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Glucocorticoid Sensitivity Is Determined by a Specific Glucocorticoid Receptor Haplotype

Endocrine Sciences Research Group and Centre for Molecular Medicine (A.S., D.W.R.), Arthritis Research Campaign Epidemiology Unit (A.S., R.D.), Centre for Integrated Genomic Medical Research (E.Z., S.J.), University of Manchester, Manchester M13 9PT, United Kingdom; and The Dermatology Centre (H.L.R., C.E.M.G.), University of Manchester School of Medicine, Hope Hospital, Manchester M6 8HD, United Kingdom

Address all correspondence and requests for reprints to: Dr. Adam Stevens, Endocrine Sciences Research Group, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: fras{at}fs1.ser.man.ac.uk.

Differences in glucocorticoid (GC) sensitivity may underlie both common diseases (e.g. hypertension) and variability in response to treatment with GCs (e.g. asthma). We tested the potential involvement of the GC receptor (GR) gene in mediating GC sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GR gene was determined in 216 U.K. Caucasians, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GR gene with only four haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a three-marker haplotype, across intron B, to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol vs. 23% in the combined other quartiles (odds ratio 2.4, 95% confidence interval 0.9–6.3, P = 0.05). This is the first comprehensive, haplotype based analysis of the GR gene. A three-point haplotype, within intron B, is associated with enhanced sensitivity to GCs. This haplotype may help predetermine variation in clinical response to GC therapy and also assist the understanding of diseases related to GC production.

This work was supported by The Medical Research Council (Grants G0001171 and G0000791) and a Glaxo-SmithKline Fellowship (to D.W.R.).

Abbreviations: GC, Glucocorticoid; GR, GC receptor; HPM, haplotype pattern mining; PDC, postdexamethasone cortisol; SNP, single nucleotide polymorphism.

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