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Epigenetic Modulation of Key Gene Contributes To Multiple Sclerosis Risk

by Lewis Chang, PhD

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) in which the immune system attacks and damages the myelin sheaths of nerve fibers in the brain and spinal cord.1 Common symptoms include cognitive difficulties, vision problems, fatigue, pain, motor problems, bladder dysfunction, and sexual problems. However, symptoms and their severity vary greatly from patient to patient depending on the location of affected nerve fibers. What triggers MS is still unknown, but a combination of genetic susceptibility and environmental factors are likely involved.2

A known genetic risk factor of MS is in the human leukocyte antigen (HLA) gene system on chromosome 6, which encodes proteins that are important in immune functions.1 One genetic variant in this region, the HLA-DRB1*15:01 allele, confers a 3-fold increase in MS risk according to a collaborative genome-wide association study.3 However, the molecular mechanism(s) through which it contributes to MS remains unclear. Researchers at Karolinska Institutet (Stockholm, Sweden) speculated that DNA methylation—an epigenetic mechanism that causes a gene to be expressed or silenced and subsequently determines how the gene is read by cells—mediated the risk of developing MS.4

They first measured DNA methylation in monocytes (a type of immune cell) sorted from both patients with MS and healthy control subjects using advanced molecular techniques, and found that homozygous HLA-DRB1*15:01 carriers (i.e., individuals who had 2 identical copies of DRB1*15:01 allele) displayed significantly lower DNA methylation levels at HLA-DRB1 compared with heterozygous carriers (i.e., those having 1 copy of DRB1*15:01 allele) and non-carriers.4 When investigating the potential functional consequences of differential methylation levels, the researchers found that the hypo-methylated DRB1*15:01 drove higher HLA-DRB1 expression.4

During their genome-wide analysis of methylation mediation in MS case-control cohorts from Sweden, Germany, and Iceland, the investigators also discovered a genetic variant in the HLA region named rs9267649 that may be protective against the risk of developing MS through the same epigenetic mechanism.4 Together these data suggest that epigenetic regulation in certain HLA-DRB1 variants may predispose or be protective against MS. Currently there is no cure for MS. The information generated from this study will be valuable for the development of therapeutic strategies that may modulate the genetic expression of HLA-DRB1 or the downstream HLA protein levels.

Why is this Clinically Relevant?

  • This study demonstrates that changes in DNA methylation of a risk gene contribute to the development of MS.4 This information will be valuable in guiding future development of therapeutic strategies.

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References

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-952.
  2. Goldenberg MM. Multiple sclerosis review. P T. 2012;37(3):175-184.
  3. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-219.
  4. Kular L, Liu Y, Ruhrmann S, et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun. 2018;9(1):2397.

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