A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.

To access publisher's full text version of this article click on the hyperlink belowWe performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. 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. 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 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.National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) CTSA International Serious Adverse Events Consortium Abbott Amgen Daiichi-Sankyo GlaxoSmithKline Merck Novartis Pfizer Roche Sanofi-Aventis Takeda Wellcome Trust National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust University of Nottingham EC 5th Framework program Spanish Medicine Agency Fondo Europeo de Desarrollo Regional - FEDER Instituto de Salud Carlos III Swedish Medical Products Agency Swedish Society of Medicine Swedish Research Council Swedish Heart and Lung Foundation National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College Londo