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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

Lookup NU author(s): Dr Olivier GovaereORCiD, Professor Ann DalyORCiD


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© 2022 AGA InstituteBackground & 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.

Publication metadata

Author(s): Nicoletti P, Dellinger A, Li YJ, Barnhart HX, Chalasani N, Fontana RJ, Odin JA, Serrano J, Stolz A, Etheridge AS, Innocenti F, Govaere O, Grove JI, Stephens C, Aithal GP, Andrade RJ, Bjornsson ES, Daly AK, Lucena MI, Watkins PB

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2023

Volume: 164

Issue: 3

Pages: 454-466

Print publication date: 01/03/2023

Online publication date: 07/12/2022

Acceptance date: 28/11/2022

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: W.B. Saunders


DOI: 10.1053/j.gastro.2022.11.036

PubMed id: 36496055


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