title: Application of high-throughput sequencing to circulating microRNAs reveals novel biomarkers for drug-induced liver injury.
abstract: Drug-induced liver injury (DILI) is a leading cause of acute liver failure and the major reason for withdrawal of drugs from the market. Preclinical evaluation of drug candidates has failed to detect about 40% of potentially hepatotoxic compounds in humans. At the onset of liver injury in humans, currently used biomarkers have difficulty differentiating severe DILI from mild, and/or predict the outcome of injury for individual subjects. Therefore, new biomarker approaches for predicting and diagnosing DILI in humans are urgently needed. Recently, circulating microRNAs (miRNAs) such as miR-122 and miR-192 have emerged as promising biomarkers of liver injury in preclinical species and in DILI patients. In this study, we focused on examining global circulating miRNA profiles in serum samples from subjects with liver injury caused by accidental acetaminophen (APAP) overdose. Upon applying next generation high-throughput sequencing of small RNA libraries, we identified 36 miRNAs, including 3 novel miRNA-like small nuclear RNAs, which were enriched in the serum of APAP overdosed subjects. The set comprised miRNAs that are functionally associated with liver-specific biological processes and relevant to APAP toxic mechanisms. Although more patients need to be investigated, our study suggests that profiles of circulating miRNAs in human serum might provide additional biomarker candidates and possibly mechanistic information relevant to liver injury.
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340 j.krauskopf@maastrichtuniversity.nl.
authors.forename: Julian
authors.initials: J
authors.lastname: Krauskopf
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Florian
authors.initials: F
authors.lastname: Caiment
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Claessen
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Roscoe L
authors.initials: RL
authors.lastname: Warner
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Shelli J
authors.initials: SJ
authors.lastname: Schomaker
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Burt
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.affiliation: *Department of Toxicogenomics, Maastricht University, Maastricht 6200 MD, The Netherlands, Pathology Department, University of Michigan, Ann Arbor, Michigan 48109 and Drug Safety Research and Development, Pfizer, Inc., Groton, Connecticut 06340.
authors.forename: Jos C
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology; D062787:Drug Overdose / Q000150:complications; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D009928:Organ Specificity; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D000082:Acetaminophen
keywords: APAP; acetaminophen overdose; miR-122; miRNA; serum; snRNA