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.
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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.