Glucocorticoid Sensitivity Is Determined by a Specific Glucocorticoid Receptor Haplotype

Stevens, Adam; Ray, David; Zeggini, Eleftheria; John, Sally; Richards, Helen L.; Griffiths, C.E.M.; Donn, Rachelle

doi:10.1210/jc.2003-031235

Cited by 164 publications

(133 citation statements)

References 37 publications

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“…SH30068). This batch of FBS was found to contain less than 9 nM cortisol as measured by RIA, as previously reported (Stevens et al 2004), giving a final calculated concentration in the cell-culture medium of less than 1 nM. The FBS was not heat inactivated (Anonymous 1996).…”

Section: Methodssupporting

confidence: 67%

Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner

Alourfi

Donn²,

Stevens³

et al. 2005

Journal of Molecular Endocrinology

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MIF is a potent proinflammatory cytokine involved in inflammatory arthritis. Glucocorticoids (GC) have been reported to induce secretion of MIF in rodent cells, and as MIF counteracts the anti-inflammatory effects of GC, this has implications for human inflammatory disease. Transient transfection studies showed that the MIF promoter was repressed by dexamethasone (Dex) (10 nM) in CEM C7A cells, with up to 50% suppression by 100 nM. However, there was no regulation of the promoter by GC in A549 cells. We also found that subnanomolar concentrations of Dex suppressed MIF secretion, measured by ELISA, by 80% in both human T lymphoblasts (CEM C7A) and human lung epithelial cells (A549). Endogenous MIF mRNA was also repressed by GC in CEM C7A cells, measured both by Northern blot and quantitative RT-PCR assays, but there was no such regulation in A549 cells. This suggests that GC affects translation rather than transcription of MIF in A549 cells. These results contradict earlier results with the rat cell line RAW 264·7. Therefore, we analysed MIF secretion from RAW 264·7 cells but found no GC effect on secretion. Understanding how GC regulates MIF in a cell-type-dependent manner may give insights into GC-refractory human inflammatory diseases.

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Section: Methodssupporting

confidence: 67%

Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner

Alourfi

Donn²,

Stevens³

et al. 2005

Journal of Molecular Endocrinology

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“…Nevertheless, we did observe trends for each of the three analyzed GR variants, some of them apparently conflicting with the previously shown characteristics of the respective GR variants. Screening samples carrying the BclI variant, which, similar to N363S, is considered to increase GR sensitivity (17,18), revealed a trend towards higher 4-androstenedione concentrations, in contrast to lower steroid hormone concentrations (11-deoxycortisol and 21-deoxycortisol) in carriers of 363S. Linear regression analysis even revealed a statistical significance for the increase of 4-androstenedione levels in carriers of one or two BclI alleles, hereby suggesting the presence of an allele dose effect.…”

Section: Discussionmentioning

confidence: 91%

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Schreiner

Tozakidou²,

Maslak³

et al. 2009

European Journal of Endocrinology

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Objective: 17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns. Design: GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody. Results: There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S-and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited. Conclusions: Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

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“…In several inflammatory diseases, variations in glucocorticoid sensitivity have been reported to be associated with SNPs in the GR gene [13,[28][29][30] . In this study we found no evidence of independent involvement of GR allelic variants (R23K and N363S) and CD phenotypic and clinical parameters, despite the reported correlations of the variants N363S with glucocorticoid hypersensitivity [13] and R23K with decreased response to dexamethasone [29] .…”

Section: Discussionmentioning

confidence: 99%

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location

Sánchez

Lévy²,

Costea³

et al. 2009

WJG

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AIM:To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS:Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS:For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively.CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.

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Glucocorticoid Sensitivity Is Determined by a Specific Glucocorticoid Receptor Haplotype

Cited by 164 publications

References 37 publications

Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner

Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location

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