DOI: 10.5061/dryad.9s4mw6mdz
title: Data from: Human-relevant mechanisms and risk factors for TAK-875-induced liver injury identified via a gene pathway-based approach in collaborative cross mice

description: Development of TAK-875 was discontinued when a small number of serious
 drug-induced liver injury (DILI) cases were observed in Phase 3 clinical
 trials. Subsequent studies have identified hepatocellular oxidative
 stress, mitochondrial dysfunction, altered bile acid homeostasis, and
 immune response as mechanisms of TAK-875 DILI and the contribution of
 genetic risk factors in oxidative response and mitochondrial pathways to
 the toxicity susceptibility observed in patients. We tested the hypothesis
 that a novel preclinical approach based on gene pathway analysis in the
 livers of Collaborative Cross mice could be used to identify
 human-relevant mechanisms of toxicity and genetic risk factors at the
 level of the hepatocyte as reported in a human genome-wide association
 study. Eight (8) male mice (4 matched pairs) from each of 45 Collaborative
 Cross lines were treated with a single oral (gavage) dose of either
 vehicle or 600 mg/kg TAK-875. As expected, liver injury was not detected
 histologically and few changes in plasma biomarkers of hepatotoxicity were
 observed. However, gene expression profiling in the liver identified
 hundreds of transcripts responsive to TAK-875 treatment across all strains
 reflecting alterations in immune response and bile acid homeostasis and
 the interaction of treatment and strain reflecting oxidative stress and
 mitochondrial dysfunction. Fold-change expression values were then used to
 develop pathway-based phenotypes for genetic mapping which identified
 candidate risk factor genes for TAK-875 toxicity susceptibility at the
 level of the hepatocyte. Taken together, these findings support our
 hypothesis that a gene pathway-based approach using Collaborative Cross
 mice could inform sensitive strains, human-relevant mechanisms of
 toxicity, and genetic risk factors for TAK-875 DILI. This novel
 preclinical approach may be helpful in understanding, predicting, and
 ultimately preventing clinical DILI for other drugs.
description: Treatment Response Phenotypes For each
 mice pair, the table includes all treatment response phenotypes of the
 pair as well as strain and batch information. (corresponding to Table
 1)  
 ST1.Phenotype_Treatment_Response
 Treatment Response in ME7, ME9 and Txn1
 Quantitative values of module 7 eigengene, module 9 eigengene
 and Txn1 fold change. (corresponding to Figure 5,6 and S6)
  
 ST2.Expression_Treatment_Response Gene
 Sets of ME7 and ME9 Gene sets composition of module
 7 and module 9 (corresponding to Figure 4)
   ST3.Genelist_ME
 Merge Analysis of ME7, ME9 and Txn1 Merge
 analysis of module 7 eigengene, module 9 eigengene and Txn1 fold change
 values. (corresponding to Figure 5,6 and S6)
   ST4.Merge_Analysis
 eQTL-transcript pairs for treatment, control and treatment
 response mapping eQTL mapping summary for treatment,
 control and treatment response (corresponding to Figure S6)
   ST5.eQTL Probe
 sets heritability and fold-change Probe sets GxT
 heritability and fold change in response to TAK-875 treatment
 (corresponding to Figure 2 and 3)
 ST6.Probe_sets_FoldChange_Heritability DAVID
 functional annotation of Probe sets DAVID functional
 annotation of probe sets with insignificant GxT heritability (red genes in
 Fig 1) and probe sets with significant GxT heritability (blue and purple
 genes in Fig 1)   ST7.
 DAVID_enrichment