The genetics of multiple sclerosis. A review

Multiple sclerosis (MS) is characterized by chronic inflammation and demyel ination 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 epide mics 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 incr eased recurrence rate in families, and the high concordance rate among iden tical 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 r egulate either the immune response or myelin production. The most consisten t finding in case-control studies was the association with the major histoc ompatibility complex (MHC) (also called human leukocyte antigen - HLA) clas s II, DR15, DQ6, Dw2 haplotype. Studies on other gene products encoded with in or close to the MHC complex on chromosome 6p21.3 (e.g., HLA DP, compleme nt components, transporter proteins, tumor necrosis factor, and myelin-olig odendrocyte glycoprotein) resulted in conflicting observations in different patient populations. The potential contribution of polymorphic alleles wit hin the genes of the T-cell receptor alpha beta chains, immunoglobulins, cy tokines, and oligodendrocyte growth factors or their receptors to MS suscep tibility either remains equivocal or is rejected. Studies on families with multiple affected members have revealed that MS is a complex trait, that th e contribution of individual genes to susceptibility is probably small, and that differences are possible between familial and sporadic forms. The dev elopment of molecular and computer technologies have facilitated the perfor mance of comprehensive genomic scans in multiplex families, which have conf irmed 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 Br itish update demonstrated segregation among regions of interest depending o n 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 coll aboration group revealed that the MHC linkage was limited to families segre gating 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 leas t one common susceptibility marker. Further identification of h-IS suscepti bility loci may involve additional family sets, more polymorphic markers, a nd the exploration of telomeric chromosomal regions. Data from these studie s may further elucidate pathogenic mechanisms of MS. (C) 1999 Editions scie ntifiques et medicales Elsevier SAS.