While an individual’s DNA sequence remains the same throughout their life, expression of the encoded genes may change over time and contribute to disease development in genetically predisposed individuals. Researchers at the Karolinska Institute have discovered the mechanism of a major risk gene for multiple sclerosis (MS) that triggers disease through epigenetic regulation. They have also found a protective genetic variant that reduces the risk for MS through the same mechanism.1
MS is a chronic inflammatory disease of the central nervous system that affects people at a relatively young age. First symptoms generally appear in individuals aged 20 through 40 years and include depression, dizziness, fatigue, numbness in the arms and legs, and visual impairment. The cause of these symptoms is inflammation in the brain and the spinal cord that breaks down the myelin sheath protecting the nerves, thus damaging the axons. There is currently no cure for MS, but medication can often halt the disease activity.
Over 40 years ago, researchers discovered the strongest risk factor for developing MS is a genetic variation in the so-called HLA region, which encodes molecules associated with the immune system. However, the specific genes and molecular mechanisms behind the development of the disease were not fully established.
Through molecular analyses and meta-analysis—including approximately 14,000 patients with MS and a control group of more than 170,000 healthy individuals—researchers at the Karolinska Institute found that people with the major risk variant HLA-DRB1*15:01 have increased expression of the HLA-DRB1 gene and therefore increased risk for developing the disease. The researchers further discovered epigenetic regulation of HLA expression as the mechanism mediating this effect.
“We show for the first time that epigenetic mechanisms can cause the disease,” says Maja Jagodic, researcher in the department of clinical neuroscience at the Karolinska Institute and one of the authors. “In addition, we can connect this mechanism to the genetic variant with the strongest risk for developing MS.”
The researchers also discovered a new HLA gene variant, rs9267649, which reduces the risk of developing MS. This protective variant decreases expression of the HLA-DRB1 gene through the same epigenetic regulation mechanism, and therefore reduces the risk for MS. The results suggest potential for alternative treatments based on specific epigenetic modulation, such as the artificial prevention of gene expression, which is hopeful for people with MS and other autoimmune diseases.
“Almost all autoimmune diseases are associated with HLA,” says Lara Kular, researcher in the department of clinical neuroscience at the Karolinska Institute and coauthor of the study.
- 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; doi: 1038/s41467-018-04732-5.