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

Rikke S Møller (Medlem af forfattergruppering), EPIGEN Consortium;

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Resumé

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.

OriginalsprogEngelsk
TidsskriftNeurology
Vol/bind90
Udgave nummer4
Sider (fra-til)e332-e341
ISSN0028-3878
DOI
StatusUdgivet - 23. jan. 2018

Fingeraftryk

Complement Factor H
Phenytoin
Exanthema
Hypersensitivity
Alternative Complement Pathway
Drug and Narcotic Control
Genome-Wide Association Study
Linkage Disequilibrium
Population Genetics
Drug-Related Side Effects and Adverse Reactions
Alleles
Odds Ratio
Confidence Intervals
Skin
Proteins

Bibliografisk note

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Citer dette

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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 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 K{\'a}ri Stef{\'a}nsson 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} and M{\o}ller, {Rikke S} and {EPIGEN Consortium;}",
note = "Copyright {\circledC} 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",
year = "2018",
month = "1",
day = "23",
doi = "10.1212/WNL.0000000000004853",
language = "English",
volume = "90",
pages = "e332--e341",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams & Wilkins",
number = "4",

}

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. / Møller, Rikke S (Medlem af forfattergruppering); EPIGEN Consortium;.

I: Neurology, Bind 90, Nr. 4, 23.01.2018, s. e332-e341.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Genetic variation in CFH predicts 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 - Stefánsson, Kári

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

AU - EPIGEN Consortium;

A2 - Møller, Rikke S

N1 - Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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.

U2 - 10.1212/WNL.0000000000004853

DO - 10.1212/WNL.0000000000004853

M3 - Journal article

C2 - 29288229

VL - 90

SP - e332-e341

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 4

ER -