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Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype
Adam Stevens1, David W Ray, Eleftheria Zeggini
1Endocrine Sciences Research Group and Centre for Molecular Medicine, Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester M13 9PT, United Kingdom. fras@fs1.ser.man.ac.uk
The Journal of Clinical Endocrinology and Metabolism
|February 7, 2004
Summary
Glucocorticoid (GC) receptor gene variations influence GC sensitivity. A specific three-marker haplotype in intron B is linked to enhanced GC sensitivity, potentially impacting disease and treatment responses.
Area of Science:
- Genetics
- Endocrinology
- Pharmacogenomics
Background:
- Glucocorticoid (GC) sensitivity differences contribute to common diseases and variable treatment responses.
- The glucocorticoid receptor (GR) gene is a candidate for mediating GC sensitivity.
Purpose of the Study:
- To investigate the role of the GR gene in GC sensitivity using haplotype analysis.
- To identify specific GR gene variations associated with GC sensitivity.
Main Methods:
- Haplotype analysis of the GR gene in 216 U.K. Caucasians.
- Low-dose dexamethasone suppression test in 116 participants.
- Linkage disequilibrium analysis and linear regression.
Main Results:
- Strong linkage disequilibrium observed across the GR gene; four haplotypes accounted for 95% of variants.
- A three-marker haplotype within intron B was significantly associated with low postdexamethasone cortisol levels (P = 0.03).
- Carriage of this haplotype was more frequent in individuals with low postdexamethasone cortisol (41% vs. 23%).
Conclusions:
- This study provides the first comprehensive, haplotype-based analysis of the GR gene.
- A specific three-point haplotype in intron B is associated with enhanced GC sensitivity.
- This finding may help predict clinical responses to GC therapy and understand GC-related diseases.