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Drug-Induced Liver Injury (DILIN) GWAS

ABSTRACT: Drug-Induced Liver Injury (DILIN) GWAS

PROVIDER: PRJNA219213 | ENA |

REPOSITORIES: ENA

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NIDDK Drug-Induced Liver Injury Network (DILIN)

Project description:<p>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.</p>

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Small RNAs in anti-tuberculosis drug-induced liver injury

Project description:The antimicrobials isoniazid and pyrazinamide, used for the treatment of tuberculosis are known to cause drug-induced liver injury in humans. This limits the effectiveness of tuberculosis treatment, resulting in incomplete cure, relapse and the development of antimicrobial resistance. MicroRNAs are known to be good biomarkers of disease, with the microRNA miR-122 being diagnostic for liver injury. In this study zebrafish larvae were exposed to the anti-tuberculosis drugs isoniazid and pyrazinamide at concentrations which demonstrated liver injury by microscopy and histology. The aim of this study is to understand small RNA changes occurring in anti-tuberculosis drug-induced liver injury and to attempt to identify novel microRNA biomarkers of liver injury.

2023-12-25 | GSE146260 | GEO

Small RNAs in anti-tuberculosis drug-induced liver injury

Project description:Small RNAs in anti-tuberculosis drug-induced liver injury

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The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

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.

2024-04-15 | GSE255038 | GEO

Proteomic-based identification of APCS as candidate protein for diagnosis of patients exhibiting Anti-tubercular drug induced liver injury

Project description:In the present study, the proteomics approach identified potential protein signatures with high discriminative ability in TB patients with and without drug-induced liver injury which might play a crucial role in developing Anti-tubercular drug-induced liver injury.

2021-11-12 | MSV000088373 | MassIVE

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

Project description:The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

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Polygenic architecture informs potential vulnerability to drug-induced liver injury

Project description:Polygenic architecture informs potential vulnerability to drug-induced liver injury

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Hepatic p53 protein level governs liver s sensitivity to drug-induced liver injury

Project description:Hepatic p53 protein level governs liver s sensitivity to drug-induced liver injury

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Polygenic architecture informs potential vulnerability to drug-induced liver injury

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.

2020-09-07 | GSE152447 | GEO

Genome-wide methylation analysis in Anti-tuberculosis Drug Induced Liver Injury case and control samples

Project description:Association analysis of DNA methylation in Anti-tuberculosis Drug Induced Liver Injury case and control samples from peripheral blood

2021-12-24 | GSE124415 | GEO

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