title: Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Research Division, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.
authors.forename: Marissa C
authors.initials: MC
authors.lastname: Blank
authors.forename: Radu N
authors.initials: RN
authors.lastname: Stefanescu
authors.forename: Emi
authors.initials: E
authors.lastname: Masuda
authors.forename: Francesc
authors.initials: F
authors.lastname: Marti
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Redecha
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wurzburger
authors.forename: Margaret G E
authors.initials: MG
authors.lastname: Peterson
authors.forename: Shizuko
authors.initials: S
authors.lastname: Tanaka
authors.forename: Luminita
authors.initials: L
authors.lastname: Pricop
mesh_terms: 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*
chemical_list: C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; D017452:Receptors, IgG; D018808:Transcription Factor AP-1