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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 singletime-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 acetaminophenmetabolizing 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 acetaminopheninduced ALF.

Original languageEnglish (US)
Pages (from-to)28-32
Number of pages5
JournalDrug Metabolism and Disposition
Volume42
Issue number1
DOIs
StatePublished - Jan 2014

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Acute Liver Failure
Acetaminophen
Cytochrome P-450 CYP3A
Genes
Alleles
Odds Ratio
Genotype
Cytochrome P-450 CYP2E1
Enzymes
Healthy Volunteers
Confidence Intervals
Liver

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure. / Court, Michael H.; Peter, Inga; Hazarika, Suwagmani; Vasiadi, Magdalini; Greenblatt, David J.; Lee, William M.

In: Drug Metabolism and Disposition, Vol. 42, No. 1, 01.2014, p. 28-32.

Research output: Contribution to journalArticle

Court, Michael H. ; Peter, Inga ; Hazarika, Suwagmani ; Vasiadi, Magdalini ; Greenblatt, David J. ; Lee, William M. / Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure. In: Drug Metabolism and Disposition. 2014 ; Vol. 42, No. 1. pp. 28-32.
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