Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia
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Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia. / Nolsøe, R L; Kelly, J A; Pociot, F; Moser, Kjeld; Kristiansen, O P; Mandrup-Poulsen, Thomas; Harley, J B.
I: Genes and Immunity, Bind 6, Nr. 8, 01.12.2005, s. 699-706.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 6
SP - 699
EP - 706
JO - Genes and Immunity
JF - Genes and Immunity
SN - 1466-4879
IS - 8
ER -
ID: 33902347