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Rapid CommunicationShort Communication

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

Michael H. Court, Inga Peter, Suwagmani Hazarika, Magdalini Vasiadi, David J. Greenblatt, William M. Lee and The Acute Liver Failure Study Group
Drug Metabolism and Disposition January 2014, 42 (1) 28-32; DOI: https://doi.org/10.1124/dmd.113.053546
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.)
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Inga Peter
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.)
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Suwagmani Hazarika
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.)
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Magdalini Vasiadi
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.)
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David J. Greenblatt
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.)
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William M. Lee
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.)
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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.)
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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.

Footnotes

    • Received June 26, 2013.
    • Accepted October 7, 2013.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM061834 and R01-GM102130] (to M.H.C.); and by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant U01-DK058369] (to W.M.L. for the Acute Liver Failure Study Group), and [Contract N01-DK-7-0004 / HHSN267200700004C] (to the Liver Tissue and Cell Distribution System, Minneapolis, Minnesota).

  • dx.doi.org/10.1124/dmd.113.053546.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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Rapid CommunicationShort Communication

Polymorphisms Associated with APAP-ALF

Michael H. Court, Inga Peter, Suwagmani Hazarika, Magdalini Vasiadi, David J. Greenblatt, William M. Lee and The Acute Liver Failure Study Group
Drug Metabolism and Disposition January 1, 2014, 42 (1) 28-32; DOI: https://doi.org/10.1124/dmd.113.053546

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Rapid CommunicationShort Communication

Polymorphisms Associated with APAP-ALF

Michael H. Court, Inga Peter, Suwagmani Hazarika, Magdalini Vasiadi, David J. Greenblatt, William M. Lee and The Acute Liver Failure Study Group
Drug Metabolism and Disposition January 1, 2014, 42 (1) 28-32; DOI: https://doi.org/10.1124/dmd.113.053546
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