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

dc.contributorHáskóli Íslandsen_US
dc.contributorUniversity of Icelanden_US
dc.contributor.authorMcCormack, Mark
dc.contributor.authorGui, Hongsheng
dc.contributor.authorIngason, Andrés
dc.contributor.authorSpeed, Doug
dc.contributor.authorWright, Galen E.B.
dc.contributor.authorZhang, Eunice J.
dc.contributor.authorSecolin, Rodrigo
dc.contributor.authorYasuda, Clarissa
dc.contributor.authorKwok, Maxwell
dc.contributor.authorWolking, Stefan
dc.contributor.authorBecker, Felicitas
dc.contributor.authorRau, Sarah
dc.contributor.authorAvbersek, Andreja
dc.contributor.authorHeggeli, Kristin
dc.contributor.authorLeu, Costin
dc.contributor.authorDepondt, Chantal
dc.contributor.authorSills, Graeme J.
dc.contributor.authorMarson, Anthony G.
dc.contributor.authorAuce, Pauls
dc.contributor.authorBrodie, Martin J.
dc.contributor.authorFrancis, Ben
dc.contributor.authorJohnson, Michael R.
dc.contributor.authorKoeleman, Bobby P.C.
dc.contributor.authorStriano, Pasquale
dc.contributor.authorCoppola, Antonietta
dc.contributor.authorZara, Federico
dc.contributor.authorKunz, Wolfram S.
dc.contributor.authorSander, Josemir W.
dc.contributor.authorLerche, Holger
dc.contributor.authorKlein, Karl Martin
dc.contributor.authorWeckhuysen, Sarah
dc.contributor.authorKrenn, Martin
dc.contributor.authorGudmundsson, Lárus J.
dc.contributor.authorStefansson, Kari
dc.contributor.authorKrause, Roland
dc.contributor.authorShear, Neil
dc.contributor.authorRoss, Colin J.D.
dc.contributor.authorDelanty, Norman
dc.contributor.authorPirmohamed, Munir
dc.contributor.authorCarleton, Bruce C.
dc.contributor.authorCendes, Fernando
dc.contributor.authorLopes-Cendes, Iscia
dc.contributor.authorLiao, Wei-ping
dc.contributor.authorO'Brien, Terence J.
dc.contributor.authorSisodiya, Sanjay M.
dc.contributor.authorCherny, Stacey
dc.contributor.authorKwan, Patrick
dc.contributor.authorBaum, Larry
dc.contributor.authorCavalleri, Gianpiero L.
dc.contributor.departmentLæknadeild (HÍ)en_US
dc.contributor.departmentFaculty of Medicine (UI)en_US
dc.contributor.schoolHeilbrigðisvísindasvið (HÍ)en_US
dc.contributor.schoolSchool of Health Sciences (UI)en_US
dc.date.accessioned2018-11-09T11:38:11Z
dc.date.available2018-11-09T11:38:11Z
dc.date.issued2017-12-29
dc.descriptionPublisher's version (útgefin grein)en_US
dc.description.abstractObjective 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.en_US
dc.description.sponsorshipThis 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.en_US
dc.description.versionPeer Revieweden_US
dc.format.extente332-e341en_US
dc.identifier.citationMcCormack, 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.0000000000004853en_US
dc.identifier.doi10.1212/WNL.0000000000004853
dc.identifier.issn0028-3878
dc.identifier.issn1526-632X (eISSN)
dc.identifier.journalNeurologyen_US
dc.identifier.urihttps://hdl.handle.net/20.500.11815/890
dc.language.isoenen_US
dc.publisherOvid Technologies (Wolters Kluwer Health)en_US
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/279062en_US
dc.relation.ispartofseriesNeurology;90(4)
dc.relation.urlhttps://syndication.highwire.org/content/doi/10.1212/WNL.0000000000004853en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectEpilepsyen_US
dc.subjectSeizuresen_US
dc.subjectNeurologyen_US
dc.subjectCase control studiesen_US
dc.subjectAntiepileptic drugsen_US
dc.subjectAssociation studies in geneticsen_US
dc.subjectPublic healthen_US
dc.subjectFlogaveikien_US
dc.subjectTaugavísindien_US
dc.subjectErfðarannsókniren_US
dc.subjectLýðheilsaen_US
dc.titleGenetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patientsen_US
dc.typeinfo:eu-repo/semantics/articleen_US
dcterms.licenseThis 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.en_US

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