Transcriptional regulation of the human FCGR2B gene mediated by promoter polymorphisms associated with Systemic Lupus Erythematosus (35.38)

Abstract

Abstract The inihibitory Fc gamma receptor IIb is an important negative regulator of peripheral tolerance. The [−343 G to C] SNP in the human FCGR2B promoter is associated with Systemic lupus erythematosus (SLE). The mutant promoter [−343C/C] hasdecreased transcriptional activity. Analyses by electromobility shift, chromatin immunoprecipitation and promoter pull-down assays demonstrated binding of AP1 factors to the FCGR2B promoter. The binding of AP1 factors was decreased with the mutant FCGR2B promoter compared with the common promoter. The −343 G to C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with AP1 for binding at the −343 site, and contributed to the repression of the mutant FCGR2B promoter activity. The [−343 C/C] genotype was found to be in linkage disequilibrium with the [−77 T to A] SNP relative to the transcription initiation site. The [−77 A/A] promoter constructs displayed increased activity compared with [−77 T/T] promoter constructs in luciferase assays, suggesting a role for the −77 SNP in the transactivation of the FCGR2B promoter. Allelic variations at positions −343 and −77 identified in the human FCGR2B promoter differentially modulate the transcriptional activity and may play a role in the expression and progression of SLE disease.