%D 2018
%O Copyright © 2017 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
%P e332-e341
%V 90
%L discovery10041504
%C United States
%N 4
%A M McCormack
%A H Gui
%A A Ingason
%A D Speed
%A GEB Wright
%A EJ Zhang
%A R Secolin
%A C Yasuda
%A M Kwok
%A S Wolking
%A F Becker
%A S Rau
%A A Avbersek
%A K Heggeli
%A C Leu
%A C Depondt
%A GJ Sills
%A AG Marson
%A P Auce
%A MJ Brodie
%A B Francis
%A MR Johnson
%A BPC Koeleman
%A P Striano
%A A Coppola
%A F Zara
%A WS Kunz
%A JW Sander
%A H Lerche
%A KM Klein
%A S Weckhuysen
%A M Krenn
%A LJ Gudmundsson
%A K Stefánsson
%A R Krause
%A N Shear
%A CJD Ross
%A N Delanty
%A . EPIGEN Consortium
%A M Pirmohamed
%A BC Carleton
%A . Canadian Pharmacogenomics Network for Drug Safety
%A F Cendes
%A I Lopes-Cendes
%A W-P Liao
%A TJ O'Brien
%A SM Sisodiya
%A . EpiPGX Consortium
%A S Cherny
%A P Kwan
%A L Baum
%A . ILAE-CGC
%A GL Cavalleri
%T Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients
%J Neurology
%X 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.