We have investigated whether three intragenic polymorphisms of the CTLA-4 g
ene, 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), w
ere associated with genetic susceptibility to multiple sclerosis (MS). We o
bserved a significant association (p < 0.05) for homozygosity for the G(49)
allele in a case-control analysis of 378 MS patients and 237 controls, and
a transmission disequilibrium (p < 0.02) for the G(49) allele in 31 MS fam
ilies. This was further corroborated by evidence for linkage by the affecte
d pedigree member (APM) analysis (p < 0.0002) and a transmission distortion
(p < 0.05) of the exon 4(642) polymorphism. Sequencing of the promoter, th
e first and second exons and the parts of the first intron revealed no furt
her polymorphisms. Our results suggest that a dysregulation of CTLA-4-drive
n downregulntion of T-cell activation could be involved in the pathogenesis
of MS. (C) 1999 Elsevier Science B.V. All rights reserved.