The Mystery of MS Severity: After sifting through more than seven million genetic variants, scientists have found the one that determines the course of MS progression.
A groundbreaking investigation involving over 22,000 individuals diagnosed with multiple sclerosis (MS) has successfully uncovered the first genetic mutation linked to an accelerated progression of the disease, a debilitating condition that gradually robs patients of their mobility and independence.
MS arises when the immune system mistakenly launches attacks on the brain and spinal cord, resulting in intermittent symptom outbreaks known as relapses, as well as long-term degeneration referred to as progression. Despite the existence of effective treatments for relapses, including some pioneered at the University of Cambridge, none have been consistently able to halt the accumulation of disability.
Today, the scientific community celebrates a significant breakthrough as the findings of a multinational collaboration of researchers are published in the esteemed journal Nature. This study reveals a genetic variant that intensifies the severity of MS, marking the first substantial advancement in comprehending and, ultimately, combatting this particular facet of the disease.
Professor Sergio Baranzini at UCSF, a co-senior author of the study, explained, “Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years.”
Professor Stephen Sawcer from the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, the other co-senior author of the study, commented, “Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression.”
Redoubling efforts to study the nervous system
The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium, two significant MS research consortia, collaborated to investigate the riddle surrounding MS severity. This made it possible for MS researchers from across the globe to combine their efforts and gather the resources required to start identifying the genetic elements impacting MS outcomes.
Previous research has shown that immune system dysfunction plays a significant role in MS susceptibility or risk, and that some of this dysfunction may be addressed to delay the onset of the illness. However, Baranzini noted that “these risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”
The data from over 12,000 persons with MS was merged by the two consortia to complete a genome-wide association study (GWAS), which employs statistics to precisely correlate genetic variations to specific features. In this case, the traits of interest were linked to how bad MS was, such as how long it took for each person to get to a certain level of inability after being diagnosed.
Scientists looked through more than seven million DNA variations and found one that was linked to a disease getting worse faster. The mutation is located between the genes DYSF and ZNF638, which had no known association with MS. The first is involved in cell repair, while the second aids in the management of viral infections. Due to the variant’s closeness to these genes, it is possible that they contribute to the development of the illness.
According to Dr. Adil Harroud, the study’s main author and a former postdoctoral researcher at the Baranzini Lab, “These genes are normally active within the brain and spinal cord, rather than the immune system.”
The findings of this study “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 research provides the first tips for treating the MS nervous system component.
The researchers also employed statistical techniques known as ‘Mendelian randomisation’ to investigate the significance of environmental impacts, finding that years of schooling and parental age lowered the severity of MS while smoking increased it. Correlation with these indirect measures of brain health highlights the significance of resilience in determining the outcome of multiple sclerosis.
This new research has “pointed us towards the key processes that underlie this resilience,” said Sawcer. “Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS,” Sawcer added.
A growing alliance to address MS severity
To make sure their results were correct, the experts looked into the genes of almost 10,000 more MS cases. Those who possessed two copies of the variant became disabled more quickly.
It will need additional investigation to pinpoint the precise effects of this genetic mutation on DYSF, ZNF638, and the nervous system as a whole. In addition, a greater number of DNA samples from MS patients are being collected by the researchers, who hope to discover other variations that contribute to MS-related long-term impairment.
According to Harroud, “This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS.”
Since the late 1980s, one of the main goals of brain study in Cambridge has been to learn more about the genes that cause multiple sclerosis. Members of the Department of Clinical Neurosciences have collaborated closely with others to identify the overwhelming majority of susceptibility-increasing gene variants.
“Having been personally involved with the identification of susceptibility genes for multiple sclerosis since the 1970s, it is a tribute to those within IMSGC who led this project that fully independent risk variants for progression have now been discovered,” said Professor Alastair Compston of the University of Cambridge and a founding member of the IMSGC.
Source: 10.1038/s41586-023-06250-x
Image Credit: Shutterstock