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Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans

Ravindra, Kodihalli C.; Vaidya, Vishal S.; Wang, Zhenyu; Federspiel, Joel D.; Virgen-Slane, Richard; Everley, Robert A.; Grove, Jane I.; Stephens, Camilla; Ocana, Mireia F.; Robles-Díaz, Mercedes; Lucena, M. Isabel; Andrade, Raul J.; Atallah, Edmond; Gerbes, Alexander L.; Weber, Sabine; Cortez-Pinto, Helena; Fowell, Andrew J.; Hussaini, Hyder; Bjornsson, Einar S.; Patel, Janisha; Stirnimann, Guido; Verma, Sumita; Elsharkawy, Ahmed M.; Griffiths, William J. H.; Hyde, Craig; Dear, James W.; Aithal, Guruprasad P.; Ramaiah, Shashi K.

Authors

Kodihalli C. Ravindra

Vishal S. Vaidya

Zhenyu Wang

Joel D. Federspiel

Richard Virgen-Slane

Robert A. Everley

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JANE GROVE jane.grove@nottingham.ac.uk
Assistant Professor

Camilla Stephens

Mireia F. Ocana

Mercedes Robles-Díaz

M. Isabel Lucena

Raul J. Andrade

Alexander L. Gerbes

Sabine Weber

Helena Cortez-Pinto

Andrew J. Fowell

Hyder Hussaini

Einar S. Bjornsson

Janisha Patel

Guido Stirnimann

Sumita Verma

Ahmed M. Elsharkawy

William J. H. Griffiths

Craig Hyde

James W. Dear

Shashi K. Ramaiah



Contributors

Kodihalli C. Ravindra
Researcher

Helena Cortez-Pinto
Researcher

James W. Dear
Researcher

Craig Hyde
Researcher

William J.H. Griffiths
Researcher

Ahmed M. Elsharkawy
Researcher

Sumita Verma
Researcher

Guido Stirnimann
Researcher

Janisha Patel
Researcher

Einar S. Bjornsson
Researcher

Hyder Hussaini
Researcher

Andrew J. Fowell
Researcher

Sabine Weber
Researcher

Vishal S. Vaidya
Researcher

Alexander L. Gerbes
Researcher

Raul J. Andrade
Researcher

M Isabel Lucena
Researcher

Mercedes Robles-Díaz
Researcher

Mireia F. Ocana
Researcher

Camilla Stephens
Researcher

Robert A. Everley
Researcher

Richard Virgen-Slane
Researcher

Joel D. Federspiel
Researcher

Zhenyu Wang
Researcher

Shashi K. Ramaiah
Researcher

Abstract

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. We used Tandem Mass Tag-labeled quantitative proteomics detecting 2323 proteins in a cohort comprising patients with DILI [at onset (DO) and follow-up (DF)], acute non-DILI [at onset (NDO) and follow-up (NDF)], and healthy volunteers (HV) to identify novel serum biomarkers. Thirteen candidates selected based on differential expression, liver-specific expression, and mechanistic relevance to liver pathology, were assessed in confirmatory and replication cohorts of HV (n=94), DO (n=123), DF (n=110), NDO (n=58) and NDF (n=37) using a targeted label-free SureQuant assay. Area under the receiver operating characteristic curve (AUC) ranging between 0.94 and 0.99 across cohorts for five of these biomarkers, reflected differentiation between DO and HV with high sensitivity and specificity. In addition, fructose-1,6-bisphosphatase 1 distinguished NDO from DO (AUC: 0.75 and 0.65) on its own or in combination with glutathione S-transferase A1 and leukocyte cell derived chemotaxin 2 (AUC: 0.78 and 0.68). These can potentially differentiate DILI and acute liver injury from non-drug etiologies.

Citation

Ravindra, K. C., Vaidya, V. S., Wang, Z., Federspiel, J. D., Virgen-Slane, R., Everley, R. A., …Ramaiah, S. K. (2023). Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans. Nature Communications, 14, Article 1215. https://doi.org/10.1038/s41467-023-36858-6

Journal Article Type Article
Acceptance Date Dec 22, 2022
Online Publication Date Mar 3, 2023
Publication Date Mar 3, 2023
Deposit Date Jan 5, 2023
Publicly Available Date Mar 8, 2023
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 14
Article Number 1215
DOI https://doi.org/10.1038/s41467-023-36858-6
Public URL https://nottingham-repository.worktribe.com/output/15715090
Publisher URL https://www.nature.com/articles/s41467-023-36858-6

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