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Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients

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dc.contributor Háskóli Íslands
dc.contributor University of Iceland
dc.contributor.author McCormack, Mark
dc.contributor.author Gui, Hongsheng
dc.contributor.author Ingason, Andrés
dc.contributor.author Speed, Doug
dc.contributor.author Wright, Galen E.B.
dc.contributor.author Zhang, Eunice J.
dc.contributor.author Secolin, Rodrigo
dc.contributor.author Yasuda, Clarissa
dc.contributor.author Kwok, Maxwell
dc.contributor.author Wolking, Stefan
dc.contributor.author Becker, Felicitas
dc.contributor.author Rau, Sarah
dc.contributor.author Avbersek, Andreja
dc.contributor.author Heggeli, Kristin
dc.contributor.author Leu, Costin
dc.contributor.author Depondt, Chantal
dc.contributor.author Sills, Graeme J.
dc.contributor.author Marson, Anthony G.
dc.contributor.author Auce, Pauls
dc.contributor.author Brodie, Martin J.
dc.contributor.author Francis, Ben
dc.contributor.author Johnson, Michael R.
dc.contributor.author Koeleman, Bobby P.C.
dc.contributor.author Striano, Pasquale
dc.contributor.author Coppola, Antonietta
dc.contributor.author Zara, Federico
dc.contributor.author Kunz, Wolfram S.
dc.contributor.author Sander, Josemir W.
dc.contributor.author Lerche, Holger
dc.contributor.author Klein, Karl Martin
dc.contributor.author Weckhuysen, Sarah
dc.contributor.author Krenn, Martin
dc.contributor.author Gudmundsson, Lárus J.
dc.contributor.author Stefánsson, Kári
dc.contributor.author Krause, Roland
dc.contributor.author Shear, Neil
dc.contributor.author Ross, Colin J.D.
dc.contributor.author Delanty, Norman
dc.contributor.author Pirmohamed, Munir
dc.contributor.author Carleton, Bruce C.
dc.contributor.author Cendes, Fernando
dc.contributor.author Lopes-Cendes, Iscia
dc.contributor.author Liao, Wei-ping
dc.contributor.author O'Brien, Terence J.
dc.contributor.author Sisodiya, Sanjay M.
dc.contributor.author Cherny, Stacey
dc.contributor.author Kwan, Patrick
dc.contributor.author Baum, Larry
dc.contributor.author Cavalleri, Gianpiero L.
dc.date.accessioned 2018-11-09T11:38:11Z
dc.date.available 2018-11-09T11:38:11Z
dc.date.issued 2017-12-29
dc.identifier.citation McCormack, M., Gui, H., Ingason, A., Speed, D., Wright, G. E. B., Zhang, E. J., . . . Cavalleri, G. L. (2018). Genetic variation in <em>CFH</em> predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology, 90(4), e332-e341. doi:10.1212/wnl.0000000000004853
dc.identifier.issn 0028-3878
dc.identifier.issn 1526-632X (eISSN)
dc.identifier.uri https://hdl.handle.net/20.500.11815/890
dc.description Publisher's version (útgefin grein)
dc.description.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.
dc.description.sponsorship This study was not industry-sponsored. 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. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. M.M.C., H.G., and G.L.C. had full access to all the data in the study and the corresponding authors had final responsibility for the decision to submit for publication. The Article Processing Charge was funded by the European Commission OpenAIRE2020 project.
dc.format.extent e332-e341
dc.language.iso en
dc.publisher Ovid Technologies (Wolters Kluwer Health)
dc.relation info:eu-repo/grantAgreement/EC/FP7/279062
dc.relation.ispartofseries Neurology;90(4)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Epilepsy
dc.subject Seizures
dc.subject Neurology
dc.subject Case control studies
dc.subject Antiepileptic drugs
dc.subject Association studies in genetics
dc.subject Public health
dc.subject Flogaveiki
dc.subject Taugavísindi
dc.subject Erfðarannsóknir
dc.subject Lýðheilsa
dc.title Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients
dc.type info:eu-repo/semantics/article
dcterms.license This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.description.version Peer Reviewed
dc.identifier.journal Neurology
dc.identifier.doi 10.1212/WNL.0000000000004853
dc.relation.url https://syndication.highwire.org/content/doi/10.1212/WNL.0000000000004853
dc.contributor.department Læknadeild (HÍ)
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)


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