HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

Mark McCormack; Ana Alfirevic; Stephane Bourgeois; John J. Farrell; Dalia Kasperaviciute; Mary Carrington; Graeme J. Sills; Tony Marson; Xiaoming Jia; Paul I. W. de Bakker; Krishna Chinthapalli; Mariam Molokhia; Michael R. Johnson; Gerard D. O&apos;Connor; Elijah Chaila; Saud Alhusaini; Kevin V. Shianna; Rodney A. Radtke; Erin L. Heinzen; Nicole Walley; Massimo Pandolfo; Werner Pichler; B. Kevin Park; Chantal Depondt; Sanjay M. Sisodiya; David B. Goldstein; Panos Deloukas; Norman Delanty; Gianpiero L. Cavalleri; Munir Pirmohamed

doi:10.1056/NEJMoa1013297

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

Mark McCormack, Ana Alfirevic, Stephane Bourgeois, John J. Farrell, Dalia Kasperaviciute, Mary Carrington, Graeme J. Sills, Tony Marson, Xiaoming Jia, Paul I. W. de Bakker, Krishna Chinthapalli, Mariam Molokhia, Michael R. Johnson, Gerard D. O'Connor, Elijah Chaila, Saud Alhusaini, Kevin V. Shianna, Rodney A. Radtke, Erin L. Heinzen, Nicole WalleyMassimo Pandolfo, Werner Pichler, B. Kevin Park, Chantal Depondt, Sanjay M. Sisodiya, David B. Goldstein, Panos Deloukas, Norman Delanty, Gianpiero L. Cavalleri, Munir Pirmohamed

Population Health Sciences

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

805 Citations (Scopus)

Abstract

BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A* 3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.

Original language	English
Pages (from-to)	1134-1143
Number of pages	10
Journal	New England Journal of Medicine
Volume	364
Issue number	12
DOIs	https://doi.org/10.1056/NEJMoa1013297
Publication status	Published - 24 Mar 2011

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McCormack, M., Alfirevic, A., Bourgeois, S., Farrell, J. J., Kasperaviciute, D., Carrington, M., Sills, G. J., Marson, T., Jia, X., de Bakker, P. I. W., Chinthapalli, K., Molokhia, M., Johnson, M. R., O'Connor, G. D., Chaila, E., Alhusaini, S., Shianna, K. V., Radtke, R. A., Heinzen, E. L., ... Pirmohamed, M. (2011). HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine, 364(12), 1134-1143. https://doi.org/10.1056/NEJMoa1013297

@article{3d364549748c4313864d2201bd215abb,

title = "HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans",

abstract = "BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A* 3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.",

author = "Mark McCormack and Ana Alfirevic and Stephane Bourgeois and Farrell, {John J.} and Dalia Kasperaviciute and Mary Carrington and Sills, {Graeme J.} and Tony Marson and Xiaoming Jia and {de Bakker}, {Paul I. W.} and Krishna Chinthapalli and Mariam Molokhia and Johnson, {Michael R.} and O'Connor, {Gerard D.} and Elijah Chaila and Saud Alhusaini and Shianna, {Kevin V.} and Radtke, {Rodney A.} and Heinzen, {Erin L.} and Nicole Walley and Massimo Pandolfo and Werner Pichler and Park, {B. Kevin} and Chantal Depondt and Sisodiya, {Sanjay M.} and Goldstein, {David B.} and Panos Deloukas and Norman Delanty and Cavalleri, {Gianpiero L.} and Munir Pirmohamed",

year = "2011",

month = mar,

day = "24",

doi = "10.1056/NEJMoa1013297",

language = "English",

volume = "364",

pages = "1134--1143",

journal = "New England Journal of Medicine",

issn = "1533-4406",

publisher = "Massachussetts Medical Society",

number = "12",

}

McCormack, M, Alfirevic, A, Bourgeois, S, Farrell, JJ, Kasperaviciute, D, Carrington, M, Sills, GJ, Marson, T, Jia, X, de Bakker, PIW, Chinthapalli, K, Molokhia, M, Johnson, MR, O'Connor, GD, Chaila, E, Alhusaini, S, Shianna, KV, Radtke, RA, Heinzen, EL, Walley, N, Pandolfo, M, Pichler, W, Park, BK, Depondt, C, Sisodiya, SM, Goldstein, DB, Deloukas, P, Delanty, N, Cavalleri, GL & Pirmohamed, M 2011, 'HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans', New England Journal of Medicine, vol. 364, no. 12, pp. 1134-1143. https://doi.org/10.1056/NEJMoa1013297

TY - JOUR

T1 - HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

AU - McCormack, Mark

AU - Alfirevic, Ana

AU - Bourgeois, Stephane

AU - Farrell, John J.

AU - Kasperaviciute, Dalia

AU - Carrington, Mary

AU - Sills, Graeme J.

AU - Marson, Tony

AU - Jia, Xiaoming

AU - de Bakker, Paul I. W.

AU - Chinthapalli, Krishna

AU - Molokhia, Mariam

AU - Johnson, Michael R.

AU - O'Connor, Gerard D.

AU - Chaila, Elijah

AU - Alhusaini, Saud

AU - Shianna, Kevin V.

AU - Radtke, Rodney A.

AU - Heinzen, Erin L.

AU - Walley, Nicole

AU - Pandolfo, Massimo

AU - Pichler, Werner

AU - Park, B. Kevin

AU - Depondt, Chantal

AU - Sisodiya, Sanjay M.

AU - Goldstein, David B.

AU - Deloukas, Panos

AU - Delanty, Norman

AU - Cavalleri, Gianpiero L.

AU - Pirmohamed, Munir

PY - 2011/3/24

Y1 - 2011/3/24

N2 - BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A* 3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.

AB - BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A* 3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.

U2 - 10.1056/NEJMoa1013297

DO - 10.1056/NEJMoa1013297

M3 - Article

C2 - 21428769

SN - 1533-4406

VL - 364

SP - 1134

EP - 1143

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 12

ER -

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

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