ArticleGastroenterology2023
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.
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Article in Gastroenterology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 39 citations in OpenAlex.
- Early Prediction of Non-recovery in Drug-induced Liver Injury by Integrating Genetic Variants and Clinical Variables: An Interpretable Machine Learning Approach.Journal of clinical and translational hepatology · 2026Article
- Pharmacogenomics of antibacterial and antiviral therapies: Clinical actionability, evidence gaps, and future directions.Pharmacological reviews · 2026Review
- HLA-B*44 Alleles and HLA-DQA1*03:01 as Genetic Risk Factors for Drug-Induced Liver Injury due to Fluoroquinolones.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Systematic review on genetic polymorphisms associated with idiosyncratic drug-induced liver injury (iDILI): iDILInet as an interactive visualization tool.Acta pharmaceutica Sinica. B · 2026Article
- Integrative Mapping of Regulatory Variation in African American Hepatocytes Using Colocalization and MPRA: Toward Precision Drug Response.Research square · 2026Article
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- Human leukocyte antigen pharmacogenetics in infectious diseases: anti-infective drug toxicity and host immune response.Frontiers in pharmacology · 2026Review
- Rare and common variants in ERAP1 and ERAP2 selected for in response to Yersinia pestis infection contribute to autoimmune disease including inflammatory bowel disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
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- Mechanisms and aetiology-dependent treatment of acute liver failure.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Methods for causality assessment of idiosyncratic drug-induced liver injury.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Liver Injury due to Intravenous Methylprednisolone in the Drug-Induced Liver Injury Network.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Polygenic modelling and machine learning approaches in pharmacogenomics: Importance in downstream analysis of genome-wide association study data.British journal of clinical pharmacology · 2025Review
- The role of endoplasmic reticulum aminopeptidase ERAP2 pathogenic mutation rs1363907 in amoxicillin clavulanate-induced liver injury: a special case report.Frontiers in pharmacology · 2025Article
- Hepatic Safety Considerations in the Use of Ulipristal Acetate for Symptomatic Uterine Fibroids.Therapeutics and clinical risk management · 2025Review
- Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Multiome-wide Association Studies: Novel Approaches for Understanding Diseases.Genomics, proteomics & bioinformatics · 2024Review
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
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Authors and funding
23 authors at 13 institutions in 4 countries.
Paola NicolettiDepartment of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: paola.nicoletti@mssm.edu.
Andrew DellingerDuke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Yi Ju LiDuke Molecular Physiology Institute, Duke University, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
Huiman X BarnhartDuke Molecular Physiology Institute, Duke University, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
Naga ChalasaniDivision of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
Robert J FontanaUniversity of Michigan, Ann Arbor, Michigan.
Joseph A OdinDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Jose SerranoNational Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
Andrew StolzUniversity of Southern California, Los Angeles, California.
Amy S EtheridgeUniversity of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Federico InnocentiUniversity of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Olivier GovaereTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Jane I GroveNottingham 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.
Camilla StephensServicios 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.
Guruprasad P AithalNottingham 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.
Raul J AndradeServicios 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.
Einar S BjornssonDepartment of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Ann K DalyTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
M Isabel LucenaServicios 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.
Paul B WatkinsUniversity 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.
Drug-Induced Liver Injury Network (DILIN)
International Drug-Induced Liver Injury Consortium (iDILIC)
Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators
Duke University · USUniversity of North Carolina at Chapel Hill · USCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · ESIcahn School of Medicine at Mount Sinai · USNewcastle University · GBAndalusian Centre for Nanomedicine and Biotechnology · ESIndiana University School of MedicineNational Health Service · GBNational Institute of Diabetes and Digestive and Kidney Diseases · USNottingham Biomedical Research Centre · GBReykjavík University · ISUniversity of Michigan–Ann Arbor · USUniversity of Southern California · US
Funding
MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (UL1): (BPCA)UL1RR024986 · NCRR · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHANLEY, THOMAS P. · 2007 to 2011
$51.2MUNC CLINICAL AND TRANSLATIONAL SCIENCE AWARD: BPCAUL1RR025747 · NCRR · UNIV OF NORTH CAROLINA CHAPEL HILL · PI RUNGE, MARSCHALL S. · 2008 to 2011
$44.6MFurthering scientific understanding of mechanisms underlying resilience to the effects of AD pathology by incorporating state of the art quantification of gliosis, inflammation, & synaptic toxicityU01AG006781 · NIA · UNIVERSITY OF WASHINGTON · PI CRANE, PAUL K, LARSON, ERIC B · 1986 to 2020
$39.3MDrug Induced Liver Injury Network Data Coordinating CenterU01DK065176 · NIDDK · DUKE UNIVERSITY · PI Huiman X Barnhart · 2003 to 2026
$25.5MJH/CIDR Genotyping for Genome-Wide Association StudiesU01HG004438 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2007 to 2011
$24.2MA Center for GEI Association StudiesU01HG004424 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY · 2007 to 2010
$21.4MINDIANA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (UL1): BPCAUL1RR025761 · NCRR · INDIANA UNIVERSITY INDIANAPOLIS · PI SHEKHAR, ANANTHA · 2008 to 2011
$21.0MCoordinating Center for the Drug Induced Liver Injury Network (DILIN)U24DK065176 · NIDDK · DUKE UNIVERSITY · PI BARNHART, HUIMAN X · 2018 to 2022
$7.6MIU Clinical Center: Drug Induced Liver Injury NetworkU01DK065211 · NIDDK · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI NAGA P CHALASANI · 2003 to 2026
$7.5MUniversity of North Carolina Clinical Center for DILINU01DK065201 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PAUL B WATKINS · 2003 to 2026
$7.3MVanderbilt Genome-Electronic Records ProjectU01HG004603 · NHGRI · VANDERBILT UNIVERSITY · PI RODEN, DAN M · 2007 to 2011
$7.3MMichigan Hepatotoxicity Clinical Research Network Renewal 2018U01DK065184 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ROBERT J FONTANA · 2003 to 2026
$7.0MDepartment of Health BRC-1215-20003NCI NIH HHS U01 CA155309NCRR NIH HHS UL1 RR024986NCRR NIH HHS UL1 RR025747NCRR NIH HHS UL1 RR025761NHGRI NIH HHS U01 HG004424NHGRI NIH HHS U01 HG004438NHGRI NIH HHS U01 HG004603NHGRI NIH HHS U01 HG004608NHGRI NIH HHS U01 HG007417NIA NIH HHS U01 AG006781NIDDK NIH HHS U01 DK065176NIDDK NIH HHS U01 DK065184NIDDK NIH HHS U01 DK065193NIDDK NIH HHS U01 DK065201NIDDK NIH HHS U01 DK065211NIDDK NIH HHS U01 DK065238NIDDK NIH HHS U01 DK082992NIDDK NIH HHS U01 DK083020NIDDK NIH HHS U01 DK083023NIDDK NIH HHS U01 DK083027NIDDK NIH HHS U01 DK100928NIDDK NIH HHS U24 DK065176NIMH NIH HHS R01 MH084098NIMH NIH HHS RC2 MH089964
Abstract
BACKGROUND &
aimsDrug-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).
methodsTranscriptome-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.
resultsTranscriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10
conclusionsWe 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.
Indexed as
Anti-Bacterial AgentsChemical and Drug Induced Liver InjuryAllelesAminopeptidasesAmoxicillin-Potassium Clavulanate CombinationGenetic Predisposition to DiseaseGenome-Wide Association StudyHLA-A AntigensHLA-DRB1 ChainsHumansLiverPolymorphism, Single NucleotideProtein Tyrosine Phosphatase, Non-Receptor Type 22Risk FactorsAminopeptidasesAmoxicillin-Potassium Clavulanate CombinationAnti-Bacterial AgentsERAP2 protein, humanHLA-A AntigensHLA-DRB1 ChainsProtein Tyrosine Phosphatase, Non-Receptor Type 22PTPN22 protein, humanAmoxicillin-ClavulanateDILIERAP2GWASHLA-B∗15:18
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