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
Cite this dataset
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 [Dataset]. Dryad. 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
Treatment Response in ME7, ME9 and Txn1
Gene Sets of ME7 and ME9
Merge Analysis of ME7, ME9 and Txn1
eQTL-transcript pairs for treatment, control and treatment response mapping
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