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Clin Pharmacol Ther. 2019 May 7. doi: 10.1002/cpt.1493. [Epub ahead of print]

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

Author information

1
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Sema4, a Mount Sinai Venture, Stamford, Connecticut, USA.
3
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
4
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
5
National Institute for Health Research (NIHR) Nottingham Biomedical Research Unit, Center at the Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.
6
UGC Digestivo, Clinical Pharmacology Service, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.
7
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
8
Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
9
Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
10
Dermatology Unit, School of Medicine, University of Southampton, Southampton, UK.
11
Clinical Research Unit for Pulmonary Diseases, Helsinki University Central Hospital, Helsinki, Finland.
12
School of Population Sciences and Health Services Research, King's College, London, UK.
13
Departiment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
14
ADR-AC GmbH, Bern, Switzerland.
15
Allergy Unit, Complesso Integrato Columbus, Rome, Italy.
16
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
17
Hospital Sírio Libanês, São Paulo, Brazil.
18
Department of Systems Biology, Columbia University, New York, New York, USA.
19
Target Sciences, GSK, King of Prussia, Pennsylvania, USA.
20
Eshelman School of Pharmacy, University of North Carolina Institute for Drug Safety Sciences, Chapel Hill, North Carolina, USA.
21
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
22
Department of Biostatistics, University of Liverpool, Liverpool, UK.

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 × 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.

PMID:
31066027
DOI:
10.1002/cpt.1493

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