Study: Epigenetic Mechanism May Trigger Multiple Sclerosis

A newly discovered mechanism may provide insight into a major risk gene for multiple sclerosis (MS) that triggers the disease through epigenetic regulation, according to a study published in Nature Communications. The research also revealed a protective genetic variant that reduces the risk for MS.
 
The human leukocyte antigen (HLA), which encodes molecules that are involved in the immune system, is known to be a genetic risk factor for MS. However, little is understood about the underlying causal variants and their molecular mechanisms.
 
For the study, the researchers used molecular analyses and conducted a meta-analysis, including approximately 14,000 patients with MS and a control group of more than 170,000 healthy individuals. From their analysis, the researchers found that individuals with the major risk variant HLA-DRB1*15:01 had an increased expression of the HLA-DRB1 gene, which increased the risk for the disease. Furthermore, they discovered that epigenetic regulation of HLA expressions mediated this effect.
 
Additionally, the researchers found a new HLA gene variant, called rs9267649, which reduces the risk of developing MS by decreasing the HLA-DRB1 gene expression through the same epigenetic regulation mechanism.
 
“We show for the first time that epigenetic mechanisms can cause the disease,” Maja Jagodic, PhD, study author, said in a press release. “In addition, we can connect this mechanism to the genetic variant with the strongest risk for developing MS.”
 
According to the researchers, the findings suggest a role for DNA methylation in the pathogenesis of MS and indicate alternative therapeutic strategies based on modulating HLA-DRB1 levels.
 
Because all autoimmune diseases are associated with HLA, the study’s findings have implications beyond MS, and may apply to other autoimmune conditions as well, according to the authors.
 
References
 
Kular L, Liu Y, Jagodic M. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications. 2018. https://www.nature.com/articles/s41467-018-04732-5
 
Mechanism controlling multiple sclerosis risk identified [news release]. Karolinska Institutet’s website. https://ki.se/en/news/mechanism-controlling-multiple-sclerosis-risk-identified. Accessed June 20, 2018. 


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