub 2008 Sep 23.
Glucocorticoids contribute to the development of atherosclerosis. Four polymorphisms in the glucocorticoid receptor (GR) gene have been reported to alter glucocorticoid sensitivity and have been associated with cardiovascular risk factors. Studies on the relationship between these GR variants and cardiovascular disease (CVD) risk, however, have yielded conflicting results.
We sought to determine whether haplotypes based on functional polymorphisms in the GR gene influenced susceptibility to CVD in a high-risk population.
DESIGN, SETTING, AND PARTICIPANTS: In a multicenter cohort study, 1830 patients with heterozygous familial hypercholesterolemia were genotyped for the functional ER22/23EK, N363S, BclI, and 9beta variants. We analyzed the combined effect of all GR variants by constructing haplotypes and using a Cox proportional hazards regression model with adjustment for year of birth and smoking. The analyses were stratified for sex.
The primary outcome measure was CVD defined as coronary, cerebral, and peripheral artery disease.
A total of 359 men (40.8%) and 224 women (23.6%) had a cardiovascular event. In men, the BclI haplotype was associated with a 34% higher CVD risk (confidence interval 1.02-1.76; P = 0.03) and the 9beta haplotype with a 41% higher CVD risk (confidence interval 1.02-1.94; P = 0.04). In women, none of the GR haplotypes was significantly related with CVD. We did not find differences in cardiovascular risk factors between GR haplotypes.
In this large cohort of high-risk individuals, two common haplotypes in the GR gene modified CVD susceptibility among men.
糖皮质激素会促进动脉粥样硬化的发展。据报道，糖皮质激素受体（GR）基因中的四种多态性会改变糖皮质激素敏感性，并与心血管危险因素相关。然而，关于这些GR变异与心血管疾病（CVD）风险之间关系的研究结果相互矛盾。
我们试图确定基于GR基因功能多态性的单倍型是否会影响高危人群对CVD的易感性。
设计、地点和参与者：在一项多中心队列研究中，对1830例杂合子家族性高胆固醇血症患者进行了功能性ER22/23EK、N363S、BclI和9β变异的基因分型。我们通过构建单倍型并使用Cox比例风险回归模型对出生年份和吸烟情况进行调整，分析了所有GR变异的综合作用。分析按性别分层。
主要结局指标为定义为冠状动脉、脑和外周动脉疾病的CVD。
共有359名男性（40.8%）和224名女性（23.6%）发生心血管事件。在男性中，BclI单倍型与CVD风险高34%相关（置信区间1.02 - 1.76；P = 0.03），9β单倍型与CVD风险高41%相关（置信区间1.02 - 1.94；P = 0.04）。在女性中，没有一种GR单倍型与CVD有显著相关性。我们未发现GR单倍型之间在心血管危险因素方面存在差异。
在这一大型高危个体队列中，GR基因中的两种常见单倍型改变了男性对CVD的易感性。
