Polygenic architecture informs potential vulnerability to drug-induced liver injury.

Abstract

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.

• Authors: Masaru Koido, Eri Kawakami, Junko Fukumura, Yui Noguchi, Momoko Ohori, Yasunori Nio, Paola Nicoletti, Guruprasad P Aithal, Ann K Daly, Paul B Watkins, Hisashi Anayama, Yvonne Dragan, Tadahiro Shinozawa, Takanori Takebe
• Journal: Nature medicine (Nat Med) Vol. 26 Issue 10 Pg. 1541-1548 (Oct 2020) ISSN: 1546-170X [Electronic] United States
• PMID: 32895570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• Sulfones
• TAK-875

Topics

• Alleles
• Benzofurans (therapeutic use)
• Case-Control Studies
• Cells, Cultured
• Chemical and Drug Induced Liver Injury (drug therapy, epidemiology, genetics)
• Cohort Studies
• Datasets as Topic (statistics & numerical data)
• Gene Expression Profiling
• Gene Frequency
• Genetic Predisposition to Disease (genetics)
• Genome-Wide Association Study
• Hepatocytes (drug effects, metabolism)
• Humans
• Microarray Analysis
• Multifactorial Inheritance (genetics)
• Polymorphism, Single Nucleotide
• Sulfones (therapeutic use)