TY - JOUR
T1 - A novel polymorphic CAAT/enhancer-binding protein β element in the FasL gene promoter alters Fas ligand expression
T2 - A candidate background gene in African American systemic lupus erythematosus patients
AU - Wu, Jianming
AU - Metz, Christine
AU - Xu, Xiulong
AU - Abe, Riichiro
AU - Gibson, Andrew W.
AU - Edberg, Jeffrey C.
AU - Cooke, Jennifer
AU - Xie, Fenglong
AU - Cooper, Glinda S.
AU - Kimberly, Robert P.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - 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 β (C/EBP/β). Electrophoretic mobility shift and supershift assays confirmed that this element binds specifically to C/EBPβ and demonstrated that the two alleles of this element have different affinities for C/EBP/β. 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.
AB - 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 β (C/EBP/β). Electrophoretic mobility shift and supershift assays confirmed that this element binds specifically to C/EBPβ and demonstrated that the two alleles of this element have different affinities for C/EBP/β. 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.
UR - http://www.scopus.com/inward/record.url?scp=0037218355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037218355&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.170.1.132
DO - 10.4049/jimmunol.170.1.132
M3 - Article
C2 - 12496392
AN - SCOPUS:0037218355
SN - 0022-1767
VL - 170
SP - 132
EP - 138
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -