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

Drug-Induced Liver Injury Network (DILIN), International Drug-Induced Liver Injury Consortium (iDILIC), Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Pages (from-to)454-466
Number of pages13
Issue number3
StatePublished - Mar 2023


  • Amoxicillin-Clavulanate
  • DILI
  • ERAP2
  • GWAS
  • HLA-B∗15:18


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