Journal
HUMAN GENETICS
Volume 117, Issue 2-3, Pages 220-227Publisher
SPRINGER
DOI: 10.1007/s00439-005-1302-3
Keywords
FCGR2B; ITIM; systemic lupus erythematosus; transcriptional regulation
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Funding
- NCRR NIH HHS [C06 RR 12538-01] Funding Source: Medline
- NIAMS NIH HHS [AR 48765] Funding Source: Medline
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The role for inhibitory Fc gamma receptors class IIb ( Fc gamma RIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of Fc gamma RIIb 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 Fc gamma RIIb 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 FccRIIb 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.
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