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A Functional Polymorphism in the Glucocorticoid Receptor Gene and Its Relation to Cardiovascular Disease Risk in Familial Hypercholesterolemia

Departments of Internal Medicine (K.C.M.C.K., E.F.C.v.R., G.M.D.-T., S.W.J.L., E.J.G.S.) and Public Health (E.W.S.), Erasmus Medical Center, 3000 AC Rotterdam, The Netherlands; and 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, D435, Erasmus Medical Center, P.O. Box 2040, 3000 AC Rotterdam, The Netherlands. E-mail: e.sijbrands{at}erasmusmc.nl.

Context: Individuals with the functional ER22/23EK variant in the glucocorticoid receptor gene are relatively resistant to the downstream consequences of glucocorticoids. Evidence suggests that carriers have a more favorable cardiovascular risk profile, but the relationship between this ER22/23EK variant and cardiovascular disease has not been hitherto assessed.

Objective: We, therefore, determined whether carriership of the ER22/23EK improves cardiovascular disease risk in patients with severe hypercholesterolemia.

Design, Setting, and Participants: In a multicenter cohort study, 2024 patients with heterozygous familial hypercholesterolemia, aged 18 yr and older, were genotyped for the ER22/23EK polymorphism. Patients were identified at lipid clinics throughout The Netherlands between 1989 and 2002.

Main Outcome Measures: The primary outcome measure was cardiovascular disease.

Results: Seventy-six (7.8%) of 977 men and 72 (6.9%) of 1047 women were carriers of the ER22/23EK variant. A total of 395 men and 247 women had a cardiovascular event. In contrast to expected results, we observed no significant association of the ER22/23EK variant with cardiovascular disease risk (men: relative risk, 0.75; 95% confidence interval, 0.50–1.14; P = 0.2; women: relative risk, 1.37; 95% confidence interval, 0.82–2.28; P = 0.2). However, we found a significant interaction between gender and the polymorphism on cardiovascular disease (P = 0.02).

Conclusions: In this large cohort of individuals with very high risk of cardiovascular disease, the association between the functional ER22/23EK polymorphism and cardiovascular risk was not significant overall, although it varied significantly by gender.

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