Paola Nicoletti
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
Nicoletti, Paola; Dellinger, Andrew; Li, Yi Ju; Barnhart, Huiman X.; Chalasani, Naga; Fontana, Robert J.; Odin, Joseph A.; Serrano, Jose; Stolz, Andrew; Etheridge, Amy S.; Innocenti, Federico; Govaere, Olivier; Grove, Jane I.; Stephens, Camilla; Aithal, Guruprasad P.; Andrade, Raul J.; Bjornsson, Einar S.; Daly, Ann K.; Lucena, M. Isabel; Watkins, Paul B.
Authors
Andrew Dellinger
Yi Ju Li
Huiman X. Barnhart
Naga Chalasani
Robert J. Fontana
Joseph A. Odin
Jose Serrano
Andrew Stolz
Amy S. Etheridge
Federico Innocenti
Olivier Govaere
JANE GROVE jane.grove@nottingham.ac.uk
Associate Professor
Camilla Stephens
GURUPRASAD AITHAL Guru.Aithal@nottingham.ac.uk
Professor of Hepatology
Raul J. Andrade
Einar S. Bjornsson
Ann K. Daly
M. Isabel Lucena
Paul B. Watkins
Abstract
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.
Citation
Nicoletti, P., Dellinger, A., Li, Y. J., Barnhart, H. X., Chalasani, N., Fontana, R. J., …Watkins, P. B. (2023). 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, 164(3), 454-466. https://doi.org/10.1053/j.gastro.2022.11.036
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 28, 2022 |
Online Publication Date | Dec 7, 2022 |
Publication Date | 2023-03 |
Deposit Date | Jan 1, 2023 |
Publicly Available Date | Dec 8, 2023 |
Journal | Gastroenterology |
Print ISSN | 0016-5085 |
Electronic ISSN | 1528-0012 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 164 |
Issue | 3 |
Pages | 454-466 |
DOI | https://doi.org/10.1053/j.gastro.2022.11.036 |
Keywords | ERAP2, GWAS, Amoxicillin-clavulanate, DILI, HLA-B*15:18 |
Public URL | https://nottingham-repository.worktribe.com/output/15431972 |
Publisher URL | https://www.sciencedirect.com/science/article/pii/S0016508522013749 |
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