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Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

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Authors
Nicoletti, Paola
Barrett, Sarah
McEvoy, Laurence
Daly, Ann K
Aithal, Guruprasad
Lucena, M Isabel
Andrade, Raul J
Wadelius, Mia
Hallberg, Pär
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
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Issue Date
2019-11

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Citation
Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, Andrade RJ, Wadelius M, Hallberg P, Stephens C, Bjornsson ES. Shared genetic risk factors across carbamazepine‐induced hypersensitivity reactions. Clinical Pharmacology & Therapeutics. 2019, 105(5):1028-36.
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.
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https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.1493
ae974a485f413a2113503eed53cd6c53
10.1002/cpt.1493
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