First genetic marker for severity and progression of multiple sclerosis identified

A genome-wide association study (GWAS) of more than 22,000 multiple sclerosis (MS) patients has revealed the first genetic variants associated with accelerated autoimmune disease progression. Autoimmune diseases can deprive patients of mobility and independence over time. A newly reported study by an international collaboration of researchers from the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium reports genetic variants that increase disease severity, suggesting that this aspect of MS may The first real progress has been made in understanding and ultimately in fighting it. . This finding gives the field the first clue to addressing the neurological component of MS.

“Inheriting this genetic mutation from both parents shortens the time to needing a walking aid by almost four years,” said Dr. Sergio Baranzini of UCSF. Dr Stephen Saucer FRCP, University of Cambridge and Cambridge University Hospitals NHS Foundation, said: “Understanding how variants affect the severity of MS could pave the way for a new generation of therapies that can prevent disease progression. is expected to open,” he added. trust. Baranzini and Sawcer are co-senior authors on papers published by the team. Naturetitled “Severity trajectories are associated with CNS resilience in multiple sclerosis progressionThe research team concludes in their paper: “To our knowledge, this GWAS, involving more than 22,000 MS patients, identifies the first factor that significantly alters long-term MS outcomes on a genome-wide scale, thereby identifying valuable potential.” Target. “

Multiple sclerosis is an autoimmune disease of the central nervous system that affects more than 2.8 million people worldwide, the authors write. The disorder results from a mistaken attack of the immune system on the brain and spinal cord, resulting in recurrent episodes of largely reversible neurological dysfunction known as relapses and long-term neurodegeneration known as progressions. increase. “The relative impact of these nearly independent features varies between patients and during an individual’s disease course,” the researchers continued.

Effective treatments for relapses have been developed, some of which were pioneered at the University of Cambridge, but do not reliably prevent the accumulation of disability. The authors conclude: “Over the past decades, the introduction of various immunotherapies has altered the ability to control the relapsing activity of the disease, making therapies that can control progression the greatest unmet clinical need today.” There is.”

The newly reported research is the result of a large international collaboration led by researchers from UCSF and the University of Cambridge, involving more than 70 institutions around the world. This collaboration allowed researchers to pool the resources they needed to begin identifying genetic factors that influence her MS outcome.

Previous research has shown that MS susceptibility, or risk, is primarily due to immune system dysfunction, and that some of this dysfunction can be treated to slow disease progression. “It is noteworthy, however, that although these risk variants are associated with a 5-year lower age of onset, they appear to have no association with disease severity,” the researchers said. “These risk factors cannot explain why some people with MS remain in wheelchairs ten years after diagnosis, while others continue to run marathons,” Barangini said.

For the GWAS, the two consortia will first integrate data from more than 12,000 MS patients, mapping genetic variation, such as the number of years it took for each individual to progress from diagnosis to a specific level, to identify specific phenotypes associated with MS severity. We used statistics that tie to traits. hindrance. After sifting through over 7 million genetic variants, scientists identified one known as rs10191329, associated with accelerating disease progression.

This variant is located between two genes (DYSF and ZNF638) that are not associated with MS. DYSF is involved in repairing damaged cells and ZNF638 helps control viral infections. The proximity of the newly identified variants to these genes suggests that they may be involved in disease progression. “We identified a significant association with rs10191329 at the DYSF-ZNF638 locus. It “resides in brain tissue,” the scientists noted, associated with increased pathology in the brainstem and cortex.

“These genes are normally active in the brain and spinal cord, not in the immune system,” said lead author Dr. Adil Haroud, a former postdoctoral fellow in the Baranzini lab. “Our findings show that resilience and repair of the nervous system determine the course of MS progression, and that we need to focus on these parts of human biology for better treatments. suggesting.”

The research team applied a statistical technique known as Mendelian randomization to investigate the importance of environmental influences and found that years of education and parental age reduced the severity of MS, while smoking exacerbated the severity of MS. I also found that it does. “Together, these results suggest an adverse effect of smoking in MS patients and suggest that educational attainment is a potential protective factor,” the researchers wrote. The finding of correlations with these indirect measures of brain health further underscores the importance of resilience in determining MS outcome.

“It’s clear that the brain’s resilience to injury determines the severity of diseases like MS, but this new study shows us the key processes underlying this resilience,” said Saucer. the professor said. To confirm their findings, the scientists also examined the genetics of nearly 10,000 of her MS patients. They found that people with two copies of the mutant became disabled more quickly.

Further research is needed to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. Researchers are also collecting a larger set of DNA samples from MS patients in hopes of discovering other mutations that contribute to long-term disability in MS. “This opens up new opportunities for us to develop new drugs that may help keep everyone who suffers from MS healthy,” Harraud said.

The study of the genetics of multiple sclerosis has been a major subject of neurological research at Cambridge since the late 1980s. Members of the Clinical Neuroscience Division, along with others, have been closely involved in the discovery of most of the susceptibility-enhancing genetic variants.

Alastair Comston, Ph.D., FRCP, MBBS, University of Cambridge, IMSGC Founding Member, added: A completely independent progression risk variant has now been discovered. This study once again demonstrates the benefits of international collaboration to advance our understanding of disease mechanisms in multiple sclerosis and other medical conditions. “

While pointing out the limitations of the study, the authors state: “In conclusion, this study provides robust evidence for the role of genetic variation in the progression of MS…We have identified genetic loci associated with MS disorders, providing new directions for functional characterization and drug development.” Targeting the neurodegenerative component of the disease that “provided sexuality”… Our findings identify that resilience and reserve of the central nervous system may be determinants of MS progression, suggesting that neurological May have broader impact on degeneration. “