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Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions
Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Sema4, Stamford, CT USA.
Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.ORCID iD: 0000-0002-2169-6735
Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
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2019 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 106, no 5, p. 1028-1036Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 106, no 5, p. 1028-1036
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Gastroenterology and Hepatology
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URN: urn:nbn:se:uu:diva-396697DOI: 10.1002/cpt.1493ISI: 000488891600027PubMedID: 31066027OAI: oai:DiVA.org:uu-396697DiVA, id: diva2:1368910
Funder
Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20120557Swedish Research Council, 521-2014-3370Swedish Research Council, 521-2011-2440Swedish Society of Medicine, 2008-21619Available from: 2019-11-08 Created: 2019-11-08 Last updated: 2019-11-08Bibliographically approved

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