Elizabeth T Cirulli1, Paola Nicoletti2, Karen Abramson3, Raul J Andrade4, Einar S Bjornsson5, Naga Chalasani6, Robert J Fontana7, Pär Hallberg8, Yi Ju Li9, M Isabel Lucena4, Nanye Long10, Mariam Molokhia11, Matthew R Nelson12, Joseph A Odin13, Munir Pirmohamed14, Thorunn Rafnar15, Jose Serrano16, Kári Stefánsson15, Andrew Stolz17, Ann K Daly18, Guruprasad P Aithal19, Paul B Watkins20. 1. Duke Center for applied Genomics and Precision Medicine, Duke University, Durham, North Carolina. 2. Department 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. 3. Duke Molecular Physiology Institute, Duke University, Durham, North Carolina. 4. UGC 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. 5. Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland. 6. Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana. 7. University of Michigan, Ann Arbor, Michigan. 8. Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 9. Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina. 10. Institute for Cyber-enabled Research, Michigan State University, East Lansing, Michigan. 11. School of Population Health & Environmental Sciences, King's College, London, UK. 12. Target Sciences, GSK, King of Prussia, Pennsylvania. 13. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 14. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. 15. deCODE genetics, 101 Reykjavik, Iceland. 16. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 17. University of Southern California, Los Angeles, California. 18. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. 19. Nottingham 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. 20. UNC 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.
Abstract
BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We 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. RESULTS: We 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 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In 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.
BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We 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. RESULTS: We 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 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In 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.
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