Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury

Maria Mikus, Kimi Drobin, Marcus Gry, Julie Bachmann, Johan Lindberg, Getnet Yimer, Eleni Aklillu, Eyasu Makonnen, Getachew Aderaye, James Roach, Ian Fier, Caroline Kampf, Jens Göpfert, Hugo Perazzo, Thierry Poynard, Camilla Stephens, Raúl J. Andrade, M. Isabel Lucena, Nadir Arber, Mathias Uhlén & 4 others Paul B. Watkins, Jochen M. Schwenk, Peter Nilsson, Ina Schuppe-Koistinen

Research output: Research - peer-reviewArticle

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Abstract

Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

LanguageEnglish (US)
Pages132-140
Number of pages9
JournalLiver International
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2017

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Chemical and Drug Induced Liver Injury
Fatty Acid-Binding Proteins
Cadherins
cadherin 5
Biomarkers
Pharmaceutical Preparations
Alanine Transaminase
Heparin
Healthy Volunteers
Antibodies
Proteins
Therapeutics
Protein Array Analysis
Tissue Distribution
Acetaminophen
Proteomics
Suspensions
Tuberculosis
HIV
Serum

Keywords

  • affinity proteomics
  • biomarker discovery
  • drug-induced liver injury
  • plasma profiling
  • suspension bead arrays

ASJC Scopus subject areas

  • Hepatology

Cite this

Mikus, M., Drobin, K., Gry, M., Bachmann, J., Lindberg, J., Yimer, G., ... Schuppe-Koistinen, I. (2017). Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. Liver International, 37(1), 132-140. DOI: 10.1111/liv.13174

Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. / Mikus, Maria; Drobin, Kimi; Gry, Marcus; Bachmann, Julie; Lindberg, Johan; Yimer, Getnet; Aklillu, Eleni; Makonnen, Eyasu; Aderaye, Getachew; Roach, James; Fier, Ian; Kampf, Caroline; Göpfert, Jens; Perazzo, Hugo; Poynard, Thierry; Stephens, Camilla; Andrade, Raúl J.; Lucena, M. Isabel; Arber, Nadir; Uhlén, Mathias; Watkins, Paul B.; Schwenk, Jochen M.; Nilsson, Peter; Schuppe-Koistinen, Ina.

In: Liver International, Vol. 37, No. 1, 01.01.2017, p. 132-140.

Research output: Research - peer-reviewArticle

Mikus, M, Drobin, K, Gry, M, Bachmann, J, Lindberg, J, Yimer, G, Aklillu, E, Makonnen, E, Aderaye, G, Roach, J, Fier, I, Kampf, C, Göpfert, J, Perazzo, H, Poynard, T, Stephens, C, Andrade, RJ, Lucena, MI, Arber, N, Uhlén, M, Watkins, PB, Schwenk, JM, Nilsson, P & Schuppe-Koistinen, I 2017, 'Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury' Liver International, vol 37, no. 1, pp. 132-140. DOI: 10.1111/liv.13174
Mikus M, Drobin K, Gry M, Bachmann J, Lindberg J, Yimer G et al. Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. Liver International. 2017 Jan 1;37(1):132-140. Available from, DOI: 10.1111/liv.13174
Mikus, Maria ; Drobin, Kimi ; Gry, Marcus ; Bachmann, Julie ; Lindberg, Johan ; Yimer, Getnet ; Aklillu, Eleni ; Makonnen, Eyasu ; Aderaye, Getachew ; Roach, James ; Fier, Ian ; Kampf, Caroline ; Göpfert, Jens ; Perazzo, Hugo ; Poynard, Thierry ; Stephens, Camilla ; Andrade, Raúl J. ; Lucena, M. Isabel ; Arber, Nadir ; Uhlén, Mathias ; Watkins, Paul B. ; Schwenk, Jochen M. ; Nilsson, Peter ; Schuppe-Koistinen, Ina. / Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. In: Liver International. 2017 ; Vol. 37, No. 1. pp. 132-140
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