Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

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Nicoletti , P , Barrett , S , McEvoy , L , Daly , A K , Aithal , G , Isabel Lucena , M , Andrade , R J , Wadelius , M , Hallberg , P , Stephens , C , Bjornsson , E S , Friedmann , P , Kainu , K , Laitinen , T , Marson , A , Molokhia , M , Phillips , E , Pichler , W , Romano , A , Shear , N , Sills , G , Tanno , L K , Swale , A , Floratos , A , Shen , Y , Nelson , M R , Watkins , P B , Daly , M J , Morris , A P , Alfirevic , A & Pirmohamed , M 2019 , ' Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions ' , Clinical Pharmacology and Therapeutics , vol. 106 , no. 5 , pp. 1028-1036 . https://doi.org/10.1002/cpt.1493

Title: Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions
Author: Nicoletti, Paola; Barrett, Sarah; McEvoy, Laurence; Daly, Ann K.; Aithal, Guruprasad; Isabel Lucena, M.; Andrade, Raul J.; Wadelius, Mia; Hallberg, Paer; Stephens, Camilla; Bjornsson, Einar S.; Friedmann, Peter; Kainu, Kati; Laitinen, Tarja; Marson, Anthony; Molokhia, Mariam; Phillips, Elizabeth; Pichler, Werner; Romano, Antonino; Shear, Neil; Sills, Graeme; Tanno, Luciana K.; Swale, Ashley; Floratos, Aris; Shen, Yufeng; Nelson, Matthew R.; Watkins, Paul B.; Daly, Mark J.; Morris, Andrew P.; Alfirevic, Ana; Pirmohamed, Munir
Contributor: University of Helsinki, Department of Dermatology, Allergology and Venereology
University of Helsinki, University Management
Date: 2019-11
Language: eng
Number of pages: 9
Belongs to series: Clinical Pharmacology and Therapeutics
ISSN: 0009-9236
URI: http://hdl.handle.net/10138/306789
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 x 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 x 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.
Subject: ADVERSE DRUG-REACTIONS
STEVENS-JOHNSON-SYNDROME
GENOME-WIDE ASSOCIATION
LIVER-INJURY
HLA GENOTYPE
POPULATION
HLA-A-ASTERISK-31/01
OXCARBAZEPINE
DISEASE
MARKERS
317 Pharmacy
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