Glucocorticoid receptor gene variant linked to rheumatoid arthritis

NEW YORK (Reuters Health) – Variations in the gene for glucocorticoid receptor-alpha have been linked to rheumatoid arthritis, according to a report in the November issue of The Journal of Rheumatology.

Polymorphisms in the human glucocorticoid receptor (hGR) gene have already been associated with glucocorticoid resistance, the authors explain, but no studies have examined potential links between these variants and the risk for rheumatic diseases.

Dr. Roel H. Derijk, from Leiden University, The Netherlands, and colleagues sought to determine whether hGR gene variants contribute to the susceptibility for rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).

A previously unreported polymorphism in the 3' untranslated region of the hGR gene was carried by 11 of 30 RA patients and 12 of 40 SLE patients, the authors report. One RA patient and two SLE patients were homozygous for the polymorphism.

The nucleotide substitution resulted in a stabilizing effect on the mRNA of the beta transcript of hGR, the report indicates, as indicated by a significantly increased half-life.

hGR-beta, a product of hGR resulting from the alternative splicing of the primary transcript, appears to inhibit the activity of hGR-alpha, the researchers note.

"The data we report here," the authors conclude, "showing a mutation in RA patients of an 'AUUUA motif' that in vitro is associated with enhanced stability of the hGR-beta, could result in increased expression of hGR-beta and consequently in glucocorticoid resistance in RA patients carrying this polymorphism."

"We suggest that this polymorphism could contribute to changes in glucocorticoid resistance by means of attenuation of hGR efficacy," the investigators write. However, "it remains to be shown if this polymorphism can be viewed as a susceptibility factor in the pathogenesis of RA."

J Rheumatol 2001;28:2383-2388.

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