Nicoletti, PaolaDellinger, AndrewLi, Yi JuBarnhart, Huiman X.Chalasani, NagaFontana, Robert J.Odin, Joseph A.Serrano, JoseStolz, AndrewEtheridge, Amy S.Innocenti, FedericoGovaere, OlivierGrove, Jane I.Stephens, CamillaAithal, Guruprasad P.Andrade, Raul J.Bjornsson, Einar S.Daly, Ann K.Lucena, M. IsabelWatkins, Paul B.Drug-Induced Liver Injury Network (DILIN)International Drug-Induced Liver Injury Consortium (iDILIC)Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators2024-06-252024-06-252023Nicoletti P, Dellinger A, Li YJ, et al. 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;164(3):454-466. doi:10.1053/j.gastro.2022.11.036https://hdl.handle.net/1805/41880Background & 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.en-USPublisher PolicyAmoxicillin-ClavulanateAminopeptidasesGenome-wide association studyLiverArticle