#ECTRIMS2022 – Genetic Variants Tied to Worse MS ID’d in New Study

Genetic variants in genes mostly active in the brain and spinal cord — the central nervous system — are associated with the severity of multiple sclerosis (MS), and linked to a faster accrual of disability and greater signs of brain tissue damage, a new study found.

Importantly, researchers estimated that nearly 13% of the variability in MS severity might ultimately be attributed to genetics.

“With this study, we are now in a position to provide evidence … to prioritize or de-prioritize candidate drugs for people with MS and for progression,” Adil Harroud, MD, a physician at the McGill University Health Center, said in an oral presentation at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“It’s been shown that drug targets with genetic evidence are twice as likely to reach regulatory approval,” said Harroud, who participated in the research as a clinical fellow at the University of California San Francisco Weill Institute for Neurosciences.

The presentation, titled “Genetic analysis of multiple sclerosis severity identifies a novel locus and implicates CNS resilience as a major determinant of outcome,” was given at ECTRIMS, held Oct. 26–28, in Amsterdam and virtually.

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Investigating genetic variants in MS

Despite decades of research, the environmental and genetic underpinnings of disease severity among MS patients remain poorly understood. While more than 200 genetic variants have been identified as increasing the risk of MS development, information on other factors that may influence disease severity is lacking.

“We know a fair bit about MS susceptibility” but “relatively little about what determines disease outcome, and what contribution genetics may have, if any,” Harroud said.

To identify such factors, Harroud and colleagues evaluated genetic sequencing data from a large group of people with MS. The 12,584 patients were followed across 21 clinical centers in North America, Europe, and Australia.

These patients were mostly women (71.7%), had a mean age of 51.7 years, and a mean disease duration of 18.2 years. Most (84.5%) had relapsing forms of MS.

Of 7.8 million evaluated genetic variants, a novel variant called rs10191329 was significantly associated with a greater age-related disease severity. Eleven others also were deemed of interest.

In a separate group of 9,805 patients, this relationship was replicated for that variant as well as for another of the variants of interest, this one known as rs149097173. Neither of these two variants had ever been linked to MS risk.

The team then investigated whether the presence of these two variants impacted long-term disease outcomes. This analysis was conducted in a subset of 8,325 patients who were followed for up to 14 years, with more than 54,000 clinic visits.

Overall, the researchers found that patients with two copies of the lead severity variant, rs10191329, tended to accrue disability significantly faster than patients without the variant. These patients also experienced 24-week confirmed disability worsening sooner.

The individuals with rs10191329 also required the use of an aid for walking short distances about 3.7 years earlier than those without the variant.

Similar associations also were observed for the second variant, rs149097173, with patients carrying at least one copy of this variant needing a walking aid 2.2 years earlier than those without.

In an analysis of autopsy brain tissue from 290 MS patients, the lead variant was linked to an almost twofold higher rate of demyelination — the loss of myelin, the protective substance surrounding nerve cells that is progressively lost in MS. They also had about twice as many lesions, or areas damaged by immune system attacks, in specific regions of the brain.

According to the researchers, both of these variants occur in genes specifically produced in oligodendrocytes, the cells that produce myelin in the brain and spinal cord.

Based on all the variants identified, the team believes that about 12.8% of variability in MS severity might be explained by genetic factors.

Additional analyses revealed little overlap between MS susceptibility and potential severity genes.

Specifically, genes that may contribute to the risk of developing MS were found largely in immune tissues, while genes likely to contribute to MS severity resided exclusively in the central nervous system (CNS), which is comprised of the brain and spinal cord.

Harroud also noted that higher levels of education are associated with a protective effect in terms of disease severity. This is “consistent with a role for neurocognitive reserve in determining outcomes,” he said.

“While MS arises from a fault in the immune system, it is resilience in the CNS as the target tissue that determines whether someone does well or poorly,” Harroud concluded.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ECTRIMS Forum 2022 Oct. 26-28. Go here to see the latest stories from the conference.