Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure

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.

Fig. 1.

Allele frequencies for candidate genes potentially involved in the pathogenesis of acetaminophen-induced acute liver failure (APAP-ALF). Shown are the frequencies determined for 261 patients who had developed ALF either unintentionally from chronic acetaminophen use (n = 79), intentionally from a single-time-point acetaminophen overdose (n = 78), or from causes other than acetaminophen (n = 103). Chi-square analysis showed a higher allele frequency (*P < 0.05) for the CYP3A5 fast-metabolizer rs776746 G allele in patients who had a single-time-point acetaminophen overdose, and for UGT1A1 slow glucuronidation -53(TA)7 or 8 alleles in the patients with ALF from causes other than acetaminophen when compared with the other two ALF groups. Also shown for comparison are allele frequencies obtained from the National Center for Biotechnology Information (NCBI) database for a race/ethnicity-matched white population (60 Utah residents with northern and western European ancestry), except for the CYP2E1*1x2 copy number variation, which were determined in this study using DNA from 42 white individuals (see the Materials and Methods section).