MS Accelerator: discovering the genetic variant driving the rapid progression of multiple sclerosis

A comprehensive study involving 22,000 multiple sclerosis patients has identified a genetic variant that accelerates disease progression. This breakthrough, achieved by researchers at Yale and the International MS Genetics Consortium, found that patients with two copies of the variant, close to the DYSF and ZNF638 genes, experienced faster disease progression. This discovery opens new avenues for the development of treatments to slow the progression of MS.

In a first-of-its-kind breakthrough, a study involving more than 22,000 multiple sclerosis patients has identified a genetic variant that accelerates disease progression.

A study of more than 22,000 people with multiple sclerosis (MS) has identified for the first time a genetic variant associated with faster disease progression, an accumulation of disability that can deprive patients of their mobility and independence over time.

Multiple sclerosis begins as an autoimmune disease in which the immune system attacks the brain and spinal cord, causing flare-ups of symptoms, called relapses, as well as a long-term degeneration known as progression. Despite the development of effective treatments for inflammatory autoimmune disease, none can prevent the increase in disability during the neurodegenerative phase of the disease.

The new study, which includes researchers from Yale and was published in Nature on June 28, is the first to identify a genetic variant that increases disease severity, an advance the authors say offers a critical step towards understanding and ultimately combating this progressive form of MS.

Although we have identified genetic variants that are predominantly immune-related associated with the risk of developing MS, this is the first study to identify neuronal genetic variants associated with the neurodegenerative aspects of the disease, said Dr. David Hafler, William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology at Yale School of Medicine, chair of the Department of Neurology, and study author.

The work was the result of a large international collaboration of the International MS Genetics Consortium (IMSGC), which includes more than 70 institutions from around the world. Hafler is co-founder of the IMSGC.

Previous studies have shown that the susceptibility or risk of MS stems largely from immune system dysfunction. Some of these dysfunctions can be treated, slowing the progression of the disease.

But these risk factors don’t explain why, 10 years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons, said Sergio Baranzini, a professor of neurology at the University of California, San Francisco (UCSF). ) and co-senior author. of study.

For the first part of the new study, the researchers combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), a research approach that uses statistics to carefully link genetic variants to traits details. 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 7 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.

They found that MS patients with two copies of the gene variant, located near two genes that help repair damaged cells and one that helps control viral infection, experienced faster disease progression. The position of the variant suggests a possible mechanism of accelerated progression.

Inheriting this genetic variant from both parents accelerates the need for a walking aid by nearly four years, Baranzini said.

These genes are normally active within the brain and spinal cord, rather than the immune system, said Adil Harroud, assistant professor of neurology at the Montreal Neurological Institute and lead author of the study. 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 significant clues to addressing the nervous system component of MS.

To confirm their findings, the scientists studied the genetics of nearly 10,000 other MS patients. Again, they found that those with two copies of the variant disabled faster.

This gives us a new opportunity to develop new medicines that can help preserve the health of everyone with MS, Harroud said.

For more on this study, see Genetic Breakthrough: What Makes Multiple Sclerosis Worse.

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

This work was supported in part by funding from the National Institute of Neurological Disorders and Stroke (part of the National Institute of Health), the European Union’s Horizon 2020 research and innovation funding programme, and the Multiple Sclerosis Society of Canada.

Hafler is a Yale Cancer Center Fellow in the Yale Cancer Immunology Research Program.