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Element in the FasL Gene Promoter Alters Fas Ligand Expression: A Candidate Background Gene in African American Systemic Lupus Erythematosus Patients1
* Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294;
Laboratory of Medical Biochemistry, Picower Institute for Medical Research, Manhasset, NY 11030;
Department of General Surgery, Rush Presbyterian St. Luke’s Medical Center, Chicago, IL 60612; and
Epidemiology Branch, National Institute on Environmental Health Sciences, Research Triangle Park, NC 27709
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 
(C/EBP). Electrophoretic mobility shift and supershift assays
confirmed that this element binds specifically to C/EBP and
demonstrated that the two alleles of this element have different
affinities for C/EBP. 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.
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