Single Gene Variant May Identify MS Patients at Risk of Liver Damage Linked to Interferon-Beta Use, Study Says

A genetic variant close to a gene called interferon regulatory factor 6 (IRF6) may help to predict those multiple sclerosis (MS) patients most at risk of liver injury while using interferon-beta therapies, a study reports.

The study, “Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis” was published in the journal Nature Genetics.

Interferon-beta works with an individual’s own interferons — naturally occurring molecules — that exist in the body to reduce inflammation.

Interferon-beta — a treatment whose brand names include Rebif, Avonex, and Plegridy — remains one of most widely used of MS therapies, especially prescribed to people with relapsing-remitting MS. However, this type of treatment is linked to a potential for liver injury.

Specifically, up to 60 percent of MS patients treated with interferon-beta therapies develop abnormalities in the liver (like changes in liver enzymes, usually mild). But a small number of them will experience therapy-induced liver injury.

Researchers have no way to predict MS patients at risk of liver damage linked to interferon beta treatment. Rather, these patients are monitored and undergo regular blood tests to detect abnormal liver enzyme levels, a potential indicator of organ injury.

“One in 50 people with MS who are treated with interferon-beta, one of the most commonly prescribed MS therapies, will develop abnormally high levels of liver enzymes,” Kaarina Kowalec, a postdoctoral fellow at Sweden’s Karolinska Institutet and study’s first author, said in a press release.

Because previous studies have reported that genomic variation contributes to other forms of drug-induced liver injury, the researchers aimed to identify biomarkers of interferon-beta-induced liver injury via a genome-wide association study. [A gene variant describes any change — benign, disease-causing, or not-yet-known — in the DNA sequences that compose a gene.]

Researchers enrolled 170 MS patients at MS clinics in Canada, and though analyses identified three regions associated with interferon-beta-induced liver injury.

In a second stage of this study, they recruited a separate group of 120 MS patients from the U.S. and Sweden. In this stage, only one genomic variant, called rs2205986, was found to be associated with liver injury due to interferon-beta.

Further tests in MS patients showed that this variant was significantly associated with increased levels of two liver enzymes, the aspartate aminotransferase and alkaline phosphatase. Increased levels of these enzymes are a sign of liver damage.

The researchers hypothesized that the variant identified may induce changes in the expression of the gene IRF6 that responds to interferon-beta and promotes cell death.

In a predictive model of liver injury, the rs2205986 varian performed well as a biomarker of such injury compared to other clinical factors; rs2205986 had a specificity of 93.7% and a sensitivity of 41.1%, the researchers reported.

“Risk of liver injury increases eight fold with this marker. It’s important that we be able to understand who might be most at risk so that we can intervene with an altered treatment plan or increased monitoring to prevent liver damage,” said Bruce Carleton at British Columbia Children’s Hospital in Vancouver, Canada and a study co-lead author.

Overall, “these findings have important implications for the development of strategies to reduce the occurrence of IFN-β [interferon-beta]-induced liver injury in MS patients,” the researchers wrote.

Testing MS patients for this particular gene variant before they start interferon-beta treatment may help to prevent treatment-induced liver injury in patients at risk.

“This is the kind of research that makes drugs safer,” Kowalec concluded. “We are now looking at newer MS drugs and taking a similar approach so that one day, genetic risk may factor into how we diagnose, treat and monitor people with MS in Canada and around the world.”