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.

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