ArticleGastroenterology2019
A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.
Open access · greenAbstract readValidation Study
In one paragraph
Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 2 of them syntheses that pooled it.
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68citing papers in PubMed, 2 pooled it
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Who cites it
68 citing papers in PubMed, 2 syntheses or guidelines pooled it, 129 citations in OpenAlex.
- Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update.Hepatology international · 2024Guideline
- [Chinese guideline for diagnosis and management of drug-induced liver injury (2023 version)].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2023Guideline
- Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate.Seminars in arthritis and rheumatism · 2022Trial
- The contemporary epidemiology, causes, and management of drug-induced liver injury.Hepatology communications · 2026Review
- Development and validation of a nomogram for predicting chemotherapy-induced liver injury in breast cancer patients.Translational cancer research · 2026Article
- Common Causes of Drug-Induced Liver Injury in 2025.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2026Review
- 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
- Antiseizure Treatments and Liver Injury: Expect (and Prevent) the Unexpected.Epilepsy currents · 2026Review
- Current status of antimicrobial resistance in Indian healthcare system: combating antimicrobial resistance with precision medicine.Frontiers in antibiotics · 2026Review
- Clinical and Genetic Associations in Cephalosporin-Induced Liver Injury: Insights From the Drug-Induced Liver Injury Network.Alimentary pharmacology & therapeutics · 2025Article
- Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity.International journal of molecular sciences · 2025Review
- Identification of key immune genes of drug-induced liver injury induced by tolvaptan based on bioinformatics.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Mechanisms of drug induced liver injury.Cellular and molecular life sciences : CMLS · 2025Review
- Drug-induced liver injury. Part I: Classification, diagnosis and treatment.Clinical and experimental hepatology · 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
- 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
- The role of endoplasmic reticulum aminopeptidase ERAP2 pathogenic mutation rs1363907 in amoxicillin clavulanate-induced liver injury: a special case report.Frontiers in pharmacology · 2025Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 18 institutions in 5 countries.
Elizabeth T CirulliDuke Center for applied Genomics and Precision Medicine, Duke University, Durham, North Carolina.
Paola NicolettiDepartment of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York; Sema4, a Mount Sinai venture, Stamford, Connecticut. Electronic address: paola.nicoletti@mssm.edu.
Karen AbramsonDuke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Raul J AndradeUGC Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain.
Einar S BjornssonDepartment of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
Naga ChalasaniDivision of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
Robert J FontanaUniversity of Michigan, Ann Arbor, Michigan.
Pär HallbergDepartment of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Yi Ju LiDuke Molecular Physiology Institute, Duke University, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
M Isabel LucenaUGC Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain.
Nanye LongInstitute for Cyber-enabled Research, Michigan State University, East Lansing, Michigan.
Mariam MolokhiaSchool of Population Health & Environmental Sciences, King's College, London, UK.
Matthew R NelsonTarget Sciences, GSK, King of Prussia, Pennsylvania.
Joseph A OdinDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Munir PirmohamedDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Thorunn RafnardeCODE genetics, 101 Reykjavik, Iceland.
Jose SerranoNational Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
Kári StefánssondeCODE genetics, 101 Reykjavik, Iceland.
Andrew StolzUniversity of Southern California, Los Angeles, California.
Ann K DalyInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Guruprasad P AithalNottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.
Paul B WatkinsUNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, North Carolina.
Drug-Induced Liver Injury Network (DILIN) investigators
International DILI consortium (iDILIC)
Centro de Investigación Biomédica en Red · ESDuke University · USdeCODE Genetics (Iceland) · ISKing's College London · GBNewcastle University · GBReykjavík University · ISUniversity of Liverpool · GBUniversity of Nottingham · GBUppsala University · SEIcahn School of Medicine at Mount Sinai · USIndiana University School of MedicineMichigan State University · USNational Institute of Diabetes and Digestive and Kidney Diseases · USSema4 (United States) · USTarget (United States) · USUniversity of Michigan · USUniversity of North Carolina at Chapel Hill · USUniversity of Southern California · US
Funding
Southern California Clinical and Translational Science InstituteUL1TR001855 · NCATS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Thomas A Buchanan, Michele D. Kipke · 2016 to 2026
$81.3MMichigan Institute for Clinical and Health Research (MICHR)UL1TR002240 · NCATS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LUMENG, JULIE C, MASHOUR, GEORGE ALEXANDER · 2017 to 2022
$54.9MCTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCHUL1RR024156 · NCRR · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2006 to 2011
$53.0MMICHIGAN 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
$44.6MDrug Induced Liver Injury Network Data Coordinating CenterU01DK065176 · NIDDK · DUKE UNIVERSITY · PI Huiman X Barnhart · 2003 to 2026
$25.5MINDIANA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (UL1): BPCAUL1RR025761 · NCRR · INDIANA UNIVERSITY INDIANAPOLIS · PI SHEKHAR, ANANTHA · 2008 to 2011
$21.0MSNP HEALTH ASSOCIATION RESOURCE (SHARE)N02HL64278 · NHLBI · PI CHIN, SIANG · 2007 to 2007
$9.2MCoordinating 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
$7.3MMichigan Hepatotoxicity Clinical Research Network Renewal 2018U01DK065184 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ROBERT J FONTANA · 2003 to 2026
$7.0MMedical Research Council MR/L006758/1Medical Research Council MR/N005953/1NCATS NIH HHS UL1 TR001855NCATS NIH HHS UL1 TR002240NCRR NIH HHS UL1 RR024156NCRR NIH HHS UL1 RR024986NCRR NIH HHS UL1 RR025747NCRR NIH HHS UL1 RR025761NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS N02HL64278NIDDK 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 DK065176Wellcome Trust
Abstract
BACKGROUND &
aimsWe performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.
methodsWe performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.
resultsWe associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10
conclusionsIn a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
Indexed as
AdultAmoxicillinAnti-Bacterial AgentsBlack or African AmericanCase-Control StudiesChemical and Drug Induced Liver InjuryClavulanic AcidFemaleGene FrequencyGenome-Wide Association StudyHispanic or LatinoHLA-A2 AntigenHLA-DRB1 ChainsHumansMaleMiddle AgedAmoxicillinAnti-Bacterial AgentsClavulanic AcidHLA-A*02:01 antigenHLA-A2 AntigenHLA-DRB1*15:01 antigenHLA-DRB1 ChainsProtein Tyrosine Phosphatase, Non-Receptor Type 22PTPN22 protein, humanAmino Acid ChangeGWASInflammationMutation
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