July 5, 2023: Researchers found a genetic variant that increases the severity of multiple sclerosis (MS) and may pave the way for a new generation of treatments to prevent disease degeneration.
An international collaboration of more than 70 global institutions led by researchers from the University of California, San Francisco and the University of Cambridge revealed that the new variant sits between two genes, DYSF, and ZNF638.
The first gene is involved in repairing damaged cells, and the second helps to control viral infections. The variant’s proximity of these genes suggests that they may be involved in disease progression.
“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Dr Adil Harroud, lead author and former postdoctoral researcher in the Baranzini 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 variant’s proximity to the two genes suggests that they may be involved in disease progression.
The findings gave first leads to address the nervous system component of MS.
Multiple sclerosis is the most common disabling neurological disease of young adults with symptom onset generally occurring between the ages of 20 years and 40 years.
The immune system cells that normally protect us from viruses, bacteria, and unhealthy cells mistakenly attack myelin in the central nervous system — brain, optic nerves, and spinal cord.
Myelin is a substance that makes up the protective sheath that coats nerve fibers.
Disability over time
The disease affects people differently. A small number of people with MS will have a mild course with little to no disability, whereas others will have a steadily worsening disease that leads to increased disability over time.
Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability.
The newly discovered genetic variant, which increases disease severity, provides the first real progress in understanding and eventually fighting this aspect of MS.
“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Professor Sergio Baranzini at UCSF, co-senior author of the study.
“Understanding how the variant exerts its effects on the MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression,” said Professor Stephen Sawcer from the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, the other co-senior author.
Wheelchair to marathons
The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium joined hands in the study.
Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease.
“These risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons,” said Prof Baranzini.
The two consortia combined data from over 12,000 people with MS to complete a genome-wide association study, which uses statistics to carefully link genetic variants to particular traits.
The traits of interest were related to MS severity, including the years it took for each individual to advance diagnosis to a certain level of disability.
After sifting through more than seven million genetic variants, the scientists found one that was associated with faster progression.
The team also used statistical methods known as ‘Mendelian randomization’ to explore the importance of environmental effects and found that years of education and parental age reduced the severity of MS while smoking worsens it.
10,000 additional patients
Finding a correlation with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS, according to the study.
“Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Prof Sawcer said.
To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.
The researchers stated that additional work would be needed to determine exactly how the new genetic variant affects the two genes, and the nervous system more generally.
The researchers are also collecting an even larger set of 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 Dr Harroud.