Newly discovered genetic variant tied to faster MS progression

Variant affects two genes highly active in brain and spinal cord

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by Steve Bryson, PhD |

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This illustration of a DNA strand shows its hallmark double helix.

Researchers identified a genetic variant that associated with faster multiple sclerosis (MS) progression and greater brain tissue damage, according to a study that combined data on more than 12,500 patients in North America, Europe and Australia.

Unlike previously detected MS-related variants linked to the immune system, this variant sits between two genes that are highly active in the brain and spinal cord, data showed.

Known variants related to MS susceptibility “do not appear to have any association with disease severity,” the study noted.

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” Sergio Baranzini, PhD, a co-senior study author with the University of California San Francisco Weill Institute for Neurosciences, said in a University of Cambridge press release.

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Two genes affected by variant had no previous ties to MS

“Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments … to prevent disease progression,” added Stephen Sawcer, PhD, the study’s other co-senior author and a professor of neurological genetics at the U.K. university.

Details were in the study “Locus for severity implicates CNS resilience in progression of multiple sclerosis,” published in the journal Nature.

An autoimmune disorder, MS is marked by a self-reactive immune response targeting and damaging the central nervous system (CNS), or the brain and spinal cord. This results in recurrent episodes of neurological symptoms, known as relapses, and longer term neurodegeneration that manifest as disability progression.

More than 200 genetic variants that increase the risk of developing MS have been identified. Still, according to Baranzini, “these risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”

An international collaboration, involving more than 70 institutions worldwide, allowed researchers to pool resources to find genetic factors that influence MS severity.

Data were combined from two large MS consortia: The MultipleMS Consortium and The International Multiple Sclerosis Genetics Consortium (IMSGC). Altogether, 12,584 MS patients of European ancestry participated in a genome-wide association study (GWAS) to identify statistical links between genetic variants and MS severity.

Simply put, a GWAS is a type of analysis that aims to identify genetic variations that are statistically more common among people with a specific trait, which implies these variations might affect the risk of developing that trait. In this case, researchers looked for variants that were more common in MS patients with faster disease progression.

2 copies of variant tied to quicker mobility loss, greater brain lesion load

Their analysis detected one variant, called rs10191329, that was significantly associated with a faster rate of MS progression. In the genome, this change in DNA was found between two genes that are highly active in the brain and spinal cord: DYSF and ZNF638.

DYSF is involved in repairing damaged cells, while ZNF638 helps to control viral infections. Neither gene previously has been connected to MS. These findings were replicated in a further 9,805 cases.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Adil Harroud, MD, the study’s lead author and a 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.”

Long-term outcome analysis, which followed over 8,000 patients for nearly 14 years, found that carrying two copies of this variant (one from each parent) significantly shortened the time to use a walking aid by a median of 3.7 years — indicating a 22% higher risk of reaching that outcome.

Further examination of post-mortem brain and spinal cord samples from 290 individuals showed those with two copies of this variant had almost twice as many brain and brain stem lesions, “confirming that the risk allele at the DYSF-ZNF638 locus is associated with worse injury at key brain locations,” the researchers wrote.

They then searched for environmental factors that may influence MS severity through Mendelian randomization, a statistical method that uses genetic variations to find causal connections to outcomes.

No causal role was detected for vitamin D and body mass index, a measure of body fat content, and MS severity. By contrast, more years of education was associated with milder MS, while heavier smoking was linked to more severe disease; both are “potentially modifiable risk factors for MS severity,” the study noted.

“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,” Sawcer said.

Study’s ‘robust evidence’ provides ‘new directions’ for MS therapy development

Lastly, known genetic variants associated with susceptibility to MS were unrelated to eventual MS severity and progression.

“In short, we found no evidence that susceptibility variants are meaningfully associated with outcomes of the disease,” the team wrote.

“This study presents robust evidence for a role of genetic variation in MS progression … [and] new directions for functional characterization and drug development targeted on the neurodegenerative component of the disease,” the researchers concluded.

Its findings also “identify CNS resilience and reserve as probable determinants of MS progression, and may have broader implications for neurodegeneration,” they added.