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

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; Kari Stefansson; Roland Krause; Neil Shear; Colin J.D. Ross; Norman 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 L. Cavalleri

doi:10.1212/WNL.0000000000004853

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

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. BrodieBen 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, Kari Stefansson, Roland Krause, Neil Shear, Colin J.D. Ross, Norman 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 L. Cavalleri

University of Iceland

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

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.

Original language	English
Pages (from-to)	e332-e341
Journal	Neurology
Volume	90
Issue number	4
DOIs	https://doi.org/10.1212/WNL.0000000000004853
Publication status	Published - 29 Dec 2017

Other keywords

Epilepsy
Seizures
Neurology
Case control studies
Antiepileptic drugs
Association studies in genetics
Public health
Flogaveiki
Taugavísindi
Erfðarannsóknir
Lýðheilsa

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10.1212/WNL.0000000000004853

https://hdl.handle.net/20.500.11815/890

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McCormack, M., Gui, H., Ingason, A., Speed, D., Wright, G. E. B., Zhang, E. J., Secolin, R., Yasuda, C., Kwok, M., Wolking, S., Becker, F., Rau, S., Avbersek, A., Heggeli, K., Leu, C., Depondt, C., Sills, G. J., Marson, A. G., Auce, P., ... Cavalleri, G. L. (2017). Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology, 90(4), e332-e341. https://doi.org/10.1212/WNL.0000000000004853

@article{0a55d21ac45e4e2e8bf49539c4c12f1c,

title = "Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients",

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.",

keywords = "Epilepsy, Seizures, Neurology, Case control studies, Antiepileptic drugs, Association studies in genetics, Public health, Flogaveiki, Taugav{\'i}sindi, Erf{\dh}aranns{\'o}knir, L{\'y}{\dh}heilsa, Epilepsy, Seizures, Neurology, Case control studies, Antiepileptic drugs, Association studies in genetics, Public health, Flogaveiki, Taugav{\'i}sindi, Erf{\dh}aranns{\'o}knir, L{\'y}{\dh}heilsa",

author = "Mark McCormack and Hongsheng Gui and Andr{\'e}s Ingason and Doug Speed and Wright, {Galen E.B.} and Zhang, {Eunice J.} and Rodrigo Secolin and Clarissa Yasuda and Maxwell Kwok and Stefan Wolking and Felicitas Becker and Sarah Rau and Andreja Avbersek and Kristin Heggeli and Costin Leu and Chantal Depondt and Sills, {Graeme J.} and Marson, {Anthony G.} and Pauls Auce and Brodie, {Martin J.} and Ben Francis and Johnson, {Michael R.} and Koeleman, {Bobby P.C.} and Pasquale Striano and Antonietta Coppola and Federico Zara and Kunz, {Wolfram S.} and Sander, {Josemir W.} and Holger Lerche and Klein, {Karl Martin} and Sarah Weckhuysen and Martin Krenn and Gudmundsson, {L{\'a}rus J.} and Kari Stefansson and Roland Krause and Neil Shear and Ross, {Colin J.D.} and Norman Delanty and Munir Pirmohamed and Carleton, {Bruce C.} and Fernando Cendes and Iscia Lopes-Cendes and Wei-ping Liao and O'Brien, {Terence J.} and Sisodiya, {Sanjay M.} and Stacey Cherny and Patrick Kwan and Larry Baum and Cavalleri, {Gianpiero L.}",

year = "2017",

month = dec,

day = "29",

doi = "10.1212/WNL.0000000000004853",

language = "English",

volume = "90",

pages = "e332--e341",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "4",

}

McCormack, M, Gui, H, Ingason, A, Speed, D, Wright, GEB, 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, Stefansson, K, Krause, R, Shear, N, Ross, CJD, Delanty, N, Pirmohamed, M, Carleton, BC, Cendes, F, Lopes-Cendes, I, Liao, W, O'Brien, TJ, Sisodiya, SM, Cherny, S, Kwan, P, Baum, L & Cavalleri, GL 2017, 'Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients', Neurology, vol. 90, no. 4, pp. e332-e341. https://doi.org/10.1212/WNL.0000000000004853

TY - JOUR

T1 - Genetic variation inCFHpredicts phenytoin-induced maculopapular exanthema in European-descent patients

AU - McCormack, Mark

AU - Gui, Hongsheng

AU - Ingason, Andrés

AU - Speed, Doug

AU - Wright, Galen E.B.

AU - Zhang, Eunice J.

AU - Secolin, Rodrigo

AU - Yasuda, Clarissa

AU - Kwok, Maxwell

AU - Wolking, Stefan

AU - Becker, Felicitas

AU - Rau, Sarah

AU - Avbersek, Andreja

AU - Heggeli, Kristin

AU - Leu, Costin

AU - Depondt, Chantal

AU - Sills, Graeme J.

AU - Marson, Anthony G.

AU - Auce, Pauls

AU - Brodie, Martin J.

AU - Francis, Ben

AU - Johnson, Michael R.

AU - Koeleman, Bobby P.C.

AU - Striano, Pasquale

AU - Coppola, Antonietta

AU - Zara, Federico

AU - Kunz, Wolfram S.

AU - Sander, Josemir W.

AU - Lerche, Holger

AU - Klein, Karl Martin

AU - Weckhuysen, Sarah

AU - Krenn, Martin

AU - Gudmundsson, Lárus J.

AU - Stefansson, Kari

AU - Krause, Roland

AU - Shear, Neil

AU - Ross, Colin J.D.

AU - Delanty, Norman

AU - Pirmohamed, Munir

AU - Carleton, Bruce C.

AU - Cendes, Fernando

AU - Lopes-Cendes, Iscia

AU - Liao, Wei-ping

AU - O'Brien, Terence J.

AU - Sisodiya, Sanjay M.

AU - Cherny, Stacey

AU - Kwan, Patrick

AU - Baum, Larry

AU - Cavalleri, Gianpiero L.

PY - 2017/12/29

Y1 - 2017/12/29

N2 - 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.

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 × 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.

KW - Epilepsy

KW - Seizures

KW - Neurology

KW - Case control studies

KW - Antiepileptic drugs

KW - Association studies in genetics

KW - Public health

KW - Flogaveiki

KW - Taugavísindi

KW - Erfðarannsóknir

KW - Lýðheilsa

KW - Epilepsy

KW - Seizures

KW - Neurology

KW - Case control studies

KW - Antiepileptic drugs

KW - Association studies in genetics

KW - Public health

KW - Flogaveiki

KW - Taugavísindi

KW - Erfðarannsóknir

KW - Lýðheilsa

U2 - 10.1212/WNL.0000000000004853

DO - 10.1212/WNL.0000000000004853

M3 - Article

SN - 0028-3878

VL - 90

SP - e332-e341

JO - Neurology

JF - Neurology

IS - 4

ER -

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

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