title: Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs.
abstract: OBJECTIVE
  Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs.
  
  
  METHODS
  DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases.
  
  
  RESULTS
  After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5×10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables.
  
  
  CONCLUSIONS
  Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study.
authors.affiliation: Center for Human Genome Variation, Duke University, Durham, NC, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Andrew
authors.initials: A
authors.lastname: Stolz
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.forename: James
authors.initials: J
authors.lastname: Rochon
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Mariam
authors.initials: M
authors.lastname: Molokhia
authors.forename: Guruprasad P
authors.initials: GP
authors.lastname: Aithal
authors.forename: Aris
authors.initials: A
authors.lastname: Floratos
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: Jose
authors.initials: J
authors.lastname: Serrano
authors.forename: Herbert
authors.initials: H
authors.lastname: Bonkovsky
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Davern
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Navarro
authors.forename: Jayant A
authors.initials: JA
authors.lastname: Talwalkar
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D012307:Risk Factors