Higher Genetic Risk for MS Linked to Disease Onset at Younger Ages

People with a higher genetic risk for multiple sclerosis (MS) are significantly more likely to develop the disease at an earlier age, a large study found.

Specifically, those with the highest genetic risk were on average five years younger at the time their symptoms started than those with the lowest genetic risk, suggesting that genetic testing could help to identify patients who might benefit from early treatment.

“The earlier the treatment is started for MS, the less disease burden a patient will have and the better their quality of life will be,” Mary Davis, PhD, a professor at the Brigham Young University’s College of Life Sciences and a study author, said in a press release.

“Prevention is key. If we can find out how many genetic variants [DNA mutations] a person has for potential onset, we can get them quicker treatment,” Davis added.

The study, “A higher burden of multiple sclerosis genetic risk confers an earlier onset,” was published in the Multiple Sclerosis Journal.

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July 22, 2021 News by Steve Bryson, PhD

Combinations of Variants Contribute to Genetic MS Risk

While MS is not an inherited disease, genetic factors are known to predispose people to it. One of the strongest genetic risk factors in MS is a mutation in the HLA-DRB1 gene called HLA-DRB1*15:01.

This gene belongs to the major histocompatibility complex (MHC), a set of genes that help the immune system discriminate between harmful molecules and those that are not. Other genes outside the MHC have also been associated with MS.

Age at MS onset is an objective predictor of a patient’s prognosis or likely outcomes. People who develop the disease earlier in life tend to have more relapses before transitioning to progressive disease. Those diagnosed at older ages tend to make this transition in less time, attaining more severe disability scores more quickly in their disease course, but “those with an earlier [age at onset] still reach these milestones at younger ages,” the study noted.

Predicting onset age for MS patients could help in determining those who require an earlier start with disease modifying therapies or a move to more effective ones.

Researchers at the Brigham Young University, Biogen, and other institutions in the U.S. set out to examine if a patient’s genetic risk score — determined by the presence of HLA-DRB1*15:01 and other disease-associated risk variants — could predict their age of onset.

The study involved data covering 3,495 adult white patients, most of whom (71%) were women, whose symptoms first appeared at a mean age of 32.

Data for 1,268 patients came from the Accelerated Cure Project for MS, a repository for clinical information and biological samples of people with MS and other demyelinating diseases being followed at 10 specialty clinics in the U.S.

The remaining 2,227 participants were from Biogen-sponsored Phase 3 trials, including the ADVANCE trial (NCT00906399), which tested Plegridy (peginterferon beta-1a), the ASCEND trial (NCT01416181) that tested Tysabri (natalizumab), and the DECIDE trial (NCT01064401) that investigated Zinbryta (daclizumab).

About 45% of all patients were positive for the HLA-DRB1*15:01 genetic variant.

Results showed that the presence of genetic variants and age at disease onset were inversely correlated, with carriers of HLA-DRB1*15:01 developing MS a full year earlier than non-carriers. In turn, an increase of 10 or 50 other genetic risk factors outside the MHC complex hastened the development of MS by one or five years.

“The variants that are associated with getting the disease are associated with how early you get MS,” Davis said. “It wasn’t an unexpected finding, but this [is] the first time it has been confirmed.”

People with the highest genetic risk, defined as a combination of HLA-DRB1*15:01 in both gene copies (one inherited from each parent) plus other high-risk gene variants, were on average five years younger at disease onset than those with the lowest genetic risk, defined as having some disease-associated genetic variants but no copies of HLA-DRB1*15:01.

“We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease,” the researchers concluded.

“Typically by the time someone is diagnosed, those patients will realize there was a time when they were teenagers or … in college where they had an event signaling future onset of the disease,” Davis said. “We want to help people to be more aware of those events before onset hits so they can take action and have a greater potential for long, healthy lives.”