A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients.
A single-nucleotide polymorphism (SNP), identified at nucleotide position -844 in the 5' promoter of the FasL gene, lies within a putative binding motif for CAAT/enhancer-binding protein beta (C/EBPbeta). Electrophoretic mobility shift and supershift assays confirmed that this element binds specifically to C/EBPbeta and demonstrated that the two alleles of this element have different affinities for C/EBPbeta. In luciferase reporter assays, the -844C genotype had twice the basal activity of the -844T construct, and basal expression of Fas ligand (FasL) on peripheral blood fibrocytes was also significantly higher in -844C than in -844T homozygous donors. FasL is located on human chromosome 1q23, a region that shows linkage to the systemic lupus autoimmune phenotype. Analysis of 211 African American systemic lupus erythematosus patients revealed enrichment of the -844C homozygous genotype in these systemic lupus erythematosus patients compared with 150 ethnically matched normal controls (p = 0.024). The -844C homozygous genotype may lead to the increased expression of FasL, to altered FasL-mediated signaling in lymphocytes, and to enhanced risk for autoimmunity. This functionally significant SNP demonstrates the potential importance of SNPs in regulatory regions and suggests that differences in the regulation of FasL expression may contribute to the development of the autoimmune phenotype.
Wu
Jianming
J
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294-0006, USA.
Metz
Christine
C
Xu
Xiulong
X
Abe
Riichiro
R
Gibson
Andrew W
AW
Edberg
Jeffrey C
JC
Cooke
Jennifer
J
Xie
Fenglong
F
Cooper
Glinda S
GS
Kimberly
Robert P
RP
D000483:Alleles; D044383:Black People / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005838:Genotype; D006801:Humans; D019169:Jurkat Cells / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism*; D001741:Black or African American
D022782:CCAAT-Enhancer-Binding Protein-beta; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor