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Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

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  • Nicholas R. Powell

    (Division of Clinical Pharmacology)

  • Tiebing Liang

    (Indiana University School of Medicine, Department of Medicine, Division of Gastroenterology Hepatology)

  • Joseph Ipe

    (Division of Clinical Pharmacology)

  • Sha Cao

    (Indiana University School of Medicine, Department of Medicine, Division of Gastroenterology Hepatology)

  • Todd C. Skaar

    (Division of Clinical Pharmacology)

  • Zeruesenay Desta

    (Division of Clinical Pharmacology)

  • Hui-Rong Qian

    (Eli Lilly and Company)

  • Philip J. Ebert

    (Eli Lilly and Company)

  • Yu Chen

    (Eli Lilly and Company)

  • Melissa K. Thomas

    (Eli Lilly and Company)

  • Naga Chalasani

    (Indiana University School of Medicine, Department of Medicine, Division of Gastroenterology Hepatology)

Abstract

Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.

Suggested Citation

  • Nicholas R. Powell & Tiebing Liang & Joseph Ipe & Sha Cao & Todd C. Skaar & Zeruesenay Desta & Hui-Rong Qian & Philip J. Ebert & Yu Chen & Melissa K. Thomas & Naga Chalasani, 2023. "Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37209-1
    DOI: 10.1038/s41467-023-37209-1
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    References listed on IDEAS

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    1. Viechtbauer, Wolfgang, 2010. "Conducting Meta-Analyses in R with the metafor Package," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 36(i03).
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    Cited by:

    1. Zhichao Yang & Avijit Mitra & Weisong Liu & Dan Berlowitz & Hong Yu, 2023. "TransformEHR: transformer-based encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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