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

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McCormack, Mark ^{[1, 2]} ; Gui, Hongsheng ^[3] ; Ingason, Andres ^[4] ; Speed, Doug ^[5] ; Wright, Galen E. B. ^[6] ; Zhang, Eunice J. ^[7] ; Secolin, Rodrigo ^[8] ; Yasuda, Clarissa ^{[9, 10]} ; Kwok, Maxwell ^{[11, 12]} ; Wolking, Stefan ^{[13, 14]} ; Becker, Felicitas ^[13] ; Rau, Sarah ^[13] ; Avbersek, Andreja ^[13] ; Heggeli, Kristin ^[13] ; Leu, Costin ^[13] ; Depondt, Chantal ^{[15, 16]} ; Sills, Graeme J. ^[7] ; Marson, Anthony G. ^{[7, 17]} ; Auce, Pauls ^{[7, 17]} ; Brodie, Martin J. ^[18] ; Francis, Ben ^[19] ; Johnson, Michael R. ^[20] ; Koeleman, Bobby P. C. ^[21] ; Striano, Pasquale ^[22] ; Coppola, Antonietta ^[23] ; Zara, Federico ^[24] ; Kunz, Wolfram S. ^[25] ; Sander, Josemir W. ^{[26, 27, 28]} ; Lerche, Holger ^[11] ; Klein, Karl Martin ^{[29, 30, 31]} ; Weckhuysen, Sarah ^[32] ; Krenn, Martin ; Gudmundsson, Larus J. ^[4] ; Stefansson, Kari ^{[4, 33]} ; Krause, Roland ^[34] ; Shear, Neil ^[35] ; Ross, Colin J. D. ^{[36, 37]} ; Delanty, Norman ^[1] ; Pirmohamed, Munir ^[7] ; Carleton, Bruce C. ^[38] ; Cendes, Fernando ^{[9, 10]} ; Lopes-Cendes, Iscia ^[8] ; Liao, Wei-ping ^{[39, 40]} ; O'Brien, Terence J. ^{[41, 42]} ; Sisodiya, Sanjay M. ^{[13, 26]} ; Cherny, Stacey ^[3] ; Kwan, Patrick ^{[41, 42]} ; Baum, Larry ^[3] ; Cavalleri, Gianpiero L. ^{[1, 43]} ; Consortium, EPIGEN ; Network, Canadian Pharmacogenomics ; for the EpiPGX Consortium ; Consortium, Int League Epilepsy

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^[1] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin - Ireland

^[2] Univ Med Ctr, Ctr Mol Med, Utrecht - Netherlands

^[3] Univ Hong Kong, Li Ka Shing Fac Med, Ctr Genom Sci, Hong Kong, Hong Kong - Peoples R China

^[4] deCODE Genet Amgen Inc, Reykjavik - Iceland

^[5] UCL, UCL Genet Inst, London - England

^[6] BC Childrens Hosp, Res Inst, Fac Med, Ctr Mol Med & Therapeut, Vancouver, BC - Canada

^[7] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside - England

^[8] Univ Estadual Campinas, Sch Med Sci, Dept Med Genet, Campinas, SP - Brazil

^[9] Brazilian Inst Neurosci & Neurotechnol BRAINN, Campinas, SP - Brazil

^[10] Univ Estadual Campinas, Sch Med Sci, Dept Neurol, Campinas, SP - Brazil

^[11] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen - Germany

^[12] Med Univ Vienna, Dept Neurol, Vienna - Austria

^[13] NIHR Univ Coll London Hosp, Dept Clin & Expt Epilepsy, London - England

^[14] Univ Hosp Antwerp, Dept Neurol, Antwerp - Belgium

^[15] UCL Inst Neurol, London - England

^[16] Univ Libre Bruxelles, Hop Erasme, Lab Expt Neurol, Brussels - Belgium

^[17] Walton Ctr NHS Fdn Trust, Liverpool, Merseyside - England

^[18] West Glasgow ACH Yorkhill, Epilepsy Unit, Glasgow, Lanark - Scotland

^[19] Univ Liverpool, Inst Translat Med, Dept Biostat, Liverpool, Merseyside - England

^[20] Imperial Coll, Fac Med, Div Brain Sci, London - England

^[21] Univ Med Ctr, Div Neurosci, Utrecht - Netherlands

^[22] Univ Genoa, Pediat Neurol & Muscular Dis Unit, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa - Italy

^[23] Univ Naples Federico II, Dept Neurosci, Reprod & Odontostomatol Sci, Naples - Italy

^[24] Inst G Gaslini, Lab Neurogenet & Neurosci, Genoa - Italy

^[25] Univ Bonn, Dept Epileptol, Bonn - Germany

^[26] Chalfont Ctr Epilepsy, Epilepsy Soc, Gerrards Cross, Bucks - England

^[27] NIHR Univ Coll London Hosp, Biomed Res Ctr, London - England

^[28] SEIN, Heemstede - Netherlands

^[29] Goethe Univ Frankfurt, Univ Hosp, Ctr Neurol & Neurosurg, Epilepsy Ctr Frankfurt Rhine Main, Dept Neurol, Frankfurt - Germany

^[30] Univ Hosp Giessen & Marburg, Dept Neurol, Epilepsy Ctr Hessen, Marburg - Germany

^[31] Philipps Univ Marburg, Marburg - Germany

^[32] VIB UAntwerp, Ctr Mol Neurol, Neurogenet Grp, Antwerp - Belgium

^[33] Univ Iceland, Fac Med, Reykjavik - Iceland

^[34] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Luxembourg - Luxembourg

^[35] Univ Toronto, Toronto, ON - Canada

^[36] Univ British Columbia, Dept Pediat, Vancouver, BC - Canada

^[37] Univ British Columbia, Dept Med Genet, Vancouver, BC - Canada

^[38] Univ British Columbia, Dept Pediat, Div Translat Therapeut, Vancouver, BC - Canada

^[39] Guangzhou Med Univ, Inst Neurosci, Guangzhou, Guangdong - Peoples R China

^[40] Guangzhou Med Univ, Affiliated Hosp 2, Guangzhou, Guangdong - Peoples R China

^[41] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic - Australia

^[42] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic - Australia

^[43] Royal Coll Surgeons Ireland, FutureNeuro Res Ctr, Dublin - Ireland

• Tipo de documento: Artigo Científico
• Fonte: Neurology; v. 90, n. 4, p. E332+, JAN 23 2018.
• Citações Web of Science: 10

Resumo

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.MethodsWe 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.ResultsWe 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 x 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.ConclusionsThe 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. (AU)

• Processo FAPESP: 13/07559-3 - Instituto Brasileiro de Neurociência e Neurotecnologia - BRAINN
• Beneficiário: Fernando Cendes
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs