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

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.

Keywords: ALT; Acetaminophen; Drug induced liver injury; Hepatotoxicity; Pharmacogenomics.

Conflict of interest statement

None

Figures

Fig. 1

a REACTOME pathway analysis. a Damaging variants associated with ALT elevation. Heat map indicating the number of genes in each pathway. Orange line denotes selected pathways with predominance of moderate impact variants. b Damaging variants associated with adduct elevation. Heat map indicating the number of genes in each pathway. Orange line denotes selected pathways with predominance of moderate impact variants.

Fig. 2

Network analysis of genes with moderate or high impact variants associated with ALT elevation, performed in REACTOME analysis. Nodes with black labels are from the input gene list (seed nodes) and nodes with a purple label are intermediate nodes that are not in the input list but connect seed nodes and have significantly many links in the network module. Each edge represents an interaction (physical, biochemical, regulatory or drug–target interaction). Gene list available in Supplement.