Glucocorticoid receptor polymorphism affects transrepression but not transactivation.
BACKGROUND
Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC transactivation of gene expression.


OBJECTIVE
The objective of the study was to investigate the effect of the GC receptor haplotype, characterized by the GR-9beta polymorphism, on GC transactivation and transrepression.


METHODS
This was a cross-sectional study in 216 persons randomly selected from participants in The Rotterdam Study, a population-based cohort study in the elderly. Clinical and biochemical parameters of GC sensitivity were measured: weight, height, waist to hip ratio, glucose, insulin, total cholesterol, high-density lipoprotein, and C-reactive protein. In a dexamethasone suppression test, the response of serum cortisol concentrations was studied. Genotyping for four GC receptor polymorphisms was performed. In addition, ex vivo experiments were performed with leukocytes of 10 healthy controls and two persons homozygous for the GR-9beta polymorphism, in which the expression of two GC-sensitive genes, GC-induced leucine zipper and IL-2, was measured.


RESULTS
Persons carrying the GR-9beta haplotype without 22/23EK (n = 53) revealed no significant differences in their body mass index, waist to hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with noncarriers (n = 113). Ex vivo, GC-induced up-regulation of GC-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9beta homozygotes, whereas the down-regulation of IL-2 expression via transrepression was decreased.


CONCLUSIONS
Persons carrying the GR-9beta haplotype seem to have a decreased GC transrepression with normal transactivation.
van den Akker
Erica L T
EL
Erasmus Medical Center, Department of Internal Medicine, Room Ee 585, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Russcher
Henk
H
van Rossum
Elisabeth F C
EF
Brinkmann
Albert O
AO
de Jong
Frank H
FH
Hokken
Anita
A
Pols
Huibert A P
HA
Koper
Jan W
JW
Lamberts
Steven W J
SW