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

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-beta (IFN-beta). Up to 60% of IFN-beta-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-beta-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 x 10(-8), odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-beta-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 x 10(-5)) and alkaline phosphatase (P = 4.9 x 10(-4)). We show that these findings may be applicable to predicting IFN-beta-induced liver injury, offering insight into its safer use.