Polygenic architecture informs potential vulnerability to drug-induced liver injury

Koido, Masaru; Kawakami, Eri; Fukumura, Junko; Noguchi, Yui; Ohori, Momoko; Nio, Yasunori; Nicoletti, Paola; Aithal, Guruprasad P.; Daly, Ann K.; Watkins, Paul B.; Anayama, Hisashi; Dragan, Yvonne; Shinozawa, Tadahiro; Takebe, Takanori

Abstract

Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market, and this is partially due to the inability to identify patients who are at risk1. Here, 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 studies (GWAS)2. 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 10 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.

Citation

Koido, M., Kawakami, E., Fukumura, J., Noguchi, Y., Ohori, M., Nio, Y., Nicoletti, P., Aithal, G. P., Daly, A. K., Watkins, P. B., Anayama, H., Dragan, Y., Shinozawa, T., & Takebe, T. (2020). Polygenic architecture informs potential vulnerability to drug-induced liver injury. Nature Medicine, 26, 1541–1548. https://doi.org/10.1038/s41591-020-1023-0

• Journal Article Type: Article
• Acceptance Date: Jul 20, 2020
• Online Publication Date: Sep 7, 2020
• Publication Date: Sep 7, 2020
• Deposit Date: Jul 21, 2020
• Publicly Available Date: Mar 8, 2021
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Pages: 1541–1548
• DOI: https://doi.org/10.1038/s41591-020-1023-0
• Public URL: https://nottingham-repository.worktribe.com/output/4780325
• Publisher URL: https://www.nature.com/articles/s41591-020-1023-0