Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles

Gastroenterology. 2011 Jul;141(1):338-47. doi: 10.1053/j.gastro.2011.04.001. Epub 2011 Apr 12.

Abstract

Background & aims: 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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics*
  • Aged
  • Aged, 80 and over
  • Amoxicillin-Potassium Clavulanate Combination / adverse effects*
  • Anti-Bacterial Agents / adverse effects*
  • Case-Control Studies
  • Chemical and Drug Induced Liver Injury / ethnology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / immunology
  • Chi-Square Distribution
  • Europe / epidemiology
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency
  • Genes, MHC Class I*
  • Genes, MHC Class II*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HLA-A Antigens / genetics
  • HLA-DQ Antigens / genetics
  • HLA-DQ beta-Chains
  • HLA-DR Antigens / genetics
  • HLA-DRB1 Chains
  • Haplotypes
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Registries
  • Risk Assessment
  • Risk Factors
  • United States / epidemiology

Substances

  • Anti-Bacterial Agents
  • HLA-A Antigens
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Amoxicillin-Potassium Clavulanate Combination