Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Paola Nicoletti; Sarah Barrett; Laurence McEvoy; Ann K Daly; Guruprasad Aithal; M Isabel Lucena; Raul J Andrade; Mia Wadelius; Pär Hallberg; Camilla Stephens; Einar S Bjornsson; Peter Friedmann; Kati Kainu; Tarja Laitinen; Anthony Marson; Mariam Molokhia; Elizabeth Phillips; Werner Pichler; Antonino Romano; Neil Shear; Graeme Sills; Luciana K Tanno; Ashley Swale; Aris Floratos; Yufeng Shen; Matthew R Nelson; Paul B Watkins; Mark J Daly; Andrew P Morris; Ana Alfirevic; Munir Pirmohamed

doi:10.1002/cpt.1493

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Paola Nicoletti, Sarah Barrett, Laurence McEvoy, Ann K Daly, Guruprasad Aithal, M Isabel Lucena, Raul J Andrade, Mia Wadelius, Pär Hallberg, Camilla Stephens, Einar S Bjornsson, Peter Friedmann, Kati Kainu, Tarja Laitinen, Anthony Marson, Mariam Molokhia, Elizabeth Phillips, Werner Pichler, Antonino Romano, Neil ShearGraeme Sills, Luciana K Tanno, Ashley Swale, Aris Floratos, Yufeng Shen, Matthew R Nelson, Paul B Watkins, Mark J Daly, Andrew P Morris, Ana Alfirevic, Munir Pirmohamed

Division of Musculoskeletal & Dermatological Sciences (L5)

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Abstract

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

Original language	English
Pages (from-to)	1028-1036
Number of pages	9
Journal	Clinical Pharmacology and Therapeutics
Volume	106
Issue number	5
Early online date	3 Jul 2019
DOIs	https://doi.org/10.1002/cpt.1493
Publication status	Published - 1 Nov 2019

Keywords

Adult
Anaplastic Lymphoma Kinase/genetics
Carbamazepine/adverse effects
Chemical and Drug Induced Liver Injury/epidemiology
Drug Hypersensitivity/genetics
Drug Hypersensitivity Syndrome/genetics
Europe
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-A Antigens/genetics
HLA-B Antigens/genetics
Humans
Male
Phenotype
Risk Factors
Stevens-Johnson Syndrome/genetics

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Nicoletti, P., Barrett, S., McEvoy, L., Daly, A. K., Aithal, G., Lucena, M. I., Andrade, R. J., Wadelius, M., Hallberg, P., Stephens, C., Bjornsson, E. S., Friedmann, P., Kainu, K., Laitinen, T., Marson, A., Molokhia, M., Phillips, E., Pichler, W., Romano, A., ... Pirmohamed, M. (2019). Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions. Clinical Pharmacology and Therapeutics, 106(5), 1028-1036. https://doi.org/10.1002/cpt.1493

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title = "Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions",

abstract = "Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.",

keywords = "Adult, Anaplastic Lymphoma Kinase/genetics, Carbamazepine/adverse effects, Chemical and Drug Induced Liver Injury/epidemiology, Drug Hypersensitivity/genetics, Drug Hypersensitivity Syndrome/genetics, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-A Antigens/genetics, HLA-B Antigens/genetics, Humans, Male, Phenotype, Risk Factors, Stevens-Johnson Syndrome/genetics",

author = "Paola Nicoletti and Sarah Barrett and Laurence McEvoy and Daly, {Ann K} and Guruprasad Aithal and Lucena, {M Isabel} and Andrade, {Raul J} and Mia Wadelius and P{\"a}r Hallberg and Camilla Stephens and Bjornsson, {Einar S} and Peter Friedmann and Kati Kainu and Tarja Laitinen and Anthony Marson and Mariam Molokhia and Elizabeth Phillips and Werner Pichler and Antonino Romano and Neil Shear and Graeme Sills and Tanno, {Luciana K} and Ashley Swale and Aris Floratos and Yufeng Shen and Nelson, {Matthew R} and Watkins, {Paul B} and Daly, {Mark J} and Morris, {Andrew P} and Ana Alfirevic and Munir Pirmohamed",

note = "{\textcopyright} 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2019",

month = nov,

day = "1",

doi = "10.1002/cpt.1493",

language = "English",

volume = "106",

pages = "1028--1036",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "John Wiley & Sons Ltd",

number = "5",

}

Nicoletti, P, Barrett, S, McEvoy, L, Daly, AK, Aithal, G, Lucena, MI, Andrade, RJ, Wadelius, M, Hallberg, P, Stephens, C, Bjornsson, ES, Friedmann, P, Kainu, K, Laitinen, T, Marson, A, Molokhia, M, Phillips, E, Pichler, W, Romano, A, Shear, N, Sills, G, Tanno, LK, Swale, A, Floratos, A, Shen, Y, Nelson, MR, Watkins, PB, Daly, MJ, Morris, AP, Alfirevic, A & Pirmohamed, M 2019, 'Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions', Clinical Pharmacology and Therapeutics, vol. 106, no. 5, pp. 1028-1036. https://doi.org/10.1002/cpt.1493

TY - JOUR

T1 - Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

AU - Nicoletti, Paola

AU - Barrett, Sarah

AU - McEvoy, Laurence

AU - Daly, Ann K

AU - Aithal, Guruprasad

AU - Lucena, M Isabel

AU - Andrade, Raul J

AU - Wadelius, Mia

AU - Hallberg, Pär

AU - Stephens, Camilla

AU - Bjornsson, Einar S

AU - Friedmann, Peter

AU - Kainu, Kati

AU - Laitinen, Tarja

AU - Marson, Anthony

AU - Molokhia, Mariam

AU - Phillips, Elizabeth

AU - Pichler, Werner

AU - Romano, Antonino

AU - Shear, Neil

AU - Sills, Graeme

AU - Tanno, Luciana K

AU - Swale, Ashley

AU - Floratos, Aris

AU - Shen, Yufeng

AU - Nelson, Matthew R

AU - Watkins, Paul B

AU - Daly, Mark J

AU - Morris, Andrew P

AU - Alfirevic, Ana

AU - Pirmohamed, Munir

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

AB - Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

KW - Adult

KW - Anaplastic Lymphoma Kinase/genetics

KW - Carbamazepine/adverse effects

KW - Chemical and Drug Induced Liver Injury/epidemiology

KW - Drug Hypersensitivity/genetics

KW - Drug Hypersensitivity Syndrome/genetics

KW - Europe

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HLA-A Antigens/genetics

KW - HLA-B Antigens/genetics

KW - Humans

KW - Male

KW - Phenotype

KW - Risk Factors

KW - Stevens-Johnson Syndrome/genetics

U2 - 10.1002/cpt.1493

DO - 10.1002/cpt.1493

M3 - Article

C2 - 31066027

SN - 0009-9236

VL - 106

SP - 1028

EP - 1036

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 5

ER -

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Abstract

Keywords

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