PMID- 29288229 OWN - NLM STAT- MEDLINE DCOM- 20190722 LR - 20240404 IS - 1526-632X (Electronic) IS - 0028-3878 (Print) IS - 0028-3878 (Linking) VI - 90 IP - 4 DP - 2018 Jan 23 TI - Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. PG - e332-e341 LID - 10.1212/WNL.0000000000004853 [doi] AB - 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 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. 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. CI - Copyright (c) 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. FAU - McCormack, Mark AU - McCormack M AD - Author affiliations are provided at the end of the article. FAU - Gui, Hongsheng AU - Gui H AD - Author affiliations are provided at the end of the article. FAU - Ingason, Andres AU - Ingason A AD - Author affiliations are provided at the end of the article. FAU - Speed, Doug AU - Speed D AD - Author affiliations are provided at the end of the article. FAU - Wright, Galen E B AU - Wright GEB AD - Author affiliations are provided at the end of the article. FAU - Zhang, Eunice J AU - Zhang EJ AD - Author affiliations are provided at the end of the article. FAU - Secolin, Rodrigo AU - Secolin R AD - Author affiliations are provided at the end of the article. FAU - Yasuda, Clarissa AU - Yasuda C AD - Author affiliations are provided at the end of the article. FAU - Kwok, Maxwell AU - Kwok M AD - Author affiliations are provided at the end of the article. FAU - Wolking, Stefan AU - Wolking S AD - Author affiliations are provided at the end of the article. FAU - Becker, Felicitas AU - Becker F AD - Author affiliations are provided at the end of the article. FAU - Rau, Sarah AU - Rau S AD - Author affiliations are provided at the end of the article. FAU - Avbersek, Andreja AU - Avbersek A AD - Author affiliations are provided at the end of the article. FAU - Heggeli, Kristin AU - Heggeli K AD - Author affiliations are provided at the end of the article. FAU - Leu, Costin AU - Leu C AD - Author affiliations are provided at the end of the article. FAU - Depondt, Chantal AU - Depondt C AD - Author affiliations are provided at the end of the article. FAU - Sills, Graeme J AU - Sills GJ AD - Author affiliations are provided at the end of the article. FAU - Marson, Anthony G AU - Marson AG AD - Author affiliations are provided at the end of the article. FAU - Auce, Pauls AU - Auce P AD - Author affiliations are provided at the end of the article. FAU - Brodie, Martin J AU - Brodie MJ AD - Author affiliations are provided at the end of the article. FAU - Francis, Ben AU - Francis B AD - Author affiliations are provided at the end of the article. FAU - Johnson, Michael R AU - Johnson MR AD - Author affiliations are provided at the end of the article. FAU - Koeleman, Bobby P C AU - Koeleman BPC AD - Author affiliations are provided at the end of the article. FAU - Striano, Pasquale AU - Striano P AD - Author affiliations are provided at the end of the article. FAU - Coppola, Antonietta AU - Coppola A AD - Author affiliations are provided at the end of the article. FAU - Zara, Federico AU - Zara F AD - Author affiliations are provided at the end of the article. FAU - Kunz, Wolfram S AU - Kunz WS AD - Author affiliations are provided at the end of the article. FAU - Sander, Josemir W AU - Sander JW AD - Author affiliations are provided at the end of the article. FAU - Lerche, Holger AU - Lerche H AD - Author affiliations are provided at the end of the article. FAU - Klein, Karl Martin AU - Klein KM AD - Author affiliations are provided at the end of the article. FAU - Weckhuysen, Sarah AU - Weckhuysen S AD - Author affiliations are provided at the end of the article. FAU - Krenn, Martin AU - Krenn M AD - Author affiliations are provided at the end of the article. FAU - Gudmundsson, Larus J AU - Gudmundsson LJ AD - Author affiliations are provided at the end of the article. FAU - Stefansson, Kari AU - Stefansson K AD - Author affiliations are provided at the end of the article. FAU - Krause, Roland AU - Krause R AD - Author affiliations are provided at the end of the article. FAU - Shear, Neil AU - Shear N AD - Author affiliations are provided at the end of the article. FAU - Ross, Colin J D AU - Ross CJD AD - Author affiliations are provided at the end of the article. FAU - Delanty, Norman AU - Delanty N AD - Author affiliations are provided at the end of the article. CN - EPIGEN Consortium; FAU - Pirmohamed, Munir AU - Pirmohamed M AD - Author affiliations are provided at the end of the article. FAU - Carleton, Bruce C AU - Carleton BC AD - Author affiliations are provided at the end of the article. CN - Canadian Pharmacogenomics Network for Drug Safety; FAU - Cendes, Fernando AU - Cendes F AD - Author affiliations are provided at the end of the article. FAU - Lopes-Cendes, Iscia AU - Lopes-Cendes I AD - Author affiliations are provided at the end of the article. FAU - Liao, Wei-Ping AU - Liao WP AD - Author affiliations are provided at the end of the article. FAU - O'Brien, Terence J AU - O'Brien TJ AD - Author affiliations are provided at the end of the article. FAU - Sisodiya, Sanjay M AU - Sisodiya SM AD - Author affiliations are provided at the end of the article. CN - EpiPGX Consortium; FAU - Cherny, Stacey AU - Cherny S AD - Author affiliations are provided at the end of the article. FAU - Kwan, Patrick AU - Kwan P AD - Author affiliations are provided at the end of the article. FAU - Baum, Larry AU - Baum L AD - Author affiliations are provided at the end of the article. CN - International League Against Epilepsy Consortium on Complex Epilepsies; FAU - Cavalleri, Gianpiero L AU - Cavalleri GL AD - Author affiliations are provided at the end of the article. gcavalleri@rcsi.ie. LA - eng GR - G0800637/MRC_/Medical Research Council/United Kingdom GR - MR/L006758/1/MRC_/Medical Research Council/United Kingdom GR - MR/L012561/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20171229 PL - United States TA - Neurology JT - Neurology JID - 0401060 RN - 0 (Anticonvulsants) RN - 0 (Apolipoproteins) RN - 33CM23913M (Carbamazepine) RN - 0 (CFH protein, human) RN - 0 (CFHR4 protein, human) RN - 80295-65-4 (Complement Factor H) RN - 0 (HLA-A Antigens) RN - 0 (HLA-A*31:01 antigen) RN - 6158TKW0C5 (Phenytoin) SB - IM CIN - Neurology. 2018 Jan 23;90(4):155-156. PMID: 29288230 EIN - Neurology. 2018 Oct 16;91(16):765. PMID: 30323078 MH - Humans MH - *Anticonvulsants/adverse effects/therapeutic use MH - *Apolipoproteins/genetics MH - Asian People/genetics MH - Carbamazepine/adverse effects/therapeutic use MH - Case-Control Studies MH - Complement Factor H/genetics MH - *Drug Eruptions/ethnology/etiology/genetics MH - Epilepsy/drug therapy/genetics MH - *Genetic Variation MH - Genome-Wide Association Study MH - HLA-A Antigens/genetics MH - Linkage Disequilibrium MH - Mutation, Missense MH - Pharmacogenomic Variants MH - *Phenytoin/adverse effects/therapeutic use MH - Retrospective Studies MH - White People/genetics PMC - PMC5798660 FIR - Berkovic, Samuel F IR - Berkovic SF FIR - Lowenstein, Daniel H IR - Lowenstein DH FIR - Heinzen, Erin L IR - Heinzen EL FIR - Hakonarson, Hakon IR - Hakonarson H FIR - Buono, Russell J IR - Buono RJ FIR - Oliver, Karen IR - Oliver K FIR - Gui, Honsheng IR - Gui H FIR - Cherny, Stacey IR - Cherny S FIR - Kwan, Patrick IR - Kwan P FIR - Baum, Larry IR - Baum L FIR - Kwok, Maxwell IR - Kwok M FIR - Speed, Doug IR - Speed D FIR - Secolin, Rodrigo IR - Secolin R FIR - Yasuda, Clarissa IR - Yasuda C FIR - Cendes, Fernando IR - Cendes F FIR - Lopes-Cendes, Iscia IR - Lopes-Cendes I FIR - Wei-Ping, Liao IR - Wei-Ping L FIR - O'Brien, Terence J IR - O'Brien TJ FIR - Ingason, Andres IR - Ingason A FIR - Gudmundsson, Larus J IR - Gudmundsson LJ FIR - Stefansson, Kari IR - Stefansson K FIR - Sisodiya, Sanjay M IR - Sisodiya SM FIR - Avbersek, Andreja IR - Avbersek A FIR - Heggeli, Kristin IR - Heggeli K FIR - Leu, Costin IR - Leu C FIR - Willis, Joseph IR - Willis J FIR - Tostevin, Anna IR - Tostevin A FIR - Chinthapalli, Krishna IR - Chinthapalli K FIR - Depondt, Chantal IR - Depondt C FIR - Borghei, Mojgansadat IR - Borghei M FIR - Cavalleri, Gianpiero L IR - Cavalleri GL FIR - Delanty, Norman IR - Delanty N FIR - McCormack, Mark IR - McCormack M FIR - Heavin, Sinead IR - Heavin S FIR - Kunz, Wolfram S IR - Kunz WS FIR - Lerche, Holger IR - Lerche H FIR - Wolking, Stefan IR - 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Tiller M FIR - Osborne, Carol-Anne IR - Osborne CA EDAT- 2017/12/31 06:00 MHDA- 2019/07/23 06:00 PMCR- 2018/01/23 CRDT- 2017/12/31 06:00 PHST- 2017/02/27 00:00 [received] PHST- 2017/10/02 00:00 [accepted] PHST- 2017/12/31 06:00 [pubmed] PHST- 2019/07/23 06:00 [medline] PHST- 2017/12/31 06:00 [entrez] PHST- 2018/01/23 00:00 [pmc-release] AID - WNL.0000000000004853 [pii] AID - NEUROLOGY2017804252 [pii] AID - 10.1212/WNL.0000000000004853 [doi] PST - ppublish SO - Neurology. 2018 Jan 23;90(4):e332-e341. doi: 10.1212/WNL.0000000000004853. Epub 2017 Dec 29.