Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

TY - JOUR

T1 - Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

AU - Nolsøe, R L

AU - Kelly, J A

AU - Pociot, F

AU - Moser, Kjeld

AU - Kristiansen, O P

AU - Mandrup-Poulsen, Thomas

AU - Harley, J B

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

KW - African Americans

KW - Alleles

KW - Antigens, CD95

KW - Apoptosis

KW - Case-Control Studies

KW - Codon

KW - European Continental Ancestry Group

KW - Fas Ligand Protein

KW - Genes, Reporter

KW - Genetic Variation

KW - Haplotypes

KW - Humans

KW - Jurkat Cells

KW - Luciferases

KW - Lupus Erythematosus, Systemic

KW - Membrane Glycoproteins

KW - Pedigree

KW - Phenotype

KW - Polymorphism, Genetic

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Thrombocytopenia

KW - Tumor Necrosis Factors

KW - United States

U2 - 10.1038/sj.gene.6364259

DO - 10.1038/sj.gene.6364259

M3 - Journal article

C2 - 16163374

SN - 1466-4879

VL - 6

SP - 699

EP - 706

JO - Genes and Immunity

JF - Genes and Immunity

IS - 8

ER -