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Related Experiment Videos

Glucocorticoid receptor polymorphism affects transrepression but not transactivation.

Erica L T van den Akker1, Henk Russcher, Elisabeth F C van Rossum

  • 1Erasmus Medical Center, Department of Internal Medicine, Room Ee 585, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

The Journal of Clinical Endocrinology and Metabolism
|May 11, 2006
PubMed
Summary

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The GR-9beta glucocorticoid receptor (GC) haplotype is linked to reduced GC transrepression, impacting gene expression regulation. This suggests a potential mechanism for altered GC sensitivity in individuals with this genetic variation.

Area of Science:

  • Pharmacogenomics
  • Molecular Endocrinology
  • Genetics

Background:

  • Glucocorticoids (GCs) are vital for treating inflammatory and autoimmune diseases, primarily through gene transrepression.
  • Adverse effects of GCs are often attributed to gene transactivation, highlighting the need to understand the balance between these pathways.
  • Genetic variations in the GC receptor may influence GC efficacy and side effect profiles.

Purpose of the Study:

  • To investigate the impact of the GC receptor haplotype, specifically the GR-9beta polymorphism, on GC transactivation and transrepression.
  • To determine if specific GC receptor genotypes correlate with clinical and biochemical markers of GC sensitivity.

Main Methods:

  • A cross-sectional study of 216 individuals from The Rotterdam Study cohort.

Related Experiment Videos

  • Measurement of clinical and biochemical parameters related to GC sensitivity, including anthropometrics, metabolic markers, and C-reactive protein.
  • Genotyping for GC receptor polymorphisms and ex vivo analysis of gene expression (GC-induced leucine zipper, IL-2) in leukocytes.

    • Main Results:

    • Individuals with the GR-9beta haplotype showed no significant differences in anthropometric measures, metabolic parameters, or cortisol response to dexamethasone compared to non-carriers.
    • Ex vivo experiments revealed that GC-induced transactivation of GC-induced leucine zipper mRNA was not significantly different in GR-9beta homozygotes.
    • However, GC-mediated transrepression of IL-2 expression was significantly decreased in individuals carrying the GR-9beta haplotype.

    Conclusions:

    • The GR-9beta haplotype is associated with impaired GC transrepression, while transactivation remains unaffected.
    • This suggests a potential mechanism for altered GC drug response and side effects in individuals with this specific GC receptor genetic variation.