Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus
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The role for inhibitory Fc gamma receptors class IIb (FcγRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcγRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G–C substitution at position –343 relative to the start of transcription) with altered FcγRIIb expression and function. The G–C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcγRIIb receptors was significantly reduced in activated B cells from (–343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in –343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.
KeywordsFCGR2B ITIM Systemic lupus erythematosus Transcriptional regulation
We thank Jane Salmon and Heidi Norbis for providing blood and DNA samples from the HSS Autoimmune Registry and Repository, and Francesco Ramirez for reviewing the manuscript. This work was supported by grants from the National Institutes of Health AR49765, the SLE Foundation, the Mary Kirkland Lupus Center and the Arthritis Foundation (to L. Pricop). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06-RR12538-01 from the National Center for Research Resources, National Institutes of Health.
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