Genetic breakthrough: what makes multiple sclerosis worse and new pathways for better treatments

Abstract concept of multiple sclerosis

Scientists have found the first genetic variant linked to faster progression of multiple sclerosis (MS), which could lead to earlier loss of mobility. The discovery pushes the focus of MS research towards the nervous system and offers new avenues for future therapies.

Researchers identify first genetic marker for MS severity, paving the way for treatments to prevent long-term disability.

A study of more than 22,000 people with multiple sclerosis (MS) has discovered the first genetic variant associated with faster disease progression, which can deprive patients of their mobility and independence over time.

Multiple sclerosis (MS) is the result of the immune system mistakenly attacking the brain and spinal cord, causing flare-ups of symptoms known as relapses and long-term degeneration, known as progression. Despite the development of effective treatments for relapses, some of which were first introduced at the University of California, San Francisco (UCSF), none can reliably prevent the accumulation of disabilities.

The results, published today (June 28) in the journal Natureindicate a genetic variant that increases the severity of the disease, providing the first real advance in understanding and ultimately combating this aspect of MS.

Inheriting this genetic variant from both parents accelerates the time it takes for a walking aid by nearly four years, said Sergio Baranzini, PhD, a professor of neurology at UCSF and a co-senior author of the study.

The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF and the University of Cambridge.

Understanding how the variant affects MS severity will hopefully pave the way for a new generation of treatments that can prevent the disease from progressing, said Stephen Sawcer, a professor at Cambridge and the study’s other senior author. .

A renewed focus on the nervous system

To tackle the mystery of the severity of MS, two large MS research consortia have joined forces: the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium. This has enabled MS researchers around the world to pool the resources needed to begin identifying the genetic factors influencing MS outcomes.

Previous studies have shown that the susceptibility or risk of MS results largely from dysfunctions of the immune system and some of these dysfunctions can be treated, slowing down the disease. But these risk factors don’t explain why, ten years after diagnosis, some people with MS are in wheelchairs while others continue to run marathons, Baranzini said.

The two consortia combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to closely link genetic variants to particular traits. In this case, the traits of interest correlated with the severity of MS, including the years it took for each individual to go from diagnosis to a certain level of disability.

After sifting through more than seven million genetic variants, scientists have found one associated with faster disease progression. The variant lies between two genes with no previous connection to MS, called DYSF and ZNF638. The former is involved in repairing damaged cells and the latter helps control viral infections. The proximity of the variants to these genes suggests that they may be involved in disease progression.

These genes are normally active in the brain and spinal cord, rather than the immune system, said Adil Harroud, MD, lead author of the study and a former postdoctoral researcher in Baranzini’s lab. Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies.

The findings give the field its first clues to addressing the nervous system component of MS.

While it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study pointed us to the key processes that underlie this resilience, Sawcer said.

An ever-expanding coalition to address the severity of MS

To confirm their findings, the scientists studied the genetics of nearly 10,000 other MS patients. Those with two copies of the variant were disabled faster.

More work will be needed to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. Researchers are also compiling an even larger set of[{” attribute=””>DNA samples from people with MS, expecting to find other variants that contribute to long-term disability in MS.

This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS, said Harroud.

Reference: Locus for severity implicates CNS resilience in progression of multiple sclerosis by International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium, 28 June 2023, Nature.
DOI: 10.1038/s41586-023-06250-x

Authors: Adil Harroud has since moved to McGill University (Canada). Other UCSF researchers include Stephen L. Hauser, Jorge R. Oksenberg and Roland G. Henry. Additional authors can be found in the paper.

Funding: This work was supported in part by funding from the NIH/NINDS (R01NS099240), the European Unions Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.

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