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Two Polymorphisms in the Glucocorticoid Receptor Gene Directly Affect Glucocorticoid-Regulated Gene Expression

Departments of Internal Medicine (H.R., P.S., E.L.T.v.d.A., E.F.C.T.v.R., F.H.d.J., S.W.J.L., J.W.K.) and Reproduction and Development (A.O.B), Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Henk Russcher, Erasmus Medical Center, Department of Internal Medicine, Room Ee593, Dr. Molewaterplein 40, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: h.russcher{at}erasmusmc.nl.

Context: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively.

Objective and Design: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor B-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR.

Results: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (–14 ± 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: –48 ± 6%, P < 0.01, n = 1; heterozygous: –21 ± 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 ± 3%; P < 0.02) and ex vivo (homozygous: 204 ± 19%, P < 0.0001, n = 1; heterozygous: 124 ± 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR.

Conclusion: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

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