title: Genomic indicators in the blood predict drug-induced liver injury.
abstract: Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross-tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors, which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis, and mitochondrial damage. The results show for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI.
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: J W
authors.initials: JW
authors.lastname: Chou
authors.forename: R S
authors.initials: RS
authors.lastname: Paules
authors.forename: K
authors.initials: K
authors.lastname: Gerrish
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: R D
authors.initials: RD
authors.lastname: Wolfinger
authors.forename: W
authors.initials: W
authors.lastname: Bao
authors.forename: T-M
authors.initials: TM
authors.lastname: Chu
authors.forename: Y
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: T
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: D
authors.initials: D
authors.lastname: Dosymbekov
authors.forename: M O
authors.initials: MO
authors.lastname: Tsyganova
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: X
authors.initials: X
authors.lastname: Fan
authors.forename: J C
authors.initials: JC
authors.lastname: Corton
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: H
authors.initials: H
authors.lastname: Fang
authors.forename: P R
authors.initials: PR
authors.lastname: Bushel
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000465:Algorithms; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D001185:Artificial Intelligence; D015415:Biomarkers; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D064420:Drug-Related Side Effects and Adverse Reactions; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000473:pathology; D008111:Liver Function Tests; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D020005:Propanols / Q000633:toxicity; D011786:Quality Control
chemical_list: D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D020005:Propanols; D000082:Acetaminophen; C006463:allyl alcohol