HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity

PLoS One. 2013 Jul 9;8(7):e68111. doi: 10.1371/journal.pone.0068111. Print 2013.

Abstract

Background and aim: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles*
  • Amoxicillin-Potassium Clavulanate Combination / toxicity*
  • Anti-Bacterial Agents / toxicity*
  • Bilirubin / metabolism
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Female
  • Genetic Association Studies
  • Genotype
  • HLA Antigens / chemistry
  • HLA Antigens / genetics*
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / genetics
  • Humans
  • Male
  • Middle Aged
  • Phenotype

Substances

  • Anti-Bacterial Agents
  • HLA Antigens
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Amoxicillin-Potassium Clavulanate Combination
  • Bilirubin

Grant support

This study was supported by the research grant Proyecto Excelencia P10-CTS-6470 and by the Agencia Española del Medicamento. CIBERehd and Red Genómica del Cancer are funded by Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.