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Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis.

ABSTRACT: A defect in hypothalamic-pituitary-adrenal (HPA) axis function has been suggested to contribute to susceptibility to rheumatoid arthritis (RA).To investigate polymorphisms of the glucocorticoid receptor (GR) gene and determine any associations with RA.Three GR polymorphisms that tag 95% of all haplotypes across the GR gene were genotyped. These are an intron B Bcl1 polymorphism, a ttg insertion/deletion within intron F (rs2307674) and the single nucleotide polymorphism (SNP) lying in the 3' untranslated region of exon 9b (rs6198). The dye terminator-based SNaPshot method or size resolution by capillary electrophoresis was performed. The study population comprised 198 UK Caucasian RA cases and 393 ethnically matched controls.No significant single point or haplotypic associations were found for GR polymorphisms with RA susceptibility. Furthermore, no evidence for GR polymorphisms with aspects of RA severity was seen.In this study of the most comprehensive coverage of GR polymorphisms with RA, no significant contributing role for GR polymorphisms with RA was found.

SUBMITTER: Donn R

PROVIDER: S-EPMC2040228 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis.

Donn Rachelle R Payne Debbie D Ray David D

Clinical endocrinology 20070528 3

<h4>Background</h4>A defect in hypothalamic-pituitary-adrenal (HPA) axis function has been suggested to contribute to susceptibility to rheumatoid arthritis (RA).<h4>Objective</h4>To investigate polymorphisms of the glucocorticoid receptor (GR) gene and determine any associations with RA.<h4>Methods</h4>Three GR polymorphisms that tag 95% of all haplotypes across the GR gene were genotyped. These are an intron B Bcl1 polymorphism, a ttg insertion/deletion within intron F (rs2307674) and the sing ...[more]

PMID: 17532759

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Project description:INTRODUCTION: The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9? are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity. METHODS: The presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined. RESULTS: Carriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9? minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNF?) therapy (P < 0.05). CONCLUSIONS: The minor alleles of the 9? and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa.

Project description:INTRODUCTION: The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9? and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum. METHODS: We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9?, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9? or 9? + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use. RESULTS: GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease. CONCLUSIONS: Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.

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Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis.

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Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis.

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