While the DNA sequence remains the same throughout a person’s life, the expression of the encoded genes may change with time and contribute to disease development in genetically predisposed individuals. Researchers at Karolinska Institutet in Sweden have now discovered a new mechanism of a major risk gene for multiple sclerosis (MS) 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 study is published in Nature Communications.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, affecting people at a relatively young age. Most are between 20 and 40 years old when they get the first symptoms, in the form of, for example numbness in the arms and legs, visual impairment and dizziness, but also fatigue and depression. However, MS can present at any age. The symptoms are caused by an inflammation in the brain and the spinal cord that breaks down the myelin sheath protecting the nerves, thus damaging the axons. Currently there is no cure for MS, but the disease activity can often be halted through medication.

Already over 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. However, the specific genes and molecular mechanisms behind the emergence of the disease are not fully established.

By using molecular analyses and combining several studies (so-called meta-analysis), including around 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.

More information: Lara Kular et al, DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis, Nature Communications(2018). DOI: 10.1038/s41467-018-04732-5

Provided by: Karolinska Institutet