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Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause is unknown, but detailed epidemiological and genetic studies have shown a clear inherited component. We review here some of the recent findings of MS genetics with a particular focus on genes of the major histocompatibility complex (MHC).Recent studies add further complexity to the role of the MHC in MS. Reported MHC associations are complex, involving haplotypes rather than single alleles and may involve epigenetic mechanisms and other modulators of gene expression. MHC class II haplotypes display a hierarchy of risks, including protective effects and epistatic interactions, which together dwarf any non-MHC genetic effect. Genes in the MHC region have been shown to influence disease severity, display parent-of-origin effects and interact with a major environmental candidate for MS, vitamin D.The MHC class II association with MS is not as straightforward as previously thought. A complete understanding of the epistatic interactions and epigenetic features of this region will be important to understand disease pathogenesis and likely aid the discovery of new therapeutics.