Dataset Information

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

ABSTRACT: Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-? (IFN-?). Up to 60% of IFN-?-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-?-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-?-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-?-induced liver injury, offering insight into its safer use.

SUBMITTER: Kowalec K

PROVIDER: S-EPMC6513312 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Kowalec Kaarina K Wright Galen E B GEB Drögemöller Britt I BI Aminkeng Folefac F Bhavsar Amit P AP Kingwell Elaine E Yoshida Eric M EM Traboulsee Anthony A Marrie Ruth Ann RA Kremenchutzky Marcelo M Campbell Trudy L TL Duquette Pierre P Chalasani Naga N Wadelius Mia M Hallberg Pär P Xia Zongqi Z De Jager Philip L PL Denny Joshua C JC Davis Mary F MF Ross Colin J D CJD Tremlett Helen H Carleton Bruce C BC

Nature genetics 20180716 8

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 genom ...[more]

PMID: 30013178

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Project description:BACKGROUND:Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. METHODOLOGY:Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. PRINCIPAL FINDINGS:Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. CONCLUSION:These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbeta.

Project description:Background and Purpose- The role of inflammation in ischemic white matter disease is increasingly recognized, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis (MS) is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesized that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically elevated white matter hyperintensity (WMH) volume was associated with increased MS risk. Methods- We investigated the genetic association in 2 cohorts with magnetic resonance imaging-quantified ischemic white matter lesion volume (WMH in stroke; n=2797 and UK Biobank; n=8353) and 14?802 cases of MS and 26?703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual-level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally, we looked for evidence of overlapping risk across the whole genome. Results- There was no association of genetic variants influencing MS with WMH volume using summary statistics in the WMH in stroke cohort (relative risk score =1.014; 95% CI, 0.936-1.110) or in the UK Biobank cohort (relative risk score =1.030; 95% CI, 0.932-1.117). Conversely, assessing the contribution of single nucleotide polymorphisms significantly associated with WMH on the risk of MS there was no significant association (relative risk score =0.930; 95% CI, 0.736-1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to the selection of single nucleotide polymorphisms at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits. Conclusions- Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischemia and MS. We propose that inflammation acts in distinct pathways because of the differing nature of the primary insult.

Dataset Information

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

Publications

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

Similar Datasets

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