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

Paola Nicoletti; 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 I Grove; Camilla Stephens; Guruprasad P Aithal; Raul J Andrade; Einar S Bjornsson; Ann K Daly; M Isabel Lucena; Paul B Watkins; Drug-Induced Liver Injury Network (DILIN); International Drug-Induced Liver Injury Consortium (iDILIC); Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators

doi:10.1053/j.gastro.2022.11.036

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 Mar;164(3):454-466. doi: 10.1053/j.gastro.2022.11.036. Epub 2022 Dec 7.

Authors

Paola Nicoletti¹, Andrew Dellinger², Yi Ju Li³, Huiman X Barnhart³, Naga Chalasani⁴, Robert J Fontana⁵, Joseph A Odin⁶, Jose Serrano⁷, Andrew Stolz⁸, Amy S Etheridge⁹, Federico Innocenti⁹, Olivier Govaere¹⁰, Jane I Grove¹¹, Camilla Stephens¹², Guruprasad P Aithal¹¹, Raul J Andrade¹², Einar S Bjornsson¹³, Ann K Daly¹⁰, M Isabel Lucena¹², Paul B Watkins¹⁴; Drug-Induced Liver Injury Network (DILIN); International Drug-Induced Liver Injury Consortium (iDILIC); Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators

Affiliations

¹ Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: paola.nicoletti@mssm.edu.
² Duke Molecular Physiology Institute, Duke University, Durham, North Carolina.
³ Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
⁴ Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
⁵ University of Michigan, Ann Arbor, Michigan.
⁶ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
⁷ National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
⁸ University of Southern California, Los Angeles, California.
⁹ University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
¹⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
¹¹ Nottingham Digestive Diseases Centre and National Institute for Health Research Nottingham Biomedical Research Centre at the Nottingham University Hospital National Health Service Trust, Nottingham, United Kingdom; University of Nottingham, Nottingham, United Kingdom.
¹² Servicios de Digestivo y Farmacologia Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA_Plataforma Bionand), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
¹³ Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴ University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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.

Keywords: Amoxicillin-Clavulanate; DILI; ERAP2; GWAS; HLA-B∗15:18.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Aminopeptidases / genetics
Amoxicillin-Potassium Clavulanate Combination
Anti-Bacterial Agents* / adverse effects
Chemical and Drug Induced Liver Injury* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-A Antigens / genetics
HLA-DRB1 Chains / genetics
Humans
Liver
Polymorphism, Single Nucleotide
Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
Risk Factors

Substances

Anti-Bacterial Agents
HLA-DRB1 Chains
Amoxicillin-Potassium Clavulanate Combination
HLA-A Antigens
PTPN22 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 22
ERAP2 protein, human
Aminopeptidases

Abstract

Publication types

MeSH terms

Substances

Grants and funding