Abstract
We have investigated whether three intragenic polymorphisms of the CTLA-4 gene, a C/T base exchange in the promoter (p.-318), an A/G substitution in exon 1 (p.49) and a dinucleotide repeat polymorphism in exon 4 (p.642), were associated with genetic susceptibility to multiple sclerosis (MS). We observed a significant association (p < 0.05) for homozygosity for the G49 allele in a case-control analysis of 378 MS patients and 237 controls, and a transmission disequilibrium (p < 0.02) for the G49 allele in 31 MS families. This was further corroborated by evidence for linkage by the affected pedigree member (APM) analysis (p < 0.0002) and a transmission distortion (p < 0.05) of the exon 4(642) polymorphism. Sequencing of the promoter, the first and second exons and the parts of the first intron revealed no further polymorphisms. Our results suggest that a dysregulation of CTLA-4-driven downregulation of T-cell activation could be involved in the pathogenesis of MS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Antigens, CD
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Antigens, Differentiation / genetics*
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Antigens, Differentiation / immunology*
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CTLA-4 Antigen
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Chromosomes, Human, Pair 2*
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DNA Primers
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DNA, Satellite / analysis
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Exons
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Family Health
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Female
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Genetic Linkage
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Genetic Markers
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Genetic Predisposition to Disease
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Genotype
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HLA-DR Antigens / analysis
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HLA-DR Antigens / immunology
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Humans
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Immunoconjugates*
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Immunosuppressive Agents / immunology*
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Lymphocyte Activation / immunology
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Male
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Middle Aged
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Molecular Sequence Data
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Multiple Sclerosis / genetics*
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Multiple Sclerosis / immunology
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Phenotype
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Polymorphism, Genetic
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Promoter Regions, Genetic / immunology
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Sequence Analysis, DNA
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T-Lymphocytes, Cytotoxic / immunology
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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DNA Primers
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DNA, Satellite
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Genetic Markers
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HLA-DR Antigens
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Immunoconjugates
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Immunosuppressive Agents
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Abatacept
Associated data
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GENBANK/M37243
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GENBANK/M74363