Andrew A Monte, Alexis Vest, Julie A Reisz, Danielle Berninzoni, Claire Hart, Layne Dylla, Angelo D'Alessandro, Kennon J Heard, Cheyret Wood, Jack Pattee
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引用次数: 0
Abstract
Background: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration.
Methods: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test.
Results: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism.
Conclusions: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.
期刊介绍:
Journal of Medical Toxicology (JMT) is a peer-reviewed medical journal dedicated to advances in clinical toxicology, focusing on the diagnosis, management, and prevention of poisoning and other adverse health effects resulting from medications, chemicals, occupational and environmental substances, and biological hazards. As the official journal of the American College of Medical Toxicology (ACMT), JMT is managed by an editorial board of clinicians as well as scientists and thus publishes research that is relevant to medical toxicologists, emergency physicians, critical care specialists, pediatricians, pre-hospital providers, occupational physicians, substance abuse experts, veterinary toxicologists, and policy makers. JMT articles generate considerable interest in the lay media, with 2016 JMT articles cited by various social media sites, the Boston Globe, and the Washington Post among others. For questions or comments about the journal, please contact jmtinfo@acmt.net.
For questions or comments about the journal, please contact jmtinfo@acmt.net.