Glucocorticoid receptor polymorphism affects transrepression but not transactivation

Context: 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-9 beta polymorphism, on GC transactivation and transrepression. Design and 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-9 beta polymorphism, in which the expression of two GC-sensitive genes, GC-induced leucine zipper and IL-2, was measured. Results: Persons carrying the GR-9 beta 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-9 beta homozygotes, whereas the down-regulation of IL-2 expression via transrepression was decreased. Conclusion: Persons carrying the GR-9 beta haplotype seem to have a decreased GC transrepression with normal transactivation.