title: Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study.
abstract: Acetaminophen is the leading cause of acute hepatic failure in many developed nations. Acetaminophen hepatotoxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI). We performed a "discovery" genome-wide association study using a cell line-based model system to study the possible contribution of genomics to NAPQI-induced cytotoxicity. A total of 176 lymphoblastoid cell lines from healthy subjects were treated with increasing concentrations of NAPQI. Inhibiting concentration 50 values were determined and were associated with "glutathione pathway" gene single nucleotide polymorphisms (SNPs) and genome-wide basal messenger RNA expression, as well as with 1.3 million genome-wide SNPs. A group of SNPs in linkage disequilibrium on chromosome 3 was highly associated with NAPQI toxicity. The p value for rs2880961, the SNP with the lowest p value, was 1.88 × 10(-7). This group of SNPs mapped to a "gene desert," but chromatin immunoprecipitation assays demonstrated binding of several transcription factor proteins including heat shock factor 1 (HSF1) and HSF2, at or near rs2880961. These chromosome 3 SNPs were not significantly associated with variation in basal expression for any of the genome-wide genes represented on the Affymetrix U133 Plus 2.0 GeneChip. We have used a cell line-based model system to identify a SNP signal associated with NAPQI cytotoxicity. If these observations are validated in future clinical studies, this SNP signal might represent a potential biomarker for risk of acetaminophen hepatotoxicity. The mechanisms responsible for this association remain unclear.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moyer
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Batzler
authors.forename: Linda L
authors.initials: LL
authors.lastname: Pelleymounter
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Yubo
authors.initials: Y
authors.lastname: Chai
authors.forename: Kendra K S
authors.initials: KK
authors.lastname: Nordgren
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D016227:Benzoquinones / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D055106:Genome-Wide Association Study; D005978:Glutathione / Q000235:genetics; D006801:Humans; D007097:Imines / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D016227:Benzoquinones; D007097:Imines; D012333:RNA, Messenger; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione