小柯机器人

日本横滨市立大学Takanori Takebe团队发现，多基因结构可预测药物性肝损伤。相关论文于2020年9月7日在线发表在《自然—医学》杂志上。

Title: Polygenic architecture informs potential vulnerability to drug-induced liver injury

Author: 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

Issue&Volume: 2020-09-07

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.

DOI: 10.1038/s41591-020-1023-0

Source: https://www.nature.com/articles/s41591-020-1023-0

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex