@article{792c763e166a4375b873058808581920,
title = "Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions",
abstract = "Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ-DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.",
author = "Paola Nicoletti and Sarah Barrett and Laurence McEvoy and Daly, {Ann K.} and Guruprasad Aithal and Lucena, {M. Isabel} and Andrade, {Raul J.} and Mia Wadelius and P{\"a}r Hallberg and Camilla Stephens and Bjornsson, {Einar S.} and Peter Friedmann and Kati Kainu and Tarja Laitinen and Anthony Marson and Mariam Molokhia and Elizabeth Phillips and Werner Pichler and Antonino Romano and Neil Shear and Graeme Sills and Tanno, {Luciana K.} and Ashley Swale and Aris Floratos and Yufeng Shen and Nelson, {Matthew R.} and Watkins, {Paul B.} and Daly, {Mark J.} and Morris, {Andrew P.} and Ana Alfirevic and Munir Pirmohamed",
note = "Funding Information: This work was supported by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a nonprofit organization dedicated to identifying and validating DNA-variants useful in predicting the risk of drug-related serious adverse events. The Consortium brings together the pharmaceutical industry, regulatory authorities, and academic centers to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC's current funding members include: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and the Wellcome Trust. M.P. is an NIHR Senior Investigator. M.P. and A.A. thank the MRC Centre for Drug Safety Science for support (MR/L006758/1). P.N. was supported by iSAEC. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (under award WT098017). This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The DILIN (https://dilin.org/) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) as a Cooperative Agreement (U01s). The Spanish DILI Registry is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional (FEDER; FIS 12/00378, FIS 16/01748). CIBERehd is funded by Instituto de Salud Carlos III. The Swedish case collection SWEDEGENE (www.swedegene.se) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), and Swedish Heart and Lung Foundation (20120557 and 20140291). The EUDRAGENE collaboration received support from the EC 5th Framework program (QLRI-CT-2002-02757). M.M. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas{\textquoteright} NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Special thanks to Arthur Holden for his help and effort in guiding this collaborative work and to the broad genotyping facility for their contribution to the genomewide association studies genotyping. We are grateful to Daniele Cusi (Hypergenes), Patrik K. Magnusson (Swedish Twin Registry), and Javier Martin (Spanish DNA bank) for provision of control data. The data presented in the current publication are also based on the use of study data downloaded from the dbGaP website, under phs000346.v1.p1. We also acknowledge the contribution of all our clinical collaborators and the study participants. Publisher Copyright: {\textcopyright} 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics",
year = "2019",
month = nov,
day = "1",
doi = "10.1002/cpt.1493",
language = "English",
volume = "106",
pages = "1028--1036",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Wiley-Blackwell",
number = "5",
}