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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.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

	Introduction

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ENDOGENOUS GLUCOCORTICOID (GC) production mediates multiple metabolic effects and increased production is required for a successful stress response. GCs are potent antiinflammatory drugs used to treat conditions such as rheumatoid arthritis and asthma. There is significant variation in response to therapeutic GCs, both in disease response and susceptibility to GC side effects. This variation has been demonstrated to be independent of age and sex and is consistent over time (1, 2). The presence of functional polymorphisms within the GC receptor (GR) gene could, in part, explain population variation in sensitivity to GCs.

Several single nucleotide polymorphisms (SNPs) in the GR gene have previously been reported to be associated with GC sensitivity. Nonsynonymous coding changes at codon 23 (R23K) and codon 363 (N363S) (3) were associated with GC sensitivity in a population of Dutch subjects (4, 5). However, neither of these polymorphisms have been shown to affect GR function (6, 7). A SNP altering a BclI restriction fragment length polymorphism has also been described (8, 9). This is within intron B and is associated with higher blood pressure and body mass index in females, and with increased GC sensitivity in both sexes (8). A further GR SNP, lying in the 3' untranslated region of exon 9, is associated with rheumatoid arthritis and alters GR mRNA stability (10, 11).

Multiple start sites for GR transcription have been defined up to 31 kb away from the translational start site, all with associated promoter regions (12). Breslin et al. recently determined the most distant of these sites, exon 1a and its promoter region, to be lymphocyte specific (Fig. 1A) (12). Genetic variation of this region has not been explored.

View larger version (35K): [in this window] [in a new window]   FIG. 1. Structure of the GR gene region. A, GR gene promoter region. Exons 1a, 1b, 1c, and 2 are shown with ; promoter regions are shown with . Exon 1a and its associated promoter region examined for polymorphism in this study () (12 ). B, GR coding region. Exons are numbered and introns marked with letters. Positions of the polymorphic sites used in this study are marked; the bar chart shows the frequency of the rare allele at each GR polymorphism studied.

To date no comprehensive genetic study has been performed for the GR gene. Our principal aim was therefore to perform haplotype analysis of GR and determine association with postdexamethasone cortisol (PDC) production. An additional objective was to identify haplotype tagging SNPs, which will be of use for future association studies of the GR gene in U.K. Caucasians (14).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subject recruitment

The study was approved by the Central Manchester and the Salford and Trafford Local Research Ethics Committees. All subjects gave written, informed consent. Patients with chronic plaque psoriasis of early onset (<40 yr of age) (n = 40) and healthy control subjects (n = 76) were recruited from the regional psoriasis clinic at the Dermatology Centre, Hope Hospital, Manchester, and from the local community by advertisement. Women were studied in the early follicular phase of the menstrual cycle, and no individuals had recent exposure to tricyclic antidepressants, hepatic enzyme-inducing drugs, GCs, or estrogens. Each individual took dexamethasone (0.25 mg) at 2200 h and had blood taken at 0900 h the next morning for plasma cortisol assay and DNA harvest (15) (Table 1). Cortisol was measured by the Chiron Diagnostics ACS:180 cortisol assay (Bayer, Newbury, UK). Interassay coefficient of variation was less than 6%. Genomic DNA was also available from 102 blood donors from the Oxford area and was used for polymorphism genotyping.

The previously reported GR polymorphic markers (3, 4, 5, 8, 10, 11, 16, 17, 18, 19, 20) were included. In addition, six validated polymorphisms spaced across the entire 122 kb of the GR gene were selected in silico using the UCSC (June 2002 freeze) and dbSNP NCBI Web sites (http://genome.ucsc.edu/ and http://www.ncbi.nlm.nih.gov/) (Fig. 1B). The PCR primers and annealing temperatures used to amplify each of these polymorphic sites are available on request. SNP genotyping was by the dye terminator based SNaPshot method (Applied Biosystems, Warrington, UK). Presence or absence of a ttg insert was determined by size resolution on an ABI Prism 3100 genetic analyzer (Applied Biosystems), using a fluorescent dye (HEX) labeled forward primer. This allows fragment size separation by capillary-based electrophoresis, relative to that of an internal size standard. The results were analyzed using Genescan analysis and Genotyper 3.6 software (Applied Biosystems).

Mutation screening of the lymphoid specific GR promoter

Mutation detection was performed using denaturing HPLC, Wave, Transgenomic, Crewe, UK) in 36 unrelated U.K. Caucasians. Four overlapping PCR fragments were generated to cover 2028 bp of the lymphocyte-specific GR exon 1a and its promoter (GenBank ID AF395116) (Fig. 1A). The entire 2028-bp region was also sequenced (BigDye ddNTP) for 18 individuals.

Statistical methods

Comparison between groups was by t test of log transformed PDC values.

Allele frequencies were compared through the ² test, and significance was taken at the P 0.05 level, after Bonferroni correction. Odds ratios and 95% confidence intervals were determined for carriage of the haplotype (Stata Corporation, College Station, TX).

The expectation-maximization algorithm was to assign haplotypes to individuals with greater than 90% certainty (http://www-gene.cimr. cam.ac.uk/clayton/software/SNPHAP.txt). EHplus was used to determine differences between the pattern of observed and expected haplotypes (21).

Haplotypes were then assigned by PDC quartile, and HPM carried out (13). The results of HPM indicated the involvement of a specific haplotype. Linear regression, with PDC as a continuous variable, was used to reexamine the association of the specific haplotype with PDC (Stata).

The distribution of PDC values by haplotype was compared using a one-tailed t test on log-transformed PDC values.

Haplotype tagging SNPs

Haplotypes occurring at a frequency of greater than 1% were selected for the 218 individuals studied. The haplotype tagging SNPs, accounting for 95% of haplotypes observed, were determined by eye.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PDC in patients with psoriasis and controls

No significant difference in PDC was found between patients with psoriasis (n = 40) and the control group (n = 76; P = 0.34) (Table 1).

Allele frequencies of the polymorphic markers

No deviation from Hardy Weinberg equilibrium and no differences in allele frequencies for any markers tested were found among the patients with psoriasis (n = 40), controls (n = 76), or the anonymized blood donors (n = 102). The rare SNP allele frequencies of the combined data set (n = 218) are given in Fig. 1B.

Analysis of variation in GC sensitivity

In both the patients with psoriasis and the locally recruited controls, a wide variation in PDC was observed. There was no difference, however, in the distribution of PDC between the two groups (Table 1). This, combined with the lack of difference in allele frequency between patients with psoriasis, the local controls or the anonymized blood donors, showed no effect of disease. Therefore, the groups were combined for analysis of genetic predictors of GC sensitivity as determined by PDC (Fig. 2).

View larger version (10K): [in this window] [in a new window]   FIG. 2. Frequency distribution of PDC concentrations from study participants. All the subjects (patients with psoriasis and controls) were pooled, and the distribution of PDC concentration plotted. The quartiles are marked with the median and interquartile range of the PDC concentration.

Individuals in the high PDC group (n = 29) were compared against the other three quartiles combined (n = 87), and allele frequencies for all 10 polymorphisms were compared. No significant association of any single polymorphism with high PDC quartile were seen. Similarly, comparisons were made between the low PDC quartile and the other three quartiles combined, and again no single significant allelic association was observed.

Linkage disequilibrium

Evidence for very strong linkage disequilibrium among the markers was obtained through EHplus (P < 10^-16). Specifically, of the 1024 possible haplotypes, only four represent 95% of all those observed.

Haplotype pattern mining

SNPHAP was used to assign 10 marker long haplotypes with greater than 90% certainty to the 116 individuals with PDC data.

HPM was then used to identify haplotypes associated with low PDC concentration (low PDC quartile, compared with the other three quartiles combined) and similarly for high PDC concentration. Haplotypes significantly associated with low PDC were retested using linear regression and PDC as a continuous variable. This confirmed the association of a three-marker-long haplotype, across intron B, with low PDC production (P = 0.03). This haplotype consisted of the G allele of the BclI SNP, the A allele of the intron B 33389, and the T allele of the intron B 33388 (Fig. 3A). Carriage of this haplotype occurred in 41% of the individuals in the low PDC quartile, compared with only 23% in the other quartiles combined (odds ratio 2.4, 95% confidence interval 0.9–6.3, P = 0.05).

View larger version (18K): [in this window] [in a new window]   FIG. 3. A, GR gene intron B haplotype associated with low PDC concentration. The GR gene intron B region. The adjacent exons are numbered. The G-A-T haplotype associated with low PDC (P = 0.03) is marked consisting of the G allele of the BclI SNP, the A allele of the intron B 33389, and the T allele of the intron B 33388. SNP codes: Intron B 33389, rs33389; intron B 33388, rs33388 (dbSNP NCBI). Relative distance between polymorphic markers as identified from the University of California, Santa Cruz web site, June 2002 freeze. B, PDC by haplotype. All individuals with at least one copy (+) of the GR haplotype (G-A-T) (n = 32) were compared with those with no copies (-) of the haplotype (n = 84). The median and interquartile range of PDC is shown, with the exact median value marked in each case. PDC is significantly reduced by the presence of at least one copy of the GR (G-A-T) allele (P = 0.04).

Effect of haplotype carriage on distribution of PDC concentrations

We have shown that a specific GR haplotype is associated with enhanced sensitivity to dexamethasone, as determined by PDC measurement. To determine the effect of this haplotype on PDC concentration, we grouped individuals by carriage of the intron B haplotype (G-A-T). There were only two (G-A-T) homozygous individuals. The median PDC level of those without the haplotype was 262nmol/liter, whereas for individuals with at least one copy of the haplotype (G-A-T), this was significantly reduced to 183 nmol/liter (P = 0.04) (Fig. 3B).

Haplotype tagging SNPs

Haplotype tagging SNPs allow the maximum number of haplotypes to be captured using the minimum number of polymorphic markers (14). In our study population, three polymorphisms tag 95% of haplotypes. These are the intron B 33388 AG, presence or absence of the ttg insertion, and the 9B3'untranslated region AG (Table 2).

No polymorphism of the 2.2-kb lymphocyte-specific GR promoter was observed in the 36 Caucasians studied. If any polymorphism does exist in this sequence, it will be at a frequency of less than 1.4% and will therefore be of limited use in any future GR association studies performed in Caucasians.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To comprehensively address the role of the GR in determining GC sensitivity, we investigated polymorphisms across the whole GR gene. This included the previously examined polymorphisms (3, 4, 5, 8, 10, 11, 16, 17, 18, 19, 20), together with other validated SNPs.

GC sensitivity can be conveniently measured by using an overnight dexamethasone suppression test. This parameter is robust over time, and indeed when subjects are retested years later, the rank order of individuals is preserved (1). In addition, correlation has been established between a 1- and 0.25-mg dexamethasone suppression test (1, 5). However, because a 1-mg dose is a relatively high dose (with 93% of subjects having PDC suppressed to 50nmol/liter), we selected the 0.25-mg dose to discern the full range of response (1, 5). In the study by Huizenga et al. (5) examining the functional importance of the GR N363S polymorphism, increased sensitivity of cortisol suppression to the 0.25-mg dexamethasone suppression test was found to be correlated with lower lumber spine bone density and with an increased insulin response to dexamethasone. Additional evidence of a genetic contribution to GC sensitivity comes from a study of healthy volunteers, which showed that peripheral blood mononuclear cell proliferation responses remained stable over an 8-month follow-up (2). The GR is a key candidate gene to explain such interindividual differences in GC sensitivity.

In our study PDC distribution from individuals who had undergone a 0.25-mg dexamethasone suppression test was divided into quartiles for initial SNP analysis. There was no significant association found between any single GR polymorphism and PDC production after Bonferroni correction for multiple comparisons. Because there is significant linkage disequilibrium across the GR gene, we performed haplotype analysis.

To identify the region within the extended haplotypes that most predicted PDC concentration, we used HPM. This approach aligns predicted haplotypes and identifies conserved regions that are overrepresented in the low PDC quartile, compared with the other three quartiles combined. HPM identified haplotypes associated with low PDC, common to which was a three-marker haplotype within intron B. All the associated haplotypes were retested using linear regression with PDC as a continuous, noncategorical variable. This confirmed the association of the three-marker haplotype with low PDC level (P = 0.03).

This three-marker haplotype spans intron B and includes a SNP that alters a BclI site. Carriage of the BclI polymorphism has previously been associated with essential hypertension (9), a potential surrogate, physiological marker of increased GC bioactivity. The BclI polymorphism has also been associated with increased body fat and an increased atherogenic profile in obesity (20). It is possible that these earlier studies (19, 20), using just the BclI polymorphism alone, may in fact reflect carriage of an extended haplotype such as defined in our study. Alternatively, one or more of these SNP changes could be, either alone or in combination, sufficient to influence gene transcription or RNA processing. It is of interest that the three SNPs alter consensus recognition sites for RNA splicing factors: SR proteins (33389 and 33388) and SF2/ASF (BclI) (22).

The effect of the three-marker haplotype on PDC, and by implication GC sensitivity, is shown in Fig. 3B. It is clear that the haplotype does not explain all the interindividual variation in PDC, but carriage does significantly influence the response to dexamethasone challenge because the PDC significantly fell from 262 nmol/liter to 183 nmol/liter (P = 0.04).

Sensitivity to the actions of endogenous GCs may be an important factor underlying the development of many human diseases including hypertension, central obesity, glucose intolerance, type 2 diabetes, and cerebral atrophy, all of which are found in states of pathological GC excess (23, 24, 25, 26, 27, 28). Indeed, previous studies using the intron B BclI polymorphism have shown association with some of these potential biomarkers of GC activity (9, 19, 20, 29, 30). However, important variation in clinical response to the antiinflammatory properties of GC is widely recognized and may derive from genetic factors, disease effects [e.g. severity of inflammation (31, 32, 33, 34, 35, 36)], or both. Thus, it is postulated that treatment resistance could result from either inherited or acquired variation in GC sensitivity. It is of importance to note that the cohort of psoriasis patients included in this study were no different from normal controls both in PDC and allele frequencies for any marker tested. This implies that for early-onset chronic plaque psoriasis, there is no genetic predisposition to altered GC sensitivity. A further manifestation of variation in responsiveness to GC is susceptibility to GC-induced side effects. Although the spectrum of side effects associated with GC therapy is well known, it is currently not possible to predict which individuals are at greatest risk. The GR haplotype we have identified, which predicts GC sensitivity, can now be used for uncovering the genetic predisposition to diseases with a putative GC etiology (e.g. hypertension), variability of treatment responsiveness (e.g. asthma and rheumatoid arthritis), and susceptibility to GC-induced side effects (e.g. osteoporosis).

	Acknowledgments

 
We thank Debbie Payne (Centre for Integrated Genomic Medical Research, University of Manchester, United Kingdom) for expert technical assistance.

	Footnotes

 
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.

Received July 25, 2003.

Accepted October 29, 2003.

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