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Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients.

ABSTRACT: AIM:To study whether the glucocorticoid receptor (GR/NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS:We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS:We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically significant association with glucocorticoid therapy success. CONCLUSION:NR3C1 haplotypes are not related to steroid therapy outcome.

SUBMITTER: Mwinyi J

PROVIDER: S-EPMC2923762 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients.

Mwinyi Jessica J Wenger Christa C Eloranta Jyrki J JJ Kullak-Ublick Gerd A GA

World journal of gastroenterology 20100801 31

<h4>Aim</h4>To study whether the glucocorticoid receptor (GR/NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD).<h4>Methods</h4>We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes.<h4>Results</h4>We d ...[more]

PMID: 20712049

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Project description:IntroductionGlucocorticoid (GC) therapy is the main treatment for systemic lupus erythematosus (SLE). However, some patients are resistant to these agents. Abnormalities of glucocorticoid receptor (GR) seem to be related to steroid resistance. This study evaluated GRs in T lymphocytes and monocytes of SLE patients by flow cytometry (FCM) using a monoclonal antibody (mAb) and FITC-Dex probes.MethodsThirty-five patients with SLE before treatment and 27 age- and sex-matched normal controls were studied. Disease activity scores were determined before and after treatment and used to divide the patients into steroid-resistant (SR) and steroid-sensitive (SS) groups. GRs in T lymphocytes (CD3+) and monocytes (CD14+) were examined by FCM with GR-mAb and FITC-Dex probes before treatment. Peripheral blood mononuclear cells (PBMCs) were isolated for in vitro GCs sensitivity assays. The validity of FCM analysis of intracellular staining for GR with GR-mAb and FITC-Dex probes was evaluated through comparison with western blot and radioligand binding assay (RLBA) in U937 and K562 cells in vitro. One-way ANOVA, student's t test, linear regression and spearman correlation were performed.ResultsA significant decrease in GR binding and the expression in K562 and U937 cells with 10-6 M dexamethasone (Dex) was found compared with those without Dex. In addition, a positive correlation was found between FCM and RLBA as well as FCM and Western blot. The expression and binding of both CD3/GR and CD14/GR in SR patients with SLE, detected by FCM, were all lower than those in SS patients with SLE, whereas there was no significant difference in SS patients and controls. In vitro corticosteroid sensitivity assay indicated that PHA-stimulated tumour necrosis factor-alpha (TNF-alpha), IL-12 and interferon-gamma (IFN-gamma) secretion was significantly inhibited by 10-6 M Dexamethasone in all controls and SS patients, compared with that in SR group, which confirms patient classification as SR and SS by disease activity index (SLEDAI) score.ConclusionsAbnormalities of expression and binding of the GR may be involved in tissue resistance to steroids in SLE patients. Determination of GR expression and binding by FCM may be useful in predicting the response to steroid treatment of SLE patients.

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Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients.

Publications

Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients.

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