Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions

Nicoletti, P. et al. (2019) Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions. Clinical Pharmacology and Therapeutics, 106(5), pp. 1028-1036. (doi: 10.1002/cpt.1493) (PMID:31066027) (PMCID:PMC7156285)

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.

• Item Type: Articles
• Additional Information: This work was supported by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a non-profit 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. MP is a NIHR Senior Investigator. MP and AA thank the MRC Centre for Drug Safety Science for support ( MR/L006758/1). PN was supported by iSAEC. Andrew P Morris 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.dcri.duke.edu/) 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).MM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: Nicoletti, P., Barrett, S., McEvoy, L., Daly, A., Aithal, G., Lucena, M. I., Andrade, R., Wadelius, M., Hallberg, P., Stephens, C., Bjornsson, E., Friedmann, P., Kainu, K., Laitinen, T., Marson, A., Molokhia, M., Phillips, E., Pichler, W. J., Romano, A., Shear, N., Sills, G., Tanno, L., Sawle, A., Floratos, A., Shen, Y., Nelson, M., Watkins, P., Daly, M. J., Morris, A., Alfirevic, A., and Pirmohamed, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Clinical Pharmacology and Therapeutics
• Publisher: Wiley
• ISSN: 0009-9236
• ISSN (Online): 1532-6535
• Published Online: 07 May 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Clinical Pharmacology and Therapeutics 106(5): 1028-1036
• Publisher Policy: Reproduced under a Creative Commons License