What is the role of genetics in multiple sclerosis (MS)?

Updated: Oct 08, 2019
  • Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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The concordance rate for MS among monozygotic twins is only 20–35%, suggesting that genetic factors have only a modest effect. The presence of predisposing non-Mendelian factors (ie, epigenetic modification in 1 twin), along with environmental effects, plays an important role. For first-degree family members (children or siblings) of people affected with MS, the risk of developing the disorder is sevenfold higher than in the general population, but familial excess lifetime risk is only 2.5–5%. [34]

Different variants of genes normally found in the general population, commonly referred to as polymorphisms, may lead to different gradations of cellular expression of those genes and therefore of the proteins that they encode. With MS susceptibility, it may be that a polymorphism within the promoter region of a gene involved in immune reactivity generates an exaggerated response (eg, elevated expression of a proinflammatory gene) to a given antigen, leading to uncontrolled immune cell proliferation and autoimmunity.

Research on single-nucleotide polymorphisms (SNPs) that confer risk of more severe disease or of developing particular forms of MS will be of great interest to the clinicians treating this complex disorder in the early stages. To date, however, HLA-DRB1 is the only chromosomal locus that has been consistently associated with MS susceptibility. Multiple other polymorphisms that may act in concert to predispose to MS have been described with genome-wide approaches, but their individual contribution to risk is not nearly as high as the risk conferred by the HLA locus. [35]

Genes that instead of conferring susceptibility to MS confer relative protection against it are also being investigated, and clues are emerging from within the major histocompatibility complex (MHC) region. For example, it has been suggested that the HLA-C*05 allele confers protection against MS. [36]

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