Skip to main content
Dryad logo

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

Citation

Cai, Yanwei et al. (2021), 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, Dryad, Dataset, https://doi.org/10.5061/dryad.9s4mw6mdz

Abstract

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.

Usage Notes

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