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

Nat Genet. 2018 Aug;50(8):1081-1085. doi: 10.1038/s41588-018-0168-y. Epub 2018 Jul 16.


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 results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemical and Drug Induced Liver Injury / genetics*
  • Female
  • Genetic Variation / genetics*
  • Genome-Wide Association Study / methods
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Interferon-beta / genetics*
  • Male
  • Multiple Sclerosis / genetics*


  • IRF6 protein, human
  • Interferon Regulatory Factors
  • Interferon-beta