The CTLA-4 gene is associated with multiple sclerosis.
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.
Department of Neurology, Karolinska Institute at Huddinge University Hospital, Sweden. artlig@mbox.ki.se
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Ligers
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Saarinen
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Hillert
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Olerup
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology*; D060908:CTLA-4 Antigen; D002889:Chromosomes, Human, Pair 2; D017931:DNA Primers; D004276:DNA, Satellite / Q000032:analysis; D005091:Exons; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000032:analysis / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000276:immunology; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D004276:DNA, Satellite; D005819:Genetic Markers; D006684:HLA-DR Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept