Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study.

Authors: Monte, Andrew A; Sonn, Brandon; Saben, Jessica; Rumack, Barry H; Reynolds, Kate M; Dart, Richard C; Heard, Kennon J

Published In J Med Toxicol, (2021 04)

Abstract: INTRODUCTION: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen. METHODS: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program. RESULTS: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53). CONCLUSIONS: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

PubMed ID: 33051802 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

Back
to Top