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

Objective. To study the occurrence and function of polymorphism in the huma n glucocorticoid receptor (hGR) gene in rheumatoid arthritis (RA) and syste mic lupus erythematosus (SLE). Methods. We used single stranded conformation polymorphism (SSCP) and direc t 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 cell s and the stability of the mRNA containing the polymorphism was tested usin g real-time PCR. Results. A polymorphism in the hGR gene in exon9 beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction of this pol ymorphism 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 un reported polymorphism in the hGR gene. This polymorphism increased stabilit y of hGR beta mRNA, which could contribute to an altered glucocorticoid sen sitivity since the hGR beta is thought to function as an inhibitor of hGR a lpha activity.