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Polygenic architecture informs potential vulnerability to drug-induced liver injury

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 risk. 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 studies.

Date: 8 September 2020



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 risk. 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 studies. 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.
 

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Takanori TAKEBE

  • Department of Regenerative Medicine,
    Institute of Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    T-CiRA Discovery, Takeda Pharmaceutical Company, Fujisawa, Kanagawa, Japan

    Institute of Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA

    The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
  • ttakebe@yokohama-cu.ac.jp