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NIDDK Drug-Induced Liver Injury Network (DILIN)

ABSTRACT:

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has established the Drug-Induced Liver Injury Network (DILIN) to collect and analyze cases of severe liver injury caused by prescription drugs, over-the-counter drugs, and alternative medicines, such as herbal products and supplements.

PROVIDER: phs000663 | dbGaP |

SECONDARY ACCESSION(S): PRJNA219214PRJNA219213

REPOSITORIES: dbGaP

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	GapExchange_phs000663.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000663.DILIN.v1.p1.MULTI.pdf	Pdf
	manifest_phs000663.DILIN.v1.p1.c1.DS-DILI-IRB.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver, but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

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Project description:Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market because of inability to identify potential patients prior to clinical testing. Here, we approached a polygenic risk score (PRS) based strategy by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS). The PRS predicted the susceptibility to DILI in patients in a clinical trial, and in multi-donor derived primary hepatocytes and stem cell-derived organoids. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress alleviated by a potent antioxidant. Furthermore, hepatocytic transcriptomic signatures related to polygenic score identified potential drugs with clinical DILI evidence through in silico 941 compound screening. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architectures underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy potentially will contribute to prospective designs of safer, more efficient, and robust clinical trials.

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