Multiple Sclerosis is Associated with Multiple Genes
ABSTRACTS & COMMENTARY
Sources: Barcellos LF, et al. Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis. JAMA 1997;278:1256-1261; Compston A. Genetic epidemiology of multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;62:553-561; Hogancamp WE, et al. Identification of multiple sclerosis-associated genes. Mayo Clin Proc 1997; 72:965-976.
Improvements in molecular genetic techniques have led to the identification of several candidate genes associated with MS. A few human genome screens with MS pedigrees have recently been reported. A study by Sawcer et al performed in the United Kingdom revealed susceptibility loci on chromosome 6p21 and 17q22 (Sawcer S, et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996;13:464-468). A U.S./French screen examined more than 400 gene markers and found linkage to a previously recognized MHC region of chromosome 6p (Multiple Sclerosis Genetics Group. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex. Nat Genet 1996;13:469-471). In a Canadian study, Ebers et al found a region on 5p with linkage to MS, but the strongest association was with a chromosome 6p marker adjacent to the HLA region (Ebers GC, et al. A full genome search in multiple sclerosis. Nat Genet 1996;13:472-476). These combined results support the concept that multiple potential genetic factors determine heritable susceptibility.
In a recent analysis of unrelated Caucasian and Asian MS patients, Barcellos et al found that, in addition to recognized HLA DR2 haplotypes, there were additional chromosome 19q13.2 single-locus and multi-locus haplotype associations near the apolipoprotein gene family. A more specific identification of the more than 60 genes mapped to this area has not yet been possible.
Two reviews by Hogancamp et al and Compston summarizing work on other candidate genes (e.g., the T-cell receptor, myelin basic protein, immunoglobulin, and tumor necrosis factor) indicate that inconsistent results have been obtained for gene polymorphisms in these areas.
COMMENTARY
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, presumably of autoimmune etiology, with probable environmental/ infectious triggers. Longstanding attempts have been made to demonstrate specific immunogenetic contributions in MS. However, even generally accepted HLA susceptibility loci are neither sufficient nor necessary for the development of MS.
Epidemiologic studies have long recognized the genetic component in MS with a 20- to 40-fold increased risk of acquiring the disease in first-degree relatives of persons affected with MS. Disease concordance between monozygotic twins is 25-30%, compared to 3-5% for dizygotic twins, indicating strong genetic factors of susceptibility. In addition to previously recognized MHC HLA class II alleles DR2 and DQ6 on chromosome 6p, more recent genomic screening analysis of MS family pedigrees has suggested multiple gene loci contributing to the disease with linkage to regions on chromosomes 5p and 7q. Other investigators have shown chromosome 19 single and multi-locus haplotype associations with MS, in the apolipoprotein alleles. However, the exact genes conferring susceptibility in what appears to be a complex polygenic disorder remain to be specifically identified. If that becomes possible, then the precise genetic mechanisms controlling this complicated disease process may be therapeutically approached. ba
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