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Multicenter Study
. 2018 Jan 23;90(4):e332-e341.
doi: 10.1212/WNL.0000000000004853. Epub 2017 Dec 29.

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Mark McCormack  1 , Hongsheng Gui  1 , Andrés Ingason  1 , Doug Speed  1 , Galen E B Wright  1 , Eunice J Zhang  1 , Rodrigo Secolin  1 , Clarissa Yasuda  1 , Maxwell Kwok  1 , Stefan Wolking  1 , Felicitas Becker  1 , Sarah Rau  1 , Andreja Avbersek  1 , Kristin Heggeli  1 , Costin Leu  1 , Chantal Depondt  1 , Graeme J Sills  1 , Anthony G Marson  1 , Pauls Auce  1 , Martin J Brodie  1 , Ben Francis  1 , Michael R Johnson  1 , Bobby P C Koeleman  1 , Pasquale Striano  1 , Antonietta Coppola  1 , Federico Zara  1 , Wolfram S Kunz  1 , Josemir W Sander  1 , Holger Lerche  1 , Karl Martin Klein  1 , Sarah Weckhuysen  1 , Martin Krenn  1 , Lárus J Gudmundsson  1 , Kári Stefánsson  1 , Roland Krause  1 , Neil Shear  1 , Colin J D Ross  1 , Norman Delanty  1 ; EPIGEN Consortium;; Munir Pirmohamed  1 , Bruce C Carleton  1 ; Canadian Pharmacogenomics Network for Drug Safety;; Fernando Cendes  1 , Iscia Lopes-Cendes  1 , Wei-Ping Liao  1 , Terence J O'Brien  1 , Sanjay M Sisodiya  1 ; EpiPGX Consortium;; Stacey Cherny  1 , Patrick Kwan  1 , Larry Baum  1 ; International League Against Epilepsy Consortium on Complex Epilepsies;; Gianpiero L Cavalleri  2
Collaborators, Affiliations
Multicenter Study

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Mark McCormack et al. Neurology. .

Erratum in

Abstract

Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.

Methods: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.

Results: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.

Conclusions: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

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Figures

Figure 1
Figure 1. Meta-analysis results across European and Han Chinese cohorts
Manhattan (a) and quantile–quantile (b) plots for the meta-analyses of maculopapular exanthema vs tolerant controls, for (A) any antiepileptic drug (genomic inflation factor [λ] = 1.01), (B) carbamazepine (λ = 1.01), (C) lamotrigine (λ = 0.99), and (D) phenytoin (λ = 0.98).
Figure 2
Figure 2. Intronic CFHR4 variants are associated with phenytoin-induced maculopapular exanthema (MPE) in Europeans
(A) Manhattan and (B) quantile–quantile plot of phenytoin-induced MPE in the European subgroup (λ = 1.01). The LocusZoom plot (C) highlights the most significant single nucleotide polymorphism (SNP), rs78239784 (purple dot), is an intronic variant in CFHR4.
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