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Lookup NU author(s): Professor Ann DalyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and TherapeuticsCarbamazepine (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(s): Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, Andrade RJ, Wadelius M, Hallberg P, Stephens C, Bjornsson ES, Friedmann P, Kainu K, Laitinen T, Marson A, Molokhia M, Phillips E, Pichler W, Romano A, Shear N, Sills G, Tanno LK, Swale A, Floratos A, Shen Y, Nelson MR, Watkins PB, Daly MJ, Morris AP, Alfirevic A, Pirmohamed M
Publication type: Article
Publication status: Published
Journal: Clinical Pharmacology and Therapeutics
Year: 2019
Volume: 106
Issue: 5
Pages: 1028-1036
Print publication date: 04/10/2019
Online publication date: 07/05/2019
Acceptance date: 17/04/2019
Date deposited: 22/07/2019
ISSN (print): 0009-9236
ISSN (electronic): 1532-6535
Publisher: Nature Publishing Group
URL: https://doi.org/10.1002/cpt.1493
DOI: 10.1002/cpt.1493
PubMed id: 31066027
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