Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions.

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Nicoletti, Paola, Barrett, Sarah, McEvoy, Laurence ORCID: 0000-0002-2169-6735, Daly, Ann K, Aithal, Guruprasad, Lucena, M Isabel, Andrade, Raul J, Wadelius, Mia, Hallberg, Pär, Stephens, Camilla et al (show 21 more authors) , Bjornsson, Einar S, Friedmann, Peter, Kainu, Kati, Laitinen, Tarja, Marson, Anthony ORCID: 0000-0002-6861-8806, Molokhia, Mariam, Phillips, Elizabeth, Pichler, Werner, Romano, Antonino, Shear, Neil, Sills, Graeme ORCID: 0000-0002-3389-8713, Tanno, Luciana K, Sawle, Ashley, Floratos, Aris, Shen, Yufeng, Nelson, Matthew R, Watkins, Paul B, Daly, Mark J, Morris, Andrew P, Alfirevic, Ana ORCID: 0000-0002-2801-9817 and Pirmohamed, Munir ORCID: 0000-0002-7534-7266 (2019) Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions. Clinical pharmacology and therapeutics, 106 (5). pp. 1028-1036.

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Abstract

Carbamazepine (CBZ) causes life-threating T-cell mediated hypersensitivity reactions (CBZ-HRs) including serious cutaneous adverse reactions (SCAR) and liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ-HRs, we performed a meta-analysis of two GWAS studies 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 (OR= 8.0; 95% CI 4.10-15.80; P=1.2x10-9 ) 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 SCAR patients was mainly driven by hypersensitivity syndrome (OR = 12.9; P=2.1x10-9 ) rather than by Stevens-Johnson Syndrome/toxic epidermal necolysis (SJS/TEN) 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. This article is protected by copyright. All rights reserved.

Item Type:	Article
Uncontrolled Keywords:	Humans, Stevens-Johnson Syndrome, Drug Hypersensitivity, Genetic Predisposition to Disease, Carbamazepine, HLA-A Antigens, HLA-B Antigens, Risk Factors, Phenotype, Adult, Europe, Female, Male, Genome-Wide Association Study, Drug Hypersensitivity Syndrome, Chemical and Drug Induced Liver Injury, Anaplastic Lymphoma Kinase
Depositing User:	Symplectic Admin
Date Deposited:	17 May 2019 07:36
Last Modified:	19 Jan 2023 00:46
DOI:	10.1002/cpt.1493
Open Access URL:	https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3041211