Journal article
Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure
Drug metabolism and disposition, Vol.42(1), pp.28-32
01/2014
Handle:
https://hdl.handle.net/2376/110318
PMCID: PMC3876784
PMID: 24104197
Abstract
Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF.
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Details
- Title
- Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure
- Creators
- Michael H Court - Pharmacogenomics Laboratory, and Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington (M.H.C.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.P.); Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts (S.H., D.J.G.); Program in Pharmacology and Experimental Therapeutics, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts (M.V., D.J.G.); and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (W.M.L.)Inga PeterSuwagmani HazarikaMagdalini VasiadiDavid J GreenblattWilliam M Lee
- Publication Details
- Drug metabolism and disposition, Vol.42(1), pp.28-32
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- HHSN267200700004G / NLM NIH HHS N01-DK-7-0004 / NIDDK NIH HHS HHSN267200700004C / NLM NIH HHS U01 DK058369 / NIDDK NIH HHS R01-GM102130 / NIGMS NIH HHS R01-GM061834 / NIGMS NIH HHS HHSN267200700004C / NIDDK NIH HHS U01-DK058369 / NIDDK NIH HHS R01 GM102130 / NIGMS NIH HHS R01 GM061834 / NIGMS NIH HHS
- Identifiers
- 99900547149101842
- Language
- English
- Resource Type
- Journal article