Researchers at Karolinska Institutet in Sweden have discovered a new mechanism of a major risk gene for multiple sclerosis that triggers disease through so-called epigenetic regulation. They also found a protective genetic variant that reduces the risk for MS through the same mechanism. The authors said the results open new avenues for potential alternative treatments based on specific epigenetic modulation, i.e. to prevent gene expression artificially.

More than 40 years ago it was discovered that genetic variation in the so-called HLA region is the strongest risk factor for developing disease. HLA encodes molecules that are involved in the immune system. By using molecular analyses and combining several studies, including about 14,000 patients with MS and a control group of more than 170,000 healthy individuals, researchers at Karolinska Institutet found that people with the major risk variant HLA-DRB1*15:01 have an increased expression of the HLA-DRB1 gene, thus increasing the risk for the disease. 

The researchers further discovered a so-called epigenetic regulation of HLA expression as the mechanism mediating this effect. A HLA gene variant, rs9267649, reduces the risk of developing MS. This protective variant decreases the HLA-DRB1 gene expression – through the same epigenetic regulation mechanism – thus reducing the risk for MS. 

The study is published in Nature Communications.