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Meta-Analysis
. 2019 Nov;106(5):1028-1036.
doi: 10.1002/cpt.1493. Epub 2019 Jul 3.

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Paola Nicoletti  1   2 , Sarah Barrett  3 , Laurence McEvoy  3 , Ann K Daly  4 , Guruprasad Aithal  5 , M Isabel Lucena  6   7 , Raul J Andrade  6   7 , Mia Wadelius  8 , Pär Hallberg  8 , Camilla Stephens  6   7 , Einar S Bjornsson  9 , Peter Friedmann  10 , Kati Kainu  11 , Tarja Laitinen  11 , Anthony Marson  3 , Mariam Molokhia  12 , Elizabeth Phillips  13 , Werner Pichler  14 , Antonino Romano  15 , Neil Shear  16 , Graeme Sills  3 , Luciana K Tanno  17 , Ashley Swale  18 , Aris Floratos  18 , Yufeng Shen  18 , Matthew R Nelson  19 , Paul B Watkins  20 , Mark J Daly  21 , Andrew P Morris  3   22 , Ana Alfirevic  3 , Munir Pirmohamed  3
Affiliations
Meta-Analysis

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Paola Nicoletti et al. Clin Pharmacol Ther. 2019 Nov.

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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Conflict of interest statement

P.N. is an employee of Sema4 Mount Sinai venture, Stamford, CT, USA. M.R.N. is an employee of GlaxoSmithKline. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Scatterplot representing the first two principal components (PCs) of the current study cohort. Colored dots are the cases divided by clinical phenotypes and the gray dots are the controls. The controls cluster in four groups representing the Italian, Spanish, United Kingdom, and Swedish major control populations. AGEP, acute generalized exanthematous pustulosis; DILI, drug‐induced liver injury; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS/TEN, Stevens‐Johnson syndrome/toxic epidermal necrolysis.
Figure 2
Figure 2
Manhattan plot displaying the results of the meta‐analysis of British and broadly European carbamazepine–serious cutaneous adverse reactions genomewide association study analyses. Single nucleotide polymorphisms in red have a significance level < 5 × 10−8.
See this image and copyright information in PMC

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