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

Mark McCormack; Hongsheng Gui; Andres Ingason; Doug Speed; Galen E.B.  Wright; Eunice J. Zhang; Rodrigo Secolin; Clarissa L. 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 John O'Brien; Sanjay M. Sisodiya; Stacey S. Cherny; Kwok Leung Patrick Kwan; Larry Baum; Gianpiero L. Cavalleri; EpiPGX Consortium; International League Against Epilepsy Consortium on Complex Epilepsies; Canadian Pharmacogenomics Network for Drug Safety

doi:10.1212/WNL.0000000000004853

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

Mark McCormack, Hongsheng Gui, Andres Ingason, Doug Speed, Galen E.B. Wright, Eunice J. Zhang, Rodrigo Secolin, Clarissa L. 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 John O'Brien, Sanjay M. Sisodiya, Stacey S. Cherny, Kwok Leung Patrick Kwan, Larry Baum, Gianpiero L. Cavalleri, EpiPGX Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Canadian Pharmacogenomics Network for Drug Safety

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

29 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
Number of pages	10
Journal	Neurology
Volume	90
Issue number	4
DOIs	https://doi.org/10.1212/WNL.0000000000004853
Publication status	Published - 23 Jan 2018
Externally published	Yes

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247504704-oaFinal published version, 991 KBLicence: CC BY

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McCormack, M., Gui, H., Ingason, A., Speed, D., Wright, G. E. B., Zhang, E. J., Secolin, R., Yasuda, C. L., Kwok, M., Wolking, S., Becker, F., Rau, S., Avbersek, A., Heggeli, K., Leu, C., Depondt, C., Sills, G. J., Marson, A. G., Auce, P., ... Canadian Pharmacogenomics Network for Drug Safety (2018). Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology, 90(4), e332-e341. https://doi.org/10.1212/WNL.0000000000004853

@article{3e42b081a69748c18492adbf412ee055,

title = "Genetic variation in CFH predicts 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.",

author = "Mark McCormack and Hongsheng Gui and Andres Ingason and Doug Speed and Wright, {Galen E.B.} and Zhang, {Eunice J.} and Rodrigo Secolin and Yasuda, {Clarissa L.} 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 Liao, {Wei Ping} and O'Brien, {Terence John} and Sisodiya, {Sanjay M.} and Cherny, {Stacey S.} and Kwan, {Kwok Leung Patrick} and Larry Baum and Cavalleri, {Gianpiero L.} and {EpiPGX Consortium} and {International League Against Epilepsy Consortium on Complex Epilepsies} and {Canadian Pharmacogenomics Network for Drug Safety}",

year = "2018",

month = jan,

day = "23",

doi = "10.1212/WNL.0000000000004853",

language = "English",

volume = "90",

pages = "e332--e341",

journal = "Neurology",

issn = "0028-3878",

publisher = "Ovid Technologies (Wolters Kluwer) - American Academy of Neurology",

number = "4",

}

McCormack, M, Gui, H, Ingason, A, Speed, D, Wright, GEB, Zhang, EJ, Secolin, R, Yasuda, CL, 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, WP, O'Brien, TJ, Sisodiya, SM, Cherny, SS, Kwan, KLP, Baum, L, Cavalleri, GL, EpiPGX Consortium, International League Against Epilepsy Consortium on Complex Epilepsies & Canadian Pharmacogenomics Network for Drug Safety 2018, 'Genetic variation in CFH predicts 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 in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

AU - McCormack, Mark

AU - Gui, Hongsheng

AU - Ingason, Andres

AU - Speed, Doug

AU - Wright, Galen E.B.

AU - Zhang, Eunice J.

AU - Secolin, Rodrigo

AU - Yasuda, Clarissa L.

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 John

AU - Sisodiya, Sanjay M.

AU - Cherny, Stacey S.

AU - Kwan, Kwok Leung Patrick

AU - Baum, Larry

AU - Cavalleri, Gianpiero L.

AU - EpiPGX Consortium

AU - International League Against Epilepsy Consortium on Complex Epilepsies

AU - Canadian Pharmacogenomics Network for Drug Safety

PY - 2018/1/23

Y1 - 2018/1/23

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.

UR - http://www.scopus.com/inward/record.url?scp=85054158133&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000004853

DO - 10.1212/WNL.0000000000004853

M3 - Article

C2 - 29288229

AN - SCOPUS:85054158133

VL - 90

SP - e332-e341

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 4

ER -

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

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