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 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.


CONCLUSIONS
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.
Derijk
R H
RH
Rijngeest Groep, Oegstgeest, The Netherlands. rderijk@rijngeestgroep.nl
Schaaf
M J
MJ
Turner
G
G
Datson
N A
NA
Vreugdenhil
E
E
Cidlowski
J
J
de Kloet
E R
ER
Emery
P
P
Sternberg
E M
EM
Detera-Wadleigh
S D
SD
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D019556:COS Cells / Q000187:drug effects; D004247:DNA / Q000032:analysis; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D020033:Protein Isoforms; D022821:RNA Splice Sites / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000145:classification / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014162:Transfection
D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C121943:glucocorticoid receptor beta; D003609:Dactinomycin; D004247:DNA