A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis

• Published in: Journal of rheumatology Vol. 28; no. 11; pp. 2383 - 2388
• Main Authors: R H Derijk, M J Schaaf, G Turner, N A Datson, E Vreugdenhil, J Cidlowski, E R de Kloet, P Emery, E M Sternberg, S D Detera-Wadleigh
• Format: Journal Article
• Language: English
• Published: Toronto, ON The Journal of Rheumatology 01-11-2001; Journal of Rheumatology Publishing
• Subjects: Animals; Arthritis, Rheumatoid - genetics; Biological and medical sciences; COS Cells - drug effects; Dactinomycin - pharmacology; Diseases of the osteoarticular system; DNA - analysis; Female; Humans; Inflammatory joint diseases; Lupus Erythematosus, Systemic - genetics; Male; Medical sciences; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Protein Isoforms; Receptors, Glucocorticoid - classification; Receptors, Glucocorticoid - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Splice Sites - genetics; RNA Stability - genetics; RNA, Messenger - analysis; RNA, Messenger - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Analysis, DNA; Transfection; Skin disease; Pathogenesis; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Single strand conformation polymorphism; Messenger RNA; Gene; Systemic disease; Glucocorticoid receptor; Genetics; Lupus erythematosus; Disseminated; Transcription factor; Human; Immunopathology; Connective tissue disease; Immune response; Exploration; Gene expression; Biological activity; Polymerase chain reaction; Chronic; DNA; Rheumatoid arthritis; Molecular biology
• ISSN: 0315-162X; 1499-2752

OBJECTIVE: To study the occurrence and function of polymorphism in the human glucocorticoid receptor (hGR) gene in rheumatoid
arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used single stranded conformation polymorphism (SSCP) and
direct sequencing to study the hGR gene in 30 patients with RA, 40 with SLE, and 24 controls. A newly identified polymorphism
was transfected in COS-1 cells and the stability of the mRNA containing the polymorphism was tested using real-time PCR. RESULTS:
A polymorphism in the hGR gene in exon9beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction
of this polymorphism in the hGRb mRNA was found to significantly increase stability in vitro compared to the wild-type sequence.
CONCLUSION: Our findings show an association between RA and a previously unreported polymorphism in the hGR gene. This polymorphism
increased stability of hGRbeta mRNA, which could contribute to an altered glucocorticoid sensitivity since the hGRbeta is
thought to function as an inhibitor of hGRalpha activity.