Multiple sclerosis (MS): microglia cells damage the myelin sheath of neuron axons.
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Scientists at the University of Exeter and at King’s College London report that a novel genetic risk tool may help prevent young people from going blind and predict patients who will progress to multiple sclerosis (MS) earlier.

The findings published in Nature Communications have shown for the first time that combining genetic risk for MS with demographic factors significantly improves MS risk prediction in people presenting with the eye disorder, which is called optic neuritis (ON).

“As a doctor caring for many patients with optic neuritis, I’m excited by the possibility of translating this pilot research into front line clinical care in the near future,” said Tasanee Braithwaite, MD, consultant ophthalmologist to the Medical Eye Unit at Guy’s and St Thomas NHS Foundation Trust, and adjunct senior lecturer at King’s College London. “Whilst more research is needed, our study provides a strong signal that we could better identify patients at high risk of MS, perhaps enabling these people to have earlier MS treatment in the future. Whereas, if we could better identify people whose optic neuritis is very unlikely to result from MS, we could treat these people urgently to reduce irreversible vision loss and blindness.”

Braithwaite is senior author of the team’s published paper in which they concluded, “This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.”

Optic neuritis (ON) is a condition that affects people of all ages, but especially young adults, usually manifesting in blurred vision and sometimes pain when moving the eyes. “It is a rare but treatable cause of blindness,” the authors wrote. Up to half of people affected in the U.K. eventually go on to develop MS, often many years later. “Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS),” the researchers continued. Emerging evidence indicates that starting the very effective MS treatments earlier may improve long term health.

Optic neuritis occurs because of swelling in or around the optic nerve. For those individuals with MS-related optic neuritis, the swelling subsides on its own, and vision usually recovers. “In MS-ON, vision usually recovers spontaneously to near-baseline over three months,” the team noted. For many people whose optic neuritis does not result from MS, the optic nerve can be permanently damaged unless high doses of steroids are given quickly, resulting in loss of sight.  “… non-MS ON often requires urgent immunosuppression to preserve vision.”

For their reported study the team analyzed more than 300 common genetic variants linked to developing MS, combining them into a genetic risk score (GRS) that helps clinicians understand an individual’s chance of developing MS. They analyzed data from 500,000 people in the UK Biobank, who shared genetic samples, questionnaires and linked health information from their electronic medical records.

The researchers identified 2,369 UK biobank participants who had MS, and 687 individuals with optic neuritis. Of those, 545 had no identifiable cause for their optic neuritis at the start of the study, and 124 went on to develop MS. Applying the genetic risk score effectively helped separate those individuals at lowest risk from those at high risk, when combined with demographic data. “Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON,” they wrote. “This pioneering investigation establishes a link between an individual’s combined genetic susceptibility, as measured by the MS-GRS encompassing numerous MS-associated loci with common alleles, and the subsequent risk of MS development in those experiencing an initial episode of undifferentiated ON.”

And although the team points out that the MS genetic risk score is not a diagnostic test, their results highlights that it could add one valuable additional piece of information to support doctors and patients to make better decisions. Importantly, the researchers validated their model across two independent cohorts from the U.S. and Finland. “Moreover, we unveil a stratification paradigm for individuals with undifferentiated ON, integrating the MS-GRS, age at ON onset, and sex, which delineates cohorts characterised by varying future MS risks: low (3.6%), intermediate (14.7%), higher (31.6%), and highest (41.2%).”

Co-author Richard Oram, PhD, associate professor at the University of Exeter Medical School, said, “Since the first genome was sequenced three decades ago, we’ve been working towards the promise of being able to use genetics to improve outcomes for individual patients. This research is an excellent example of precision genetic diagnosis in practice.” AS the authors added, “While it has been long-established that ON may be the first presentation of MS, the additional risk stratification outlined in this study could valuably aid management of ON, and greater international consensus on this, in the time-critical window before neuroimaging and serum and cerebrospinal fluid investigations are available.”

The research stemmed from a summer project led by University of Exeter Medicine student, first named author Pavel Loginovič. With funding from the University of Exeter, it expanded into a research collaboration involving academics in Finland and the U.S. Pavel said: “I’m elated to see this paper published, and it’s gratifying that it could have a real impact in moving research forward, ultimately aiming to get people with MS diagnosed and perhaps treated earlier. Leading this analysis while staying on top of my medical studies has been a challenge and an immense opportunity for growth, professional and personal. I’ve enjoyed the academic journey so far, and I’m excited for what’s to come.”

The study demonstrates how using genetic scores could be a useful way to predict who will likely continue to an MS diagnosis. “Using immunotherapies in people at high risk of MS could significantly delay the onset of the condition, but these drugs come with side effects. This exciting study opens up the possibility of finding people in which the benefits will outweigh the risks,” concluded the researchers.

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