@article { , title = {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}, 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.}, doi = {10.1053/j.gastro.2022.11.036}, eissn = {1528-0012}, issue = {3}, journal = {Gastroenterology}, note = {Need to add volume, issue, pagination. Author states in comments that open access arranged for this article. Check if gold OA when it is published in issue. Not gold OA 28/02/2023}, pages = {454-466}, publicationstatus = {Published}, publisher = {Elsevier}, url = {https://nottingham-repository.worktribe.com/output/15431972}, volume = {164}, keyword = {ERAP2, GWAS, Amoxicillin-clavulanate, DILI, HLA-B*15:18}, year = {2023}, author = {Nicoletti, Paola and Dellinger, Andrew and Li, Yi Ju and Barnhart, Huiman X. and Chalasani, Naga and Fontana, Robert J. and Odin, Joseph A. and Serrano, Jose and Stolz, Andrew and Etheridge, Amy S. and Innocenti, Federico and Govaere, Olivier and Grove, Jane I. and Stephens, Camilla and Aithal, Guruprasad P. and Andrade, Raul J. and Bjornsson, Einar S. and Daly, Ann K. and Lucena, M. Isabel and Watkins, Paul B.} }