Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury

A D B Vliegenthart; J M Shaffer; J I Clarke; L E J Peeters; A Caporali; D Nicholas Bateman; D M Wood; P I Dargan; D G Craig; J K Moore; A I Thompson; N C Henderson; D J Webb; J Sharkey; D J Antoine; B K Park; M A Bailey; E Lader; Kenneth Simpson; J W Dear

doi:10.1038/srep15501

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury

A D B Vliegenthart, J M Shaffer, J I Clarke, L E J Peeters, A Caporali, D Nicholas Bateman, D M Wood, P I Dargan, D G Craig, J K Moore, A I Thompson, N C Henderson, D J Webb, J Sharkey, D J Antoine, B K Park, M A Bailey, E Lader, Kenneth Simpson, J W Dear

Research output: Contribution to journal › Article › peer-review

Abstract

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

Original language	English
Pages (from-to)	15501
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep15501
Publication status	Published - 22 Oct 2015

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Dear - microRNA profiling liver and kidney injury
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Monocyte-macrophage activation in acute liver failure: a mechanism to develop the systemic inflammatory response syndrome
Simpson, K. (Principal Investigator) & Forbes, S. (Co-investigator)
UK central government bodies/local authorities, health and hospital authorities
1/09/12 → 28/02/15
Project: Research

Neil Henderson
- Neil.Hendersoned.acuk
- School of Regeneration and Repair - Personal Chair of Tissue Repair and Regeneration
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

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Vliegenthart, A. D. B., Shaffer, J. M., Clarke, J. I., Peeters, L. E. J., Caporali, A., Bateman, D. N., Wood, D. M., Dargan, P. I., Craig, D. G., Moore, J. K., Thompson, A. I., Henderson, N. C., Webb, D. J., Sharkey, J., Antoine, D. J., Park, B. K., Bailey, M. A., Lader, E., Simpson, K., & Dear, J. W. (2015). Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Scientific Reports, 5, 15501. https://doi.org/10.1038/srep15501

@article{e0afa10b50254849833924f81ccae19a,

title = "Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury",

abstract = "Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.",

author = "Vliegenthart, \{A D B\} and Shaffer, \{J M\} and Clarke, \{J I\} and Peeters, \{L E J\} and A Caporali and Bateman, \{D Nicholas\} and Wood, \{D M\} and Dargan, \{P I\} and Craig, \{D G\} and Moore, \{J K\} and Thompson, \{A I\} and Henderson, \{N C\} and Webb, \{D J\} and J Sharkey and Antoine, \{D J\} and Park, \{B K\} and Bailey, \{M A\} and E Lader and Kenneth Simpson and Dear, \{J W\}",

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doi = "10.1038/srep15501",

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Vliegenthart, ADB, Shaffer, JM, Clarke, JI, Peeters, LEJ, Caporali, A, Bateman, DN, Wood, DM, Dargan, PI, Craig, DG, Moore, JK, Thompson, AI, Henderson, NC , Webb, DJ, Sharkey, J, Antoine, DJ, Park, BK, Bailey, MA, Lader, E, Simpson, K & Dear, JW 2015, 'Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury', Scientific Reports, vol. 5, pp. 15501. https://doi.org/10.1038/srep15501

TY - JOUR

T1 - Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury

AU - Vliegenthart, A D B

AU - Shaffer, J M

AU - Clarke, J I

AU - Peeters, L E J

AU - Caporali, A

AU - Bateman, D Nicholas

AU - Wood, D M

AU - Dargan, P I

AU - Craig, D G

AU - Moore, J K

AU - Thompson, A I

AU - Henderson, N C

AU - Webb, D J

AU - Sharkey, J

AU - Antoine, D J

AU - Park, B K

AU - Bailey, M A

AU - Lader, E

AU - Simpson, Kenneth

AU - Dear, J W

PY - 2015/10/22

Y1 - 2015/10/22

N2 - Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

AB - Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

U2 - 10.1038/srep15501

DO - 10.1038/srep15501

M3 - Article

C2 - 26489516

SN - 2045-2322

VL - 5

SP - 15501

JO - Scientific Reports

JF - Scientific Reports

ER -

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury

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Monocyte-macrophage activation in acute liver failure: a mechanism to develop the systemic inflammatory response syndrome

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