Multiple sclerosis.

Abstract

Differences in the risk of multiple sclerosis depending on racial background, and the high clinical concordance rates in monozygotic compared with dizygotic twins, have stimulated attempts to identify and locate genes that confer susceptibility to the disease. The risk of multiple sclerosis is increased from 1 in 800 in northern European Caucasians to 1 in 3 in the monozygotic co-twins of affected individuals, with intermediate rates for siblings, offspring and more distant relatives. Concordance rates in monozygotic and dizygotic co-twins of affected individuals rise to 35% and 15%, respectively when magnetic resonance imaging is used to supplement clinical evidence for disease status. The increased recurrence risk in relatives of patients with multiple sclerosis is consistent with a model in which more than one gene contributes to susceptibility. Population studies have demonstrated an association with the class 2 major histocompatibility complex (MHC) phenotypes DR15 and DQw6 and their corresponding genotypes DRB1.1501, DRB5.0101 and DQA1.0102, DQB2.0602. An extensive search, using population studies, for other polymorphic alleles involved in restriction of the immune response may have yielded an additional candidate gene in the VH2-5 immunoglobulin heavy-chain variable region. Identity by descent analysis of candidate genes encoded within the alpha-chain of the T-cell receptor and the gene for myelin basic protein has failed to demonstrate linkage; paradoxically, this is also true for the MHC class 2 region, despite the population association. However, studies involving a large number of sibling pairs have reported a bias in the distribution of T-cell receptor beta-chain variable region haplotype sharing, favouring linkage. This becomes more marked when stratification is made for the presence of DR2 in both affected siblings, suggesting an interaction between genetic polymorphisms encoded within the MHC and T-cell receptor genes, as expected from their known functional co-operation in antigen presentation. The same is true for the immunoglobulin heavy chain, providing provisional evidence for linkage to a gene encoded within the immunoglobulin heavy-chain variable region in families reported from the UK. Taken together, these findings demonstrate the importance of family studies in elucidating the genetic basis of multiple sclerosis, and confirm that several genes are involved, one or more of which regulates genetic restriction of the immune response. The contribution made by the susceptibility genes that have provisionally been identified, occurring in isolation or together, can account for only a proportion of the increased risk of multiple sclerosis implicated by family studies.(ABSTRACT TRUNCATED AT 250 WORDS)