New gene discovery gives hope of fighting severe MS
A new study in Nature by an international team including researchers at Karolinska Institutet has identified the first genetic variant associated with disease severity in multiple sclerosis. The finding opens the door to the development of treatments that fight disease progression – a great unmet need facing people with MS.
Multiple sclerosis (MS) is a neurological disease that usually occurs between the ages of 20 and 40 and is more common in women. In MS, the immune system mistakenly attacks the brain and spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration, known as progression. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability.
A mystery why some get seriously ill
Previous studies have identified genetic factors that increase the risk of developing MS and lead to immune system dysfunction that can be treated to some extent, slowing down the disease. But these risk factors don’t explain the large variance in disease severity.
The new genome-wide association study, led by researchers from UCSF (USA), the University of Cambridge (UK), and Karolinska Institutet (Sweden), points to a genetic variant that increases disease severity. Inheriting this genetic variant from both parents accelerated the time to needing a walking aid by almost four years.
“This is a breakthrough finding because it provides the first real progress in understanding long-term disability in MS, where patients gradually lose their mobility and independence,” says Ingrid Kockum, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and principal investigator for the European part of the study. “This gives us an opportunity to develop new treatments to control progression, which is urgently needed by so many people suffering from MS.”
The variant sits between two genes called DYSF and ZNF638 with no prior connection to MS. These are normally active in the central nervous system and involved in repairing damaged cells and controlling viral infections, respectively.
Brain resilience play a key role
“The gene variant that causes more severe MS thus appears to influence mechanisms in the brain and spinal cord, unlike genes that increase the risk of developing MS, where the immune system is central,” says Pernilla Stridh, researcher in the Kockum Lab at Karolinska Institutet and coauthor of the paper. “This implies that controlling progression might require neuroprotective agents in addition to the current anti-inflammatory standard treatments.”
The researchers also found that high education was related to slower disease progression, supporting the idea that neurocognitive reserve and brain resilience play a key role in MS severity.
The work was the result of a large international collaboration of more than 70 institutions from around the world, where two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium.
Swedish data of great importance
The study included more than 22,000 people with multiple sclerosis, many of which were recruited in Sweden through the National MS studies GEMS, EIMS, IMSE, and COMBAT-MS that are coordinated at Karolinska Institutet.
“One of the strengths of these studies is that they can be combined with the Swedish MS registry which contains unique data gathered by neurologists throughout Sweden,” explains Dr Stridh. “This has been crucial to being able to track disease severity over time.”
This work was supported in part by funding from EU’s Horizon 2020 (MultipleMS project, coordinated by Ingrid Kockum, Karolinska Institutet), National Institutes of Health (International Multiple Sclerosis Genetics Consortium), the National Multiple Sclerosis Society, MS Canada, deCODE Genetics/Amgen, the Swedish Research Council, Margaretha af Ugglas foundation, and the Swedish Brain Foundation. Some of the authors have received fees/funding from pharmaceutical companies, see the scientific paper for a complete list of competing interests.
“Locus for severity implicates CNS resilience in progression of multiple sclerosis”, International Multiple Sclerosis Genetics Consortium, MultipleMS Consortium (see the paper for a complete list of authors), Nature, online 28 June 2023, doi: 10.1038/s41586-023-06250-x.
Research Briefings (summary of the findings): “Insights into the genetic architecture of multiple sclerosis severity”, Ashley Harris Beecham, Pernilla Stridh, Nature, online 28 June 2023.