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 journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)1-5
Number of pages5
JournalNature Genetics
DOIs
StateAccepted/In press - Jul 16 2018

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Interferons
Multiple Sclerosis
Liver
Wounds and Injuries
Biological Therapy
Electronic Health Records
Genome-Wide Association Study
Central Nervous System Diseases
Aspartate Aminotransferases
Pharmaceutical Preparations
Alkaline Phosphatase
Cohort Studies
Biomarkers
Odds Ratio
Genome
Confidence Intervals

ASJC Scopus subject areas

  • Genetics

Cite this

Kowalec, K., Wright, G. E. B., Drögemöller, B. I., Aminkeng, F., Bhavsar, A. P., Kingwell, E., ... Carleton, B. C. (Accepted/In press). Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. Nature Genetics, 1-5. https://doi.org/10.1038/s41588-018-0168-y

Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. / Kowalec, Kaarina; Wright, Galen E.B.; Drögemöller, Britt I.; Aminkeng, Folefac; Bhavsar, Amit P.; Kingwell, Elaine; Yoshida, Eric M.; Traboulsee, Anthony; Marrie, Ruth Ann; Kremenchutzky, Marcelo; Campbell, Trudy L.; Duquette, Pierre; Chalasani, Naga; Wadelius, Mia; Hallberg, Pär; Xia, Zongqi; de Jager, Philip L.; Denny, Joshua C.; Davis, Mary F.; Ross, Colin J.D.; Tremlett, Helen; Carleton, Bruce C.

In: Nature Genetics, 16.07.2018, p. 1-5.

Research output: Contribution to journalArticle

Kowalec, K, Wright, GEB, Drögemöller, BI, Aminkeng, F, Bhavsar, AP, Kingwell, E, Yoshida, EM, Traboulsee, A, Marrie, RA, Kremenchutzky, M, Campbell, TL, Duquette, P, Chalasani, N, Wadelius, M, Hallberg, P, Xia, Z, de Jager, PL, Denny, JC, Davis, MF, Ross, CJD, Tremlett, H & Carleton, BC 2018, 'Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis', Nature Genetics, pp. 1-5. https://doi.org/10.1038/s41588-018-0168-y
Kowalec K, Wright GEB, Drögemöller BI, Aminkeng F, Bhavsar AP, Kingwell E et al. Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. Nature Genetics. 2018 Jul 16;1-5. https://doi.org/10.1038/s41588-018-0168-y
Kowalec, Kaarina ; Wright, Galen E.B. ; Drögemöller, Britt I. ; Aminkeng, Folefac ; Bhavsar, Amit P. ; Kingwell, Elaine ; Yoshida, Eric M. ; Traboulsee, Anthony ; Marrie, Ruth Ann ; Kremenchutzky, Marcelo ; Campbell, Trudy L. ; Duquette, Pierre ; Chalasani, Naga ; Wadelius, Mia ; Hallberg, Pär ; Xia, Zongqi ; de Jager, Philip L. ; Denny, Joshua C. ; Davis, Mary F. ; Ross, Colin J.D. ; Tremlett, Helen ; Carleton, Bruce C. / Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. In: Nature Genetics. 2018 ; pp. 1-5.
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