Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus.
The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb 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 FcgammaRIIb 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 FcgammaRIIb 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.
Blank
Marissa C
MC
Research Division, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.
Stefanescu
Radu N
RN
Masuda
Emi
E
Marti
Francesc
F
King
Philip D
PD
Redecha
Patricia B
PB
Wurzburger
Robert J
RJ
Peterson
Margaret G E
MG
Tanaka
Shizuko
S
Pricop
Luminita
L
D001402:B-Lymphocytes / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; D017452:Receptors, IgG; D018808:Transcription Factor AP-1