Polygenic architecture informs potential vulnerability to drug-induced liver injury

Autor: Paola Nicoletti, Hisashi Anayama, Yasunori Nio, Yui Noguchi, Paul B. Watkins, Takanori Takebe, Momoko Ohori, Eri Kawakami, Guruprasad P. Aithal, Masaru Koido, Tadahiro Shinozawa, Junko Fukumura, Ann K. Daly, Yvonne P. Dragan
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Drug
Multifactorial Inheritance
media_common.quotation_subject
Datasets as Topic
Genome-wide association study
Bioinformatics
Polymorphism
Single Nucleotide
General Biochemistry
Genetics and Molecular Biology
Article
Cohort Studies
03 medical and health sciences
0302 clinical medicine
Gene Frequency
Medicine
Humans
Genetic Predisposition to Disease
Sulfones
Allele
Alleles
Cells
Cultured
media_common
Benzofurans
Liver injury
business.industry
Microarray analysis techniques
Gene Expression Profiling
Case-control study
General Medicine
medicine.disease
Microarray Analysis
Gene expression profiling
030104 developmental biology
Drug development
030220 oncology & carcinogenesis
Case-Control Studies
Hepatocytes
Chemical and Drug Induced Liver Injury
business
Genome-Wide Association Study
Zdroj: Nat Med
ISSN: 1078-8956
1546-170X
Popis: Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk1. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin–clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed ‘polygenicity-in-a-dish’ strategy might potentially inform designs of safer, more efficient and robust clinical trials. Polygenic risk scores can predict susceptibility to drug-induced liver injury in patients and can stratify cellular viability of iPSC-derived liver organoids and primary hepatocytes from multiple donors.
Databáze: OpenAIRE
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