Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results 1,2 , and 1 in 50 experiences drug-induced liver injury 3 . Since genomic variation contributes to other forms of drug-induced liver injury 4,5 , we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10 –8 , odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10 –5 ) and alkaline phosphatase (P = 4.9 × 10 -4 ). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.