Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population

Takeshi Ozeki, Taisei Mushiroda, Amara Yowang, Atsushi Takahashi, Michiaki Kubo, Yuji Shirakata, Zenro Ikezawa, Masafumi Iijima, Tetsuo Shiohara, Koji Hashimoto, Naoyuki Kamatani, Yusuke Nakamura

Research output: Contribution to journalArticle

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Abstract

An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 3 10-13). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 3 10-15), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.

Original languageEnglish
Article numberddq537
Pages (from-to)1034-1041
Number of pages8
JournalHuman Molecular Genetics
Volume20
Issue number5
DOIs
Publication statusPublished - 01-03-2011
Externally publishedYes

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HLA-A Antigens
Genome-Wide Association Study
Carbamazepine
Drug-Related Side Effects and Adverse Reactions
Alleles
Skin
Drug Hypersensitivity Syndrome
Population
Stevens-Johnson Syndrome
Single Nucleotide Polymorphism
Anticonvulsants
Linkage Disequilibrium
Decision Making
Japan
Chromosomes
Odds Ratio
Confidence Intervals
Sensitivity and Specificity

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ozeki, Takeshi ; Mushiroda, Taisei ; Yowang, Amara ; Takahashi, Atsushi ; Kubo, Michiaki ; Shirakata, Yuji ; Ikezawa, Zenro ; Iijima, Masafumi ; Shiohara, Tetsuo ; Hashimoto, Koji ; Kamatani, Naoyuki ; Nakamura, Yusuke. / Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 5. pp. 1034-1041.
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abstract = "An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 3 10-13). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7{\%} (37/61) of the patients with CBZ-induced cADRs, but in only 12.5{\%} (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95{\%} confidence interval 5.9-19.6, P = 3.64 3 10-15), implying that this allele has the 60.7{\%} sensitivity and 87.5{\%} specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.",
author = "Takeshi Ozeki and Taisei Mushiroda and Amara Yowang and Atsushi Takahashi and Michiaki Kubo and Yuji Shirakata and Zenro Ikezawa and Masafumi Iijima and Tetsuo Shiohara and Koji Hashimoto and Naoyuki Kamatani and Yusuke Nakamura",
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Ozeki, T, Mushiroda, T, Yowang, A, Takahashi, A, Kubo, M, Shirakata, Y, Ikezawa, Z, Iijima, M, Shiohara, T, Hashimoto, K, Kamatani, N & Nakamura, Y 2011, 'Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population', Human Molecular Genetics, vol. 20, no. 5, ddq537, pp. 1034-1041. https://doi.org/10.1093/hmg/ddq537

Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. / Ozeki, Takeshi; Mushiroda, Taisei; Yowang, Amara; Takahashi, Atsushi; Kubo, Michiaki; Shirakata, Yuji; Ikezawa, Zenro; Iijima, Masafumi; Shiohara, Tetsuo; Hashimoto, Koji; Kamatani, Naoyuki; Nakamura, Yusuke.

In: Human Molecular Genetics, Vol. 20, No. 5, ddq537, 01.03.2011, p. 1034-1041.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population

AU - Ozeki, Takeshi

AU - Mushiroda, Taisei

AU - Yowang, Amara

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Shirakata, Yuji

AU - Ikezawa, Zenro

AU - Iijima, Masafumi

AU - Shiohara, Tetsuo

AU - Hashimoto, Koji

AU - Kamatani, Naoyuki

AU - Nakamura, Yusuke

PY - 2011/3/1

Y1 - 2011/3/1

N2 - An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 3 10-13). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 3 10-15), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.

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