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Introduction Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case–control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. Methods and analysis The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p

To identify and characterize drug-induced liver injury (DILI) associated with IFN-β in multiple sclerosis (MS) using recommended criteria.This retrospective, mixed methods design included a cohort of IFN-β exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-β product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites.In BC, 18/942 (1.9%) of IFN-β exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-β-1a SC (44 mcg 3 × weekly) (adjusted Hazard Ratios: 3.15;95% CI:0.72 - 13.72, p = 0.13 and 6.26;95%CI:0.78 - 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006).Approximately 1 in 50 IFN-β exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.

The immunomodulatory drugs for multiple sclerosis (MS) are associated with a variety of adverse drug reactions, including liver and cardiac injury, acute leukemia and progressive multifocal leukoencephalopathy. Minimizing or preventing the toxicity of MS drugs represents a major clinical objective. The science of pharmacogenomics is used to identify genetic variants associated with a high or low risk of experiencing a specific adverse drug reaction or therapeutic response. Combined with clinical and demographic factors, pharmacogenomics holds promise to better optimize a drugs' risk/benefit profile. The application of pharmacogenomics for MS therapies is currently focused on finding markers of drug response. This review highlights the potential for pharmacogenomics to assist in predicting and/or preventing some of the more severe adverse reactions associated with MS therapies. We reviewed the literature surrounding seven serious adverse drug reactions associated with MS therapies, to serve as a springboard for future research: interferon-beta associated liver injury; lipoatrophy related to glatiramer acetate; progressive multifocal leukoencephalopathy associated with natalizumab, mitoxantrone associated cardiotoxicity and leukemia; and viral infections and cardiac effects associated with fingolimod. Predictive genetic testing for adverse drug reactions in the MS clinic could lead to a better risk profiling of patients before an MS therapy is initiated.

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. A genome-wide study identifies common variation near IRF6 associated with liver injury induced by IFN-β in individuals treated for multiple sclerosis. The risk locus is associated with differential expression of IRF6 and may help guide safer use of this biologic.

Features of occult hepatitis B infection in community-based populations have yet to be described. In this study we documented: (1) the prevalence and demographics, (2) associated serology and viral loads, and (3) clinical outcomes of occult hepatitis B infection in community-based populations. Hepatitis B surface antigen (HBsAg)-negative sera collected from three Northern Canadian communities (HBsAg prevalences: 11–12%) in 1983–1985 were tested for HBV-DNA by nested stage polymerase chain reaction. Of 706 HBsAg negative sera, 9 (1.3%) were HBV-DNA positive. The median age of occult hepatitis B infected patients at the time of sampling was 9.8 years (range 3.1–50.4 years) and six (67%) were female. Two (22%) individuals were anti-HBs positive (in the absence of prior vaccination). Viral loads were undetectable in all but two samples (2.40 and 2.86 log10 IU/ml). Only one of the five (20%) patients who were assessed clinically, remained HBV-DNA positive at 25–30 year follow-up. There was no clinical, biochemical or radiologic evidence of chronic hepatitis, cirrhosis or hepatocellular carcinoma in these individuals or on review of the charts from the remaining four infected patients. The results of this study suggest that in community-based populations: (1) occult hepatitis B infection is not as common as HBsAg positive infection, (2) the majority of infected subjects are young females, (3) a minority are anti-HBs positive, (4) viral loads are either undetectable or low, and (5) in the absence of concurrent liver disease, occult hepatitis B infection does not appear to be associated with long term adverse clinical outcomes. J. Med. Virol. 84:1369–1375, 2012. © 2012 Wiley Periodicals, Inc.

Hepatitis B virus (HBV) infection is highly prevalent in circumpolar indigenous peoples. However, the clinical outcome is extremely variable, such that while hepatocellular carcinoma (HCC) is uncommon in Canadian Inuit, the incidence of HCC is slightly higher in Greenlanders than in Danes, and it is especially high in Alaskan Native people infected with HBV genotypes F (HBV/F) and C (HBV/C). These differences may be associated with the genomic variability of the predominant HBV genotype in each group. The purpose of this study was to determine the rate, nature and regional susceptibility of HBV genomic mutations among circumpolar indigenous individuals. Paired serum samples, separated by 5-6 years, were analysed from Canadian and Greenlandic Inuit infected with HBV genotype B6 (HBV/B6) and HBV/D, respectively, and from Alaskan Native people infected with HBV/F, each having subsequently developed HCC. Phylogenetic and mutational analyses were performed on full-genome sequences, and the dynamic evolution within the quasispecies population of each patient group was determined by clonal analysis of the non-overlapping core coding region. Mutations associated with severe outcomes predominated in HBV/F, mostly within the precore/core and PreS1 region. HBV/B6 genomes exhibited higher diversity compared to HBV/D and HBV/F, particularly within the core coding region. Thus, differing mutational profiles and genetic variability were observed among different HBV genotypes predominating in circumpolar indigenous patients. The unusual observation of persistently high genetic variability with HBV/B6 despite clinical inactivity could be due to the evolution of a host-pathogen balance, but other possible factors also need to be explored.

The use of interferon-beta in multiple sclerosis is associated with various forms of hepatotoxicity, including autoimmune hepatitis and liver failure. We describe a case with features of autoimmune liver disease and primary biliary cirrhosis occurring during long-term treatment with interferon-beta in a patient with relapsing-remitting multiple sclerosis. This case highlights the importance of monitoring biochemical liver test results throughout interferon-beta treatment of multiple sclerosis.