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It has been suggested that dysregulation of the neuroendocrine system is an important pathogenetic mechanism of rheumatoid arthritis (RA). The dramatic response of patients with RA to glucocorticoids, the aggravation of RA after resection of bilateral adrenal glands, the inappropriately normal plasma cortisol levels in patients with RA, the blunted plasma cortisol responses after surgical stress, and the essential role of glucocorticoids in the development of streptococcal cell wall induced arthritis in Lewis rats provide evidence that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis or relative glucocorticoid deficiency might play a part in the development of RA.1,2 The involvement of glucocorticoids in the development of thymocytes further supports the role of glucocorticoid in autoimmune diseases like RA.3
The human glucocorticoid receptor (hGR) is a transcriptional factor activated by glucocorticoids, and regulates the expressions of various inflammatory cytokine genes by interacting with DNA bound NF-κB or activator protein 1. The hGR gene is located on chromosome 5 (locus 5q31) and consists of nine exons and eight introns.4 Of the several single nucleotide polymorphisms identified in the hGR gene, the BclI restriction fragment length polymorphism (RFLP) was found to be located in intron 2, 647 bp from the exon 2/intron 2 junction.5
BclI RFLP was found to be associated with tissue-specific corticosteroid sensitivity.6,7 Furthermore, BclI GG homozygotes showed increased cortisol response to a standardised lunch8 and depressed response to severe psychosocial stress.9 These findings suggest that the BclI polymorphism of hGR plays a part in the dysregulation of the HPA axis. The role of the BclI polymorphism in corticosteroid sensitivity and dysregulation of the HPA axis suggests that it may play a part in the pathogenesis of RA. Therefore, we investigated the hGR +647 G/C genetic polymorphism in Korean patients with RA and in healthy blood donors matched for age and sex, in an attempt to understand the role of the HPA axis related hGR polymorphism in the development of RA.
A total of 149 Korean patients with RA were enrolled at the rheumatology clinic of Seoul National University Hospital between March 1998 and February 2000. All patients fulfilled the 1987 American Rheumatism Association revised criteria for the classification of RA.10 The patients comprised 132 women and 17 men, with mean (SD) age 50.8 (12.1) years and a mean disease duration of 7.9 years (range 0.17–50.2). Rheumatoid factor was present in 112 (75%) and HLA-DR4 in 86 (58%), radiographic erosions were found in 100 (67%), and extra-articular complications in 25 (17%) patients. One hundred and forty nine Korean healthy blood donors matched for age and sex were enrolled as controls.
Genomic DNA was extracted from peripheral blood using a QIAamp blood kit (Qiagen, Valencia, USA), and HLA-DR4 was genotyped by polymerase chain reaction (PCR)-single strand conformation polymorphism. The hGR +647 G/C polymorphism was genotyped by PCR-RFLP, using 5′-AAA TTG AAG CTT AAC AAT TTT GGC-3′, and 5′-GCA GTG AAC AGT GTA CCA GAC C-3′ as primers, and BclI endonuclease (New England Bioblabs, Beverly, USA).5
Genotype or allele frequencies of hGR +647 G/C did not differ between patients with RA and controls (table 1) (allele frequencies of hGR G/C were 0.73/0.27 in patients and 0.78/0.22 in the controls (p = 0.18, OR = 0.78, 95% CI 0.53 to 1.13). Subgroup analysis showed no genotype or allele frequency differences between the patients with rheumatoid factor, joint erosion, or extra-articular complications and the healthy controls. When patients were stratified according to HLA-DR4 status, these results were unchanged. In conclusion, hGR +647 G/C polymorphisms probably do not play a part in the pathogenesis of RA in Korean patients.
This study was supported by a grant from the Ministry of Science and Technology of Korea through the National Research Laboratory Programme.
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