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

Kaarina Kowalec, Galen E.B. Wright, Britt I. Drögemöller, Folefac Aminkeng, Amit P. Bhavsar, Elaine Kingwell, Eric M. Yoshida, Anthony Traboulsee, Ruth Ann Marrie, Marcelo Kremenchutzky, Trudy L. Campbell, Pierre Duquette, Naga Chalasani, Mia Wadelius, Pär Hallberg, Zongqi Xia, Philip L. De Jager, Joshua C. Denny, Mary F. Davis, Colin J.D. RossHelen Tremlett, Bruce C. Carleton

Research output: Contribution to journalLetter

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1081-1085
Number of pages5
JournalNature genetics
Volume50
Issue number8
DOIs
StatePublished - Aug 1 2018

ASJC Scopus subject areas

  • Genetics

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    Kowalec, K., Wright, G. E. B., Drögemöller, B. I., Aminkeng, F., Bhavsar, A. P., Kingwell, E., Yoshida, E. M., Traboulsee, A., Marrie, R. A., Kremenchutzky, M., Campbell, T. L., Duquette, P., Chalasani, N., Wadelius, M., Hallberg, P., Xia, Z., De Jager, P. L., Denny, J. C., Davis, M. F., ... Carleton, B. C. (2018). Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. Nature genetics, 50(8), 1081-1085. https://doi.org/10.1038/s41588-018-0168-y