title: Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
abstract: OBJECTIVE
  Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.
  
  
  METHODS
  We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background.
  
  
  RESULTS
  AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)).
  
  
  CONCLUSIONS
  Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.
authors.affiliation: Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Campus Universitario s/n, Málaga and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.forename: Mariam
authors.initials: M
authors.lastname: Molokhia
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Guruprasad P
authors.initials: GP
authors.lastname: Aithal
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: Peter T
authors.initials: PT
authors.lastname: Donaldson
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gomez
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Navarro
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.forename: Max
authors.initials: M
authors.lastname: Groome
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bondon-Guitton
authors.forename: Anita
authors.initials: A
authors.lastname: Conforti
authors.forename: Bruno H C
authors.initials: BH
authors.lastname: Stricker
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carvajal
authors.forename: Luisa
authors.initials: L
authors.lastname: Ibanez
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Yue
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Aris
authors.initials: A
authors.lastname: Floratos
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: John F
authors.initials: JF
authors.lastname: Dillon
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D016009:Chi-Square Distribution; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D019980:Amoxicillin-Potassium Clavulanate Combination