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The clinical and pharmacogenomic determinants of interferon beta induced liver injury in multiple sclerosis

University of British Columbia

Drug-induced liver injury is a common cause of acute liver failure; it is also the leading reason for a drug’s withdrawal from the market. Interferon-beta (IFN-β) is a commonly used disease-modifying drug for multiple sclerosis (MS) and is generally safe. However, 30-60% of IFN-β exposed patients experience liver aminotransferase elevations, with an unknown proportion experiencing more severe, medically significant elevations. To date, there are no means of predicting who will experience this adverse drug reaction (ADR), although the application of pharmacogenomics could assist with identifying predictive genomic factors. The purpose of this dissertation was to identify predictive factors associated with IFN-β induced liver injury to mitigate toxicity. The research in this dissertation commenced with a review article summarizing the potential application of pharmacogenomics to severe ADRs in MS and a case report of a patient experiencing a hepatic autoimmune-like complication of IFN-β therapy. An original research article followed; utilizing 942 IFN-β exposed MS patients, primarily from Canada. This population-based study examined the rate of liver injury due to IFN-β in MS patients. Approximately 1 in 50 (or 1.9%) IFN-β exposed patients’ experienced liver injury. A pharmacogenomic case-control study followed, involving 182 patients and a genome-wide scan of 785,230 genomic variants, to identify predictors of IFN-β induced liver injury. A genetic variant within synaptotagmin-14 was strongly associated with the ADR (odds ratio 9.83, 95% confidence interval 4.01-24.10, P-value 9.39 x 10-9) and was specific for liver injury from IFN-β and has been previously correlated with hepatic expression of interferon regulatory factor 6. This represents the first genome-wide association study of an ADR from an MS drug and of drug induced liver injury due to a biological therapy. The clinical, demographic and genomic characteristics identified here could modify the risk of experiencing a clinically significant ADR that often results in the cessation of a potentially useful treatment. Predictive characteristics of those at an increased risk will direct preventative strategies, such as enhanced monitoring for early signs of toxicity or alternative treatment regimens. This dissertation contributes towards the personalization of MS therapy and to the broader pharmacogenomic literature on biological therapies.

Text

2019-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57596

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/