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

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posted on 2022-03-07, 12:30 authored by Mark McCormack, Hongsheng Gui, Andrés Ingason, Doug Speed, Galen E B Wright, Eunice J Zhang, Rodrigo Secolin, Clarissa 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 Brodie, Ben 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, Kári Stefánsson, Roland Krause, Neil Shear, Colin J D Ross, Norman DelantyNorman Delanty, Munir Pirmohamed, Bruce C Carleton, Fernando Cendes, Iscia Lopes-Cendes, Wei-Ping Liao, Terence J O'Brien, Sanjay M Sisodiya, Stacey Cherny, Patrick Kwan, Larry Baum, Gianpiero CavalleriGianpiero Cavalleri

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.


The work was supported by a grant from the European Commission (7th Framework Programme Grant 279062, EpiPGX). M.M.C. and G.L.C. are supported by Science Foundation Ireland, grant 13/CDA/2223, and an RCSI seed funding grant GA 14-1899. This project was supported by the General Research Funds (HKU7623/08M and HKU7747/07M to S.C., CUHK4466/06M to P.K.) and Health and Medical Research Fund (HMRF 01120086 to P.K.) from Hong Kong. Some results presented in this article were prepared using the HPC facilities of the University of Luxembourg. This work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme (J.W.S., S.M.S.). The work was also supported by the Epilepsy Society, UK (J.W.S., S.M.S.), by the foundation “no epilep,” the German Chapter of the ILAE (DGfE) (both to H.L.). F.C. and I.L.-C. are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil, through grant 2013/07559-3. J.E.Z. and M.P. thank the NHS Chair of Pharmacogenetics programme and MRC Centre for Drug Safety Science for support in Liverpool. B.C.C. and C.J.D.R. are supported by the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (FRN-117588), the Canada Foundation for Innovation and the Canadian Dermatology Foundation. G.E.B.W. is supported by a CIHR Fellowship.



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McCormack M, Gui H, Ingason A, Speed D, Wright GB, Zhang EJ, Secolin R, Yasuda C, Kwok M, Wolking S, Becker F, Rau S, Avbersek A, Heggeli K, Leu C, Depondt C, Sills GJ, Marson AG, Auce P, Brodie MJ, Francis B, Johnson MR, Koeleman BPC, Striano P, Coppola A, Zara F, Kunz WS, Sander JW, Lerche H, Klein KM, Weckhuysen S, Krenn M, Gudmundsson LJ, Stefánsson K, Krause R, Shear N, Ross CJD, Delanty N, Pirmohamed M, Carleton BC, Cendes F, Lopes-Cendes I, Liao WP, O'Brien TJ, Sisodiya SM for the EpiPGX Consortium, Cherny S, Kwan P, Baum L, Cavalleri GL. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology. 2018; 90(4):e332-e341.

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  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

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