Gene Variant Flags Patients With MS at Risk for Treatment-Related Liver Injury

Damian McNamara

July 20, 2018

Patients with multiple sclerosis (MS) who carry a specific genetic variant identified through genome-wide testing are at significantly elevated risk for liver toxicity when treated with interferon-β, new research reveals.

Investigators found that 38 patients with MS positive for the rs2205986 variant had more than an eightfold greater likelihood of drug-induced liver injury (DILI) compared with 113 controls without this genetic feature.

"The take-home message for clinicians treating people with MS with interferon-β is that it is a relatively safe drug. However, adverse effects like liver toxicity can occur in up to 1 in 50 people treated with this drug," co-lead author Kaarina Kowalec, PhD, from the Division of Neurology, Faculty of Medicine, University of British Columbia in Vancouver, Canada, at the time of the study, told Medscape Medical News.

"This is why we wanted to look for genomic biomarkers to help predict who might be at higher risk for experiencing liver toxicity such that a more precise or personalized treatment plan could be developed."

The research was published online July 16 in Nature Genetics.

Leading Cause of Liver Failure

DILI remains the leading cause of acute liver failure in the United States. Currently there is no method for clinicians to predict which patients with MS will experience this type of liver injury when treated with interferon-β.

In addition, unlike many small-molecule medications with a known mechanism of action that can inform toxicity, biologics like interferon-β are a different story.

"In MS…the mechanisms by which the biologics work to prevent disability are relatively unknown and this makes it even harder to predict what type of drugs reactions will occur and in whom," said Kowalec, who is now a postdoctoral research at Karolinska Institutet in Stockholm, Sweden.

To find out more, the investigators assessed patients with relapsing-remitting or secondary progressive MS at Canadian MS clinics. All participants had exposure to interferon-β therapy and a normal baseline liver enzyme test. This was the first study to explore genetic variants associated with DILI and any biologic agent in this population, including interferon-β.

The investigators reviewed medical records for each patient to collect demographic and clinical information, including a comprehensive assessment of adverse drug reactions.

All patients developed DILI within 700 days of starting interferon-β. DILI was defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at least five times  the upper limit of normal; ALT at least three times the upper limit of normal plus elevation of bilirubin at least two times the upper limit of normal; or alkaline phosphatase (ALP) greater than two times the upper limit of normal.

Controls were also treated with interferon-β. The researchers followed this group out to 2 years to confirm that they did not develop DILI.

Genome-wide testing revealed three regions associated with interferon-β–induced liver injury. The strongest association was with the region on chromosome 1q32.2 containing rs2205986. The rs2205986 variant was previously associated with differential expression of the interferon regulatory factor-6 gene (IRF6).

Excited, Hopeful

To confirm involvement of these three regions, Kowalec and colleagues performed a second step. They ran genetic testing in a separate cohort of 34 patients with MS from the United States and Sweden and found that  1q32.2 containing rs2205986 was the only region associated with interferon-β–induced liver injury.

At this point, Kowalec said she was "relieved, because you always want to hope that your finding is a true finding, and excited and hopeful — because ultimately it could actually help someone one day."

They further supported these findings by examining the frequency of the top three implicated genetic regions in 1319 disease-matched population controls who were not screened for abnormal liver test results. They found the frequency of rs2205986 was higher among cases: a minor allele frequency of 21% compared with 9% among controls.

When the two stage analyses were combined, rs2205986 surpassed genome-wide significance with an odds ratio of 8.3. This is why participants with this genetic variant were at more than eight times the risk for developing DILI.

When Kowalec and colleagues added rs2205986 to a predictive model for DILI based on clinical factors alone, the additional information significantly improved prediction of liver injury (P = .0039). According to this model, the variant had a specificity of 94% and a sensitivity of 41%, and the number needed to screen for rs2205986 to prevent one case was 117.

Developing rs2205986 into a commercially available genetic biomarker to predict DILI associated with interferon-β therapy might also prove useful to identify risk for milder forms of liver injury, the researchers noted.

An exploratory case-control analysis of people with mild DILI, defined as ALT or AST greater than two times the upper limit of normal, also revealed an association with the genetic finding (odds ratio, 4.3).

The investigators also confirmed their findings by evaluating 279 MS patient samples previously genotyped at Vanderbilt University Medical Center and entered in their BioVU electronic medical record system.

De-identified data from this source were available for 87 patients with MS, interferon-β exposure, and biochemical liver tests. Assessing this cohort revealed that rs2205986 was significantly associated with elevations in AST and ALP levels. Each rs2205968 G allele was linked with an increase of an average 29 units of AST and 52 units of ALP.

Other Variants at Play?

When asked if genetic variant testing could someday replace current monitoring for liver injury, Kowalec noted it is more likely that testing of this genomic variant would be used alongside the liver biochemistry testing. "The more information you have, the better," she said.

In addition, testing for rs2205986 or other variants could reduce the frequency of liver biochemistry testing in people with MS taking interferon-β therapy, particularly in the first 6 months.  Currently, Canadians taking interferon-β have their blood tested once a month for 6 months and then once every 6 months thereafter.

The investigators believe that rs2205986 elevates the risk for liver injury through apoptosis.

"We propose it would be liver cells that contain the liver injury marker, ALT, that are dying in the presence of interferon-β," Kowalec said.

"We propose that when someone takes interferon-β, it damages these hepatocytes and the people with the rs2205986 variant experience more severe liver injury than those who do not have the rs2205986 variant."

The investigators restricted their study to participants with a European genetic ancestry to minimize population stratification. However, they added that because MS is most prevalent among people with northern European ancestry, "these results are expected to be applicable to the majority of people with MS."

In addition, because of sample size limitations, Kowalec and colleagues could identify only one pharmacogenetic predictor of interferon-β–induced liver injury. Additional variants could emerge from larger studies in the future.

Kowalec would like to recruit an additional cohort of individuals treated with interferon-β to replicate the findings again.

"We are hoping to work with a private US company, Emerald Lake Safety, to do this work and get testing available to people with MS one day."

The investigators would also like to expand this research to identify genomic biomarkers of lymphopenia. These severe reductions or drops in white blood cells can occur during treatment with dimethyl fumarate (Tecfidera, Biogen) in people with MS.

Important Contribution

Commenting on the findings for Medscape Medical News, Bruce Bebo, PhD, executive vice president for research at the National MS Society in New York, described the research as a "rigorous study performed by a highly regarded team of researchers."

"They identify a genetic variant that appears to have a strong association with interferon-β–induced liver damage. The variant is a member of a biochemical pathway that regulates the cellular response to interferons, so it also has biological plausibility. The association with elevated liver enzymes from the EHR [electronic health record] adds even more confidence to this observation," he said.

Bebo agreed with Kowalec about the need to replicate the findings. "If it holds up, it could be quite useful in identifying patients at high risk for liver damage — in conjunction with a medical exam and history.

"This study makes an important contribution that could lead to more individualized treatment for MS."

The British Columbia Clinical Genomics Network and doctoral studentships from the Canadian Institutes of Health Research (CIHR), the CIHR Drug Safety and Effectiveness Cross-Disciplinary Training Program, the MS Society of Canada, the University of British Columbia and the Canadian Pharmacogenomics Network for Drug Safety supported this research. Kowalec has a consulting agreement with Emerald Lake Safety. Bebo has disclosed no relevant financial relationships.

Nat Genet. Published online July 16, 2018. Abstract

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