Scientists have identified the first genetic marker for multiple sclerosis (MS) severity, a discovery that opened the door to treatments for long-term disability, said researchers.
MS results in relapses and longer-term progression. An estimated 2,500,000 people in the world have the condition, with around 130,000 people in the UK living with it, according to the MS Trust. Research had suggested the proportion of women with MS was "increasing", the Trust said, and that roughly between two and three women had MS for every man with the condition.
"Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability," pointed out the authors of a new observational study published in Nature.
To date, studies had identified "over 200" gene variants associated with susceptibility to MS, highlighted the authors, with the strongest effects coming from the major histocompatibility complex (MHC), and implicated genes being "overwhelmingly enriched for immune relevance".
Although these risk variants were associated with a reduced age at onset, it was "notable that they did not appear to have any association with disease severity", the authors pointed out.
"These risk factors don’t explain why 10 years after diagnosis, some MS patients are in wheelchairs, while others continue to run marathons," said Professor Sergio Baranzini, University of California, San Francisco (UCSF), co-senior author.
Previous research had suggested that an "independent genetic architecture" determined the clinical course of the disease. However, "published efforts to systematically interrogate severity" had, to date, involved only "modest" numbers of cases and had "unanimously" fallen short of identifying any convincingly associated genetic variants, the authors explained.
Key Gene Variant Identified
For the study, an international collaboration of more than 70 institutions from around the world, led by University of Cambridge and UCSF researchers, set out to address the "mystery" of MS severity. Through the joining of two large MS research consortia, the International Multiple Sclerosis Genetics Consortium and The MultipleMS Consortium, researchers were able to begin to identify the genetic factors that influenced MS outcomes.
To provide insight into the potential mechanisms involved in progression, the researchers combined data from 12,584 people of European ancestry with MS to complete a genome-wide association study - which uses statistics carefully to link genetic variants to particular traits. The traits of interest, they said, were related to MS severity, and included the years it took for each individual to advance from diagnosis to a certain level of disability.
After "sifting through" 7.8 million genetic variants, the researchers found one – rs10191329 – that was associated with faster disease progression. "The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638," the authors explained.
Gene Variant Accelerates Progression
They said that the first of these genes was involved in repairing damaged cells, and the second helped to control viral infections. "The variant’s proximity to these genes suggests that they may be involved in disease progression," they proposed.
They then replicated their findings in a further 9805 MS cases, and found that those with two copies of the variant became disabled faster.
"We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with shortening of the median time to requiring a walking aid by up to 3.7 years, and with increased brainstem and cortical pathology in brain tissue," highlighted the authors.
Dr Adil Harroud, UCSF, and lead author, stressed that these genes were "normally active within the brain and spinal cord", rather than the immune system. "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," he urged.
"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," said Professor Stephen Sawcer, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, and co-senior author.
The team also used Mendelian randomisation to explore the importance of environmental effects. They discovered that more years of education and higher parental age reduced the severity of MS, while smoking worsened it. "Finding correlation with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS," the authors stressed.
Opportunity to Meet Unmet Treatment Need
Further work was needed to determine exactly how this genetic variant affected DYSF, ZNF638, and the nervous system more generally, emphasised the researchers, who were also collecting a larger set of DNA samples from people with MS, with the expectation of finding other variants that contributed to long-term disability in MS.
"Our findings demonstrate that at least 13% of the variance in long-term MS severity can be attributed to common and low frequency single nucleotide variation, explaining some of the considerable variability in MS outcome," highlighted the authors. It might also partly explain why immunosuppressive therapies have thus far had "little or no effect" on disability accumulation in progressive MS trials, they pointed out.
Despite the "therapeutic revolution" in MS over the past few decades, treatment of progression in MS remained an "unmet need" the authors stressed.
They hoped that the new discovery of a genetic locus associated with disability in MS would provide "new directions for functional characterisation and drug development" targeted on the neurodegenerative component of the disease.
"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," said Professor Sawcer.
This work was supported in part by funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the European Union's Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.