Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate

Gastroenterology. 2023 Mar;164(3):454-466. doi: 10.1053/j.gastro.2022.11.036. Epub 2022 Dec 7.


Background & aims: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).

Methods: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases.

Results: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model.

Conclusions: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Keywords: Amoxicillin-Clavulanate; DILI; ERAP2; GWAS; HLA-B∗15:18.

Publication types

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

MeSH terms

  • Alleles
  • Aminopeptidases / genetics
  • Amoxicillin-Potassium Clavulanate Combination
  • Anti-Bacterial Agents* / adverse effects
  • Chemical and Drug Induced Liver Injury* / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HLA-A Antigens / genetics
  • HLA-DRB1 Chains / genetics
  • Humans
  • Liver
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Risk Factors


  • Anti-Bacterial Agents
  • HLA-DRB1 Chains
  • Amoxicillin-Potassium Clavulanate Combination
  • HLA-A Antigens
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • ERAP2 protein, human
  • Aminopeptidases