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.
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We gratefully acknowledge the participation of all patients and families who took part in this study across Canada, Europe, and the USA. This work would not have been possible without their generous participation. We also acknowledge the contributions of the Canadian Pharmacogenomics Network for Drug Safety Consortium (C. Hildebrand, A. Borrie, T. Wong, T. Bendyshe-Walton, N. Massah, F. Miao, M. Higginson, M. Staub, K. Shaw, B. Malkin, and J. Stortz), Winnipeg Health Sciences Centre MS Clinic (N. Hall and B. Stranger), London Health Sciences Centre MS Clinic (H. Rosehart), Dalhousie MS Clinic (K. Stadnyk, K. Sabourin, and B. DeCoste), and Centre Hospitalier de L’Université de Montréal (É. Roger). We thank all the MS clinic neurologists who contributed to the study through patient examination and data collection. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the original Wellcome Trust Case Control Consortium project was provided by the following Wellcome Trust awards: 076113, 085475 and 090355. This investigation was supported by a pilot grant from the British Columbia Clinical Genomics Network (to H.T. (the principal investigator)). Doctoral studentships provided additional funding for K.K. from the Canadian Institutes of Health Research (CIHR), CIHR Drug Safety and Effectiveness Cross-Disciplinary Training Program (DSECT), MS Society of Canada, University of British Columbia, and Canadian Pharmacogenomics Network for Drug Safety. G.E.B.W. received fellowships from the CIHR and CIHR DSECT programs. B.I.D. received stipends from the British Columbia Children’s Hospital Research Institute, CIHR DSECT, CIHR, and the Michael Smith Foundation for Health Research during the period of this study. The Drug-Induced Liver Injury Network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) as part of the Cooperative Agreements (U01s) project under grants U01-DK065176 (Duke), U01-DK065201 (UNC), U01-DK065184 (Michigan), U01-DK065211 (Indiana), U01DK065193 (UConn), U01-DK065238 (UCSF/CPMC), U01-DK083023 (UTSW), U01-DK083027 (TJH/UPenn), U01-DK082992 (Mayo), U01-DK083020 (USC), and U01-DK100928 (Icahn). Additional funding was provided by CTSA grants UL1 RR025761 (Indiana), UL1 RR025747 (UNC), and UL1 UL1 RR024986 (UMich), and the Intramural Research Program of the National Cancer Institute. Vanderbilt University Medical Center BioVU is supported by institutional funding and Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by P50GM115305 from NIGMS. H.T. and B.C.C. had full access to all the data in the study, and take full responsibility for the integrity of the data and the accuracy of the data analysis. The study funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
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Neurological Sciences (2019)