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Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Lookup NU author(s): Professor Ann Daly

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

Issue: ePub ahead of Print

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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