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Two Common Haplotypes of the Glucocorticoid Receptor Gene Are Associated with Increased Susceptibility to Cardiovascular Disease in Men with Familial Hypercholesterolemia

Departments of Internal Medicine (K.C.M.C.K., J.B.v.d.N., E.F.C.v.R., S.W.J.L., E.J.G.S.) and Public Health (J.B.v.d.N., E.W.S.), Erasmus Medical Center, University Medical Center, 3000 CA Rotterdam, The Netherlands; and the Department of Vascular Medicine (J.C.D., J.J.P.K.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. E. J. G. Sijbrands, Department of Internal Medicine, D-435, Erasmus Medical Center, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: e.sijbrands{at}erasmusmc.nl.

Context: 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.

Objective: 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 9β 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.

Main Outcome Measures: The primary outcome measure was CVD defined as coronary, cerebral, and peripheral artery disease.

Results: 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 9β 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.

Conclusions: In this large cohort of high-risk individuals, two common haplotypes in the GR gene modified CVD susceptibility among men.