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

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

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29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e332-e341
Number of pages10
JournalNeurology
Volume90
Issue number4
DOIs
Publication statusPublished - 23 Jan 2018
Externally publishedYes

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