Susceptibility gene mapping in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by relapsing or progressive demyelination of the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS resulting in an unknown mode of inheritance as a complex trait. Although the HLA region has been identified as important in MS, non-HLA loci have not been clearly identified. Autoimmunity to self-myelin components has been proposed as being of key importance in the pathogenesis of MS. Therefore, major myelin proteins and critical regulatory factors involved in autoimmune responses could be considered to be candidates for genetic analysis in MS. The gene encoding myelin basic protein (MBP), a potential autoantigen in MS, has been reported linked and associated with MS in the Finnish population, but this observation lacks confirmation in other populations. A limitation of previous studies has been the low resolution of the typing procedure. We performed linkage and case-control analyses with the same MBP gene polymorphic marker genotyped by use of a fluorescence-based DNA sequencer which allowed the identification of discrete alleles of a 1.3 kb tetranucleotide repeat. Our results did not provide any evidence for linkage or association with Swedish MS families and patients. Tumor necrosis factor-a (TNF-a) is a potent proinflammatory cytokine which is thought to have a proinflammatory role in MS. We investigated a bi-allelic polymorphism in the TNF-a promoter at position -308 bp (TNFa-308), which is reported to influence transcriptional activity, in a group of patient with MS and optic neuritis using an allele-specific PCR technique, and correlated the genotypes with nurnbers of TNF-a mRNA expressing cells. No significant difference was found in the distribution of TNFa-308 alleles between patients and controls was found. TNFa-308 alleles did not correlate with numbers of TNF-a mRNA expressing cells in patients. Autoantibodies may participate in the pathogenesis of MS. We studied a highly polymorphic VNTR marker located in the centre of the Ig heavy chain locus in a number of MS families and sporadic patients. No evidence was found for linkage or association of this marker with Swedish families and MS patients. We further investigated a number of candidated genes in MS, genes encoding cytokines (IFN-y, IL-2, IL-4, IL-4 receptor, IL-10, TGF-,ß1 and -,ß2) and myelin proteins (CNP:ase, MAG, OMGP, PLP) in MS by two-point linkage, affected pedigree member (APM) and association analyses. No evidence for linkage was observed except for a slightly positive lod score of 0.88 (0 = 0.01) for IFN-y. APM analysis indicated a possible linkage with TGF-ß2 (p = 0.008) and IL-4R (p = 0.043). None of the cytokine markers were associated with MS. A genetically isolated Swedish population with a high prevalence of MS was studied using a haplotype sharing method. We searched for haplotypes shared by affected individuals in a large kindred by genome search of 4 nuclear families and located regions demonstrating identity-by descent by linkage disequilibrium analysis. Our data suggest the location of a gene with an importance for MS in this population at chromosome 17p.