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The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study.
- Source :
-
Journal of medical toxicology : official journal of the American College of Medical Toxicology [J Med Toxicol] 2021 Apr; Vol. 17 (2), pp. 160-167. Date of Electronic Publication: 2020 Oct 13. - Publication Year :
- 2021
-
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.<br />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.<br />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).<br />Conclusions: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.
- Subjects :
- Adult
Female
Genetic Variation
Genome-Wide Association Study
Humans
Immune System
Male
Middle Aged
Pilot Projects
Young Adult
Acetaminophen therapeutic use
Acetaminophen toxicity
Analgesics, Non-Narcotic toxicity
Chemical and Drug Induced Liver Injury drug therapy
Chemical and Drug Induced Liver Injury genetics
Genetic Predisposition to Disease
Pain drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1937-6995
- Volume :
- 17
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of medical toxicology : official journal of the American College of Medical Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 33051802
- Full Text :
- https://doi.org/10.1007/s13181-020-00815-2