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Open Access Highly Accessed Research article

Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis

Manon JM van Oosten1, Radboud JEM Dolhain2, Jan W Koper1, Elisabeth FC van Rossum1, Marieke Emonts3, Khik H Han4, Jacques MGW Wouters5, Johanne MW Hazes2, Steven WJ Lamberts1 and Richard A Feelders1*

Author Affiliations

1 Department of Internal Medicine, Section of Endocrinology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

2 Department of Rheumatology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

3 Department of Pediatrics and Department of Immunology, Erasmus MC-Sophia, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands

4 Department of Rheumatology, Maasstad Hospital, Olympiaweg 350, 3078 HT, Rotterdam, The Netherlands

5 Department of Rheumatology, Sint Franciscus Hospital, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands

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Arthritis Research & Therapy 2010, 12:R159  doi:10.1186/ar3118

Published: 21 August 2010

Abstract

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 9β 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, 9β 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 (TNFα) therapy (P < 0.05).

Conclusions

The minor alleles of the 9β 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.