title: HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.
abstract: OBJECTIVE
  The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.
  
  
  METHODS
  High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.
  
  
  RESULTS
  The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).
  
  
  CONCLUSIONS
  HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.
authors.affiliation: Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain. cstephens@uma.es
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.forename: Miguel-Ángel
authors.initials: MÁ
authors.lastname: López-Nevot
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ulzurrun
authors.forename: Germán
authors.initials: G
authors.lastname: Soriano
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
authors.forename: Antonia
authors.initials: A
authors.lastname: Moreno-Casares
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000633:toxicity*; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001663:Bilirubin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype
chemical_list: D000900:Anti-Bacterial Agents; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D019980:Amoxicillin-Potassium Clavulanate Combination; D001663:Bilirubin