A recent breakthrough in genetics has shed light on the varying effects of multiple sclerosis (MS) on individuals. Scientists have now pinpointed a genetic variation that appears to correlate with a quicker progression of symptoms in those with MS, potentially leading to a swifter decline in mobility and independence.
In a groundbreaking study published in the journal Nature on June 28, an international team of researchers examined over 22,000 individuals with MS. Their findings revealed the presence of a genetic variant situated between two previously unassociated genes, DYSF and ZNF638, marking the first instance of such a genetic marker being linked to the prediction of accelerated symptom progression in MS patients.
“We studied millions of DNA variants across the genome [of people with MS],” said Sergio E. Baranzini, PhD. He is a distinguished professor of neurology at the University of California in San Francisco as well as the co-senior author of the study.
“After rigorous statistical controls and independent replication, we identified one that is more frequent in persons with more severe MS,” he also said.
While neither of the implicated genes has been directly associated with multiple sclerosis (MS), the researchers have observed that DYSF plays a role in cell repair, and ZNF638 contributes to the body’s defense against viral infections. Given that MS results from an erroneous immune system attack on cells in the brain and spinal cord, leading to nerve and muscle damage, it is logical to consider their involvement in the progression of symptoms.
Furthermore, the genetic variant’s proximity to DYSF and ZNF638 suggests that they could potentially serve as therapeutic targets for addressing the central nervous system (CNS) component of this condition, as proposed by the researchers.
Dr. Baranzini and his team specifically found that individuals with MS who inherit both copies of this genetic variant (one from each parent) experience Expanded Disability Status Scale (EDSS) scores of 6 or higher nearly four years earlier than those who do not inherit both copies.
The EDSS is a neurological test that is often utilized for measuring disability in MS, and a score of 6 means that “intermittent or unilateral (one-sided) constant assistance (cane, crutch, brace) [is] required to walk about 100 meters with or without resting.”
Genes That Predict MS Risk Against Those that Predict Outcome
“This is a very substantial effect for a single genetic variant,” Baranzini elaborated. “Furthermore, this variant affects genes that are active in the CNS, a clear contrast to variants that confer risk, which overwhelmingly affect the immune system.”
“Previous studies have identified genetic factors that determine the risk for developing MS, most of which were related to immune function, [but] this study shows that different genetic factors determine disease outcome, namely factors that affect the nervous system’s ability to compensate for damage,” Jeffrey Cohen, MD, said. He is a neurologist and director of the Cleveland Clinic’s Mellen Center for MS Treatment.
“These genetic factors could be used to predict outcome — or prognosis — to help determine how aggressive disease therapy needs to be,” Dr. Cohen added, He, however, wasn’t part of the Nature study.
Gene Discovery – Its Implications for MS Therapies
Baranzini and his team emphasize the importance of this discovery due to the limitations of current treatments for relapsing-remitting MS. Presently, available therapies, specifically immune system modulators, or immunomodulators, can merely slow down the progression of the disease and are incapable of halting its long-term symptom deterioration.
Furthermore, this genetic variant may shed light on the varying rates of progression experienced by individuals with the condition. As Baranzini explains, some patients may require a wheelchair within a decade of diagnosis, while others are able to maintain their ability to walk unassisted.
Based on their findings, “the genetics of disease severity now suggest that the CNS should be the target of [any] new class of therapeutics,” he says. “Development of therapies carries a big risk for the pharmaceutical industry, where only a small percentage of drugs make it to the market. [However], genetic information significantly de-risks drug development.”
Wide International Collaboration
The Nature study represented a collaborative effort between researchers associated with two prominent consortia: the International Multiple Sclerosis Genetics Consortium and The MultipleMS Consortium. This extensive collaboration encompassed over 70 institutions spanning the globe. Leading the research were Baranzini and his fellow researchers from the University of California, San Francisco (UCSF), in conjunction with neuroscientists hailing from the University of Cambridge in England.
The research team amalgamated data from a cohort exceeding 12,000 individuals diagnosed with Multiple Sclerosis (MS) for a comprehensive genome-wide association study. This rigorous statistical approach facilitated the precise linkage of genetic variations to specific traits. Moreover, they meticulously recorded the duration it took for each study participant to progress from their initial diagnosis to the onset of disability, as quantified by the Expanded Disability Status Scale (EDSS).
To bolster the credibility of their discoveries, the team scrutinized the genetic data of an additional group of nearly 10,000 individuals diagnosed with MS.
Environmental Factors and Its Roles
The researchers employed Mendelian randomization, a statistical approach, to evaluate the role of environmental factors in the progression of multiple sclerosis (MS). Their analysis revealed that higher levels of education and older parental age were associated with decreased MS severity, whereas smoking was linked to an increased severity of the condition.
“The study shows that other factors that affect brain resilience — like education, exercise, diet, smoking — also affect [progression],” Cohen said. “These are things that can be addressed now,” through lifestyle modifications as part of the plan for MS.
More Work to Be Done
However, the researchers emphasize that the work is far from finished. They plan to conduct additional studies to investigate the impact of the recently discovered genetic variant on DYSF, ZNF638, and the central nervous system (CNS). Furthermore, the team is actively gathering DNA samples from individuals with multiple sclerosis (MS) in order to identify additional variants that play a role in long-term disability associated with MS.
“The statistical results of this study are conclusive, and we are confident that this association is real,” Baranzini said. “However, translating this discovery into clinical practice depends on many additional factors that need to be considered by medical providers.”
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