title: Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Mikus
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Kimi
authors.initials: K
authors.lastname: Drobin
authors.affiliation: Global Safety Assessment, Molecular Toxicology, Former AstraZeneca R&D, Södertälje, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Gry
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Bachmann
authors.affiliation: Global Safety Assessment, Molecular Toxicology, Former AstraZeneca R&D, Södertälje, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.affiliation: Department of Pharmacology, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.affiliation: Department of Pharmacology, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: Department of Internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.affiliation: Momenta Pharmaceuticals, Cambridge, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Roach
authors.affiliation: Momenta Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Fier
authors.affiliation: Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Uppsala, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampf
authors.affiliation: Biochemistry Department, Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Göpfert
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Perazzo
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.affiliation: UGC Gastroenterologia y Hepatologia y Serv Farmacología Clínica, IBIMA, Hospital U Virgen de la Victoria, University of Malaga, Málaga, Spain.
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.affiliation: UGC Gastroenterologia y Hepatologia y Serv Farmacología Clínica, IBIMA, Hospital U Virgen de la Victoria, University of Malaga, Málaga, Spain.
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
authors.affiliation: UGC Gastroenterologia y Hepatologia y Serv Farmacología Clínica, IBIMA, Hospital U Virgen de la Victoria, University of Malaga, Málaga, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.affiliation: The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Nadir
authors.initials: N
authors.lastname: Arber
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlén
authors.affiliation: Schools of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Jochen M
authors.initials: JM
authors.lastname: Schwenk
authors.affiliation: Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|AstraZeneca R&D, Innovative Medicines Personalised Healthcare & Biomarkers, SciLifeLab, Stockholm, Sweden.
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D015703:Antigens, CD / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D015820:Cadherins / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood*; D050556:Fatty Acid-Binding Proteins / Q000097:blood*; D005260:Female; D015658:HIV Infections; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D040901:Proteomics; D012307:Risk Factors; D014376:Tuberculosis; D055815:Young Adult; D000099152:Cadherin 5
chemical_list: D000082:Acetaminophen; D000410:Alanine Transaminase; D015703:Antigens, CD; D015415:Biomarkers; D015820:Cadherins; D050556:Fatty Acid-Binding Proteins; D006493:Heparin; D000099152:Cadherin 5; C493319:FABP1 protein, human
keywords: affinity proteomics; biomarker discovery; drug-induced liver injury; plasma profiling; suspension bead arrays