The genetics of multiple sclerosis. A review

Multiple sclerosis (MS) is characterized by chronic inflammation and demyelination in the central nervous system (CNS). Although the etiology of MS is unknown, both genetic and environmental contributions to the pathogenesis are inferred from epidemiologic studies. Geographic distributions and epidemics of MS and data from migration studies provide evidence for some, thus far unidentified, environmental effects. The co-occurrence of MS with high and low frequencies in ethnic groups often sharing an environment, the increased recurrence rate in families, and the high concordance rate among identical twins point to inheritable determinants of susceptibility. Based on the autoimmune hypothesis of demyelination, genetic studies sought associations between MS and polymorphic alleles of candidate genes which regulate either the immune response or myelin production. The most consistent finding in case-control studies was the association with the major histocompatibility complex (MHC) (also called human leukocyte antigen - HLA) class II, DR15, DQ6, Dw2 haplotype. Studies on other gene products encoded within or close to the MHC complex on chromosome 6p21.3 (e.g., HLA DP, complement components, transporter proteins, tumor necrosis factor, and myelin-oligodendrocyte glycoprotein) resulted in conflicting observations in different patient populations. The potential contribution of polymorphic alleles within the genes of the T-cell receptor alpha beta chains, immunoglobulins, cytokines, and oligodendrocyte growth factors or their receptors to MS susceptibility either remains equivocal or is rejected. Studies on families with multiple affected members have revealed that MS is a complex trait, that the contribution of individual genes to susceptibility is probably small, and that differences are possible between familial and sporadic forms. The development of molecular and computer technologies have facilitated the performance of comprehensive genomic scans in multiplex families, which have confirmed the possible linkage of multiple loci to susceptibility, each with a minor contribution. Several provisional sites were reported, but only 6p21 (MHC complex), 5p14, and 17q22 were positive in more than one study. The British update demonstrated segregation among regions of interest depending on DR15 sharing, and excluded a gene of major effect from 95%, and one with a moderate effect from 65% of the genome. The extended study by the US collaboration group revealed that the MHC linkage was limited to families segregating HLA DR2 alleles, which suggested that linkage to the MHC is related to the KLA DR2 association, and that sporadic and familial MS share at least one common susceptibility marker. Further identification of h-IS susceptibility loci may involve additional family sets, more polymorphic markers, and the exploration of telomeric chromosomal regions. Data from these studies may further elucidate pathogenic mechanisms of MS. (C) 1999 Editions scientifiques et medicales Elsevier SAS.