NEW YORK (GenomeWeb) – Researchers have uncovered a common genetic variant that is associated with liver injury in multiple sclerosis patients who have been treated with interferon-β, suggesting a new way to pick out patients at risk of the adverse reaction.
IFN-βs are the most commonly used treatments for multiple sclerosis, but up to 60 percent of patients given the drug develop abnormal biochemical liver test results and 2 percent experience drug-induced liver injury.
A University of British Columbia-led team of researchers conducted a two-stage genome-wide association study to identify a genetic variant linked to drug-induced liver injury. As they reported yesterday in Nature Genetics, they found the variant was also associated with increased liver enzyme levels. This suggested to them that the variant could be used to guide treatment options.
"Risk of liver injury increases eightfold 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," co-senior author Bruce Carleton from BC Children's Hospital said in a statement
The researchers conducted genome-wide genotyping using the Illumina MEGA array for 38 cases and 113 controls, all of European genetic ancestry, from MS clinics in Canada. Both cases and controls had either relapsing–remitting or secondary-progressive definite MS and had been treated with IFN-β. However, the cases had altered biochemical liver test results following treatment, while the controls did not.
In this cohort, the researchers uncovered three regions linked to IFN-β-induced liver injury, with the strongest association on chromosome 1q32.2. This variant was associated with an 8.5-fold increase of liver injury risk in this cohort.
In a separate cohort of 18 cases and 13 controls of European ancestry from the US and Sweden, the researchers confirmed the association between the chromosome 1q32.2 variant and treatment-induced liver injury. In this cohort, the variant was associated with an 8.3-fold increase in liver injury risk.
Among patients in Vanderbilt University Medical Center's repository of electronic health record data, the researchers found that the variant they identified was associated with increased aspartate aminotransferase and alkaline phosphatase levels during IFN-β treatment. One individual who was homozygous for the risk allele had increased alanine aminotransferase levels as well as increased aspartate aminotransferase and alkaline phosphatase levels, suggesting a marked increased risk for people with this genotype.
According to Genotype-Tissue Expression Project data, this risk allele is an expression quantitative trait locus for the interferon regulatory factor-6 (IRF6) gene, which is located 137 kilobases upstream of the SNP. The researchers noted that many of the nine known IRFs have been implicated in liver damage in other studies. IRF3, for instance, has been linked to tolvaptan-induced liver damage, they said.
IRF6, they added, promotes apoptosis following brain injury, suggesting that this variant could promote apoptosis in the presence of IFN-β.
Adding this allele into a predictive model of drug-induced liver injury improved the model's performance, as compared to clinical factors alone, the researchers reported. The allele has a specificity of 93.7 percent and a sensitivity of 41.1 percent to predict IFN-β-induced liver injury.
"There's a lot of talk about precision medicine, and whether it can work as well as we hope," co-first author Kaarina Kowalec, a postdoc at the Karolinska Institute, said in a statement. "Pharmacogenomic testing is a big part of that and we're showing that it is possible. It's something that's been done outside for cancer therapies but now we've shown that there's potential for precision medicine in MS as well."
The researchers noted, though, that their sample size was small and restricted to individuals of European ancestry. But since multiple sclerosis is most common among individuals of northern European ancestry, the researchers said they expect their results to be applicable to most of the MS patient population.