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

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 and Naga Chalasani ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37209-1

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