Paola Nicoletti1, Guruprasad P Aithal2, Einar S Bjornsson3, Raul J Andrade4, Ashley Sawle1, Marco Arrese5, Huiman X Barnhart6, Emmanuelle Bondon-Guitton7, Paul H Hayashi8, Fernando Bessone9, Alfonso Carvajal10, Ingolf Cascorbi11, Elizabeth T Cirulli6, Naga Chalasani12, Anita Conforti13, Sally A Coulthard14, Mark J Daly15, Christopher P Day14, John F Dillon16, Robert J Fontana17, Jane I Grove2, Pär Hallberg18, Nelia Hernández19, Luisa Ibáñez20, Gerd A Kullak-Ublick21, Tarja Laitinen22, Dominique Larrey23, M Isabel Lucena4, Anke H Maitland-van der Zee24, Jennifer H Martin25, Mariam Molokhia26, Munir Pirmohamed27, Elizabeth E Powell28, Shengying Qin29, Jose Serrano30, Camilla Stephens4, Andrew Stolz31, Mia Wadelius18, Paul B Watkins32, Aris Floratos1, Yufeng Shen1, Matthew R Nelson33, Thomas J Urban34, Ann K Daly35. 1. Department of Systems Biology, Columbia University, New York, New York. 2. National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital, National Health Service Trust, and University of Nottingham, Nottingham, United Kingdom. 3. Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland. 4. Unidad de Gestión Clínica Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Málaga, Spain. 5. Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. 6. Duke University, Durham, North Carolina. 7. Universite de Toulouse, Toulouse, France. 8. Department of Internal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina. 9. Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina. 10. Universidad de Valladolid, Valladolid, Spain. 11. Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany. 12. Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana. 13. University Hospital, Verona, Italy. 14. Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom. 15. Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts. 16. Medical Research Institute, University of Dundee, Ninewells Hospital, Dundee, United Kingdom. 17. University of Michigan, Ann Arbor, Michigan. 18. Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 19. Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay. 20. Fundació Institut Català de Farmacologia, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 21. Department of Clinical Pharmacology and Toxicology, University Hospital and University of Zurich, Zurich, Switzerland. 22. Clinical Research Unit for Pulmonary Diseases, Helsinki University Central Hospital, Helsinki, Finland. 23. Liver Unit, Centre Hospitalier Universitaire, St Eloi Hospital, Montpellier, France. 24. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, Netherlands. 25. School of Medicine and Public Health, University of Newcastle, New South Wales, Australia. 26. Department of Primary Care and Public Health Sciences, King's College, London, United Kingdom. 27. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. 28. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia. 29. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China. 30. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 31. University of Southern California, Los Angeles, California. 32. University of North Carolina Institute for Drug Safety Sciences, Eshelman School of Pharmacy, Chapel Hill, North Carolina. 33. Target Sciences, GlaxoSmithKlein, King of Prussia, Pennsylvania. 34. UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina. 35. Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom. Electronic address: a.k.daly@ncl.ac.uk.
Abstract
BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
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