IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement

Mayumi Ueta, Hiromi Sawai, Chie Sotozono, Yuki Hitomi, Nahoko Kaniwa, Mee Kum Kim, Kyoung Yul Seo, Kyung Chul Yoon, Choun Ki Joo, Chitra Kannabiran, Tais Hitomi Wakamatsu, Virender Sangwan, Varsha Rathi, Sayan Basu, Takeshi Ozeki, Taisei Mushiroda, Emiko Sugiyama, Keiko Maekawa, Ryosuke Nakamura, Michiko AiharaKayoko Matsunaga, Akihiro Sekine, José Álvaro Pereira Gomes, Junji Hamuro, Yoshiro Saito, Michiaki Kubo, Shigeru Kinoshita, Katsushi Tokunaga

Research output: Contribution to journalArticle

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Abstract

Background Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes, including the ocular surface, oral cavity, and genitals. These reactions are very rare but are often associated with inciting drugs, infectious agents, or both. Objective We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). Methods A genome-wide association study was performed in 808 Japanese subjects (117 patients with CM-SJS/TEN with SMI and 691 healthy control subjects), and subsequent replication studies were performed in 204 other Japanese subjects (16 cases and 188 control subjects), 117 Korean subjects (27 cases and 90 control subjects), 76 Indian subjects (20 cases and 56 control subjects), and 174 Brazilian subjects (39 cases and 135 control subjects). Results In addition to the most significant susceptibility region, HLA-A, we identified IKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs T]; odds ratio, 0.5; P = 8.5 × 10-11). Furthermore, quantitative ratios of the IKZF1 alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes. Conclusion We identified IKZF1 as a susceptibility gene for CM-SJS/TEN with SMI not only in Japanese subjects but also in Korean and Indian subjects and showed that the Ik2/Ik1 ratio might be influenced by IKZF1 single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI.

Original languageEnglish
Pages (from-to)1538-1545.e17
JournalJournal of Allergy and Clinical Immunology
Volume135
Issue number6
DOIs
Publication statusPublished - 01-06-2015

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Stevens-Johnson Syndrome
Medicine
Genes
HLA-A Antigens
Genome-Wide Association Study
Alternative Splicing
Single Nucleotide Polymorphism
Mouth
Meta-Analysis
Healthy Volunteers
Protein Isoforms
Mucous Membrane
Odds Ratio
Genotype
Skin
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Ueta, Mayumi ; Sawai, Hiromi ; Sotozono, Chie ; Hitomi, Yuki ; Kaniwa, Nahoko ; Kim, Mee Kum ; Seo, Kyoung Yul ; Yoon, Kyung Chul ; Joo, Choun Ki ; Kannabiran, Chitra ; Wakamatsu, Tais Hitomi ; Sangwan, Virender ; Rathi, Varsha ; Basu, Sayan ; Ozeki, Takeshi ; Mushiroda, Taisei ; Sugiyama, Emiko ; Maekawa, Keiko ; Nakamura, Ryosuke ; Aihara, Michiko ; Matsunaga, Kayoko ; Sekine, Akihiro ; Gomes, José Álvaro Pereira ; Hamuro, Junji ; Saito, Yoshiro ; Kubo, Michiaki ; Kinoshita, Shigeru ; Tokunaga, Katsushi. / IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 135, No. 6. pp. 1538-1545.e17.
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title = "IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement",
abstract = "Background Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes, including the ocular surface, oral cavity, and genitals. These reactions are very rare but are often associated with inciting drugs, infectious agents, or both. Objective We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). Methods A genome-wide association study was performed in 808 Japanese subjects (117 patients with CM-SJS/TEN with SMI and 691 healthy control subjects), and subsequent replication studies were performed in 204 other Japanese subjects (16 cases and 188 control subjects), 117 Korean subjects (27 cases and 90 control subjects), 76 Indian subjects (20 cases and 56 control subjects), and 174 Brazilian subjects (39 cases and 135 control subjects). Results In addition to the most significant susceptibility region, HLA-A, we identified IKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs T]; odds ratio, 0.5; P = 8.5 × 10-11). Furthermore, quantitative ratios of the IKZF1 alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes. Conclusion We identified IKZF1 as a susceptibility gene for CM-SJS/TEN with SMI not only in Japanese subjects but also in Korean and Indian subjects and showed that the Ik2/Ik1 ratio might be influenced by IKZF1 single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI.",
author = "Mayumi Ueta and Hiromi Sawai and Chie Sotozono and Yuki Hitomi and Nahoko Kaniwa and Kim, {Mee Kum} and Seo, {Kyoung Yul} and Yoon, {Kyung Chul} and Joo, {Choun Ki} and Chitra Kannabiran and Wakamatsu, {Tais Hitomi} and Virender Sangwan and Varsha Rathi and Sayan Basu and Takeshi Ozeki and Taisei Mushiroda and Emiko Sugiyama and Keiko Maekawa and Ryosuke Nakamura and Michiko Aihara and Kayoko Matsunaga and Akihiro Sekine and Gomes, {Jos{\'e} {\'A}lvaro Pereira} and Junji Hamuro and Yoshiro Saito and Michiaki Kubo and Shigeru Kinoshita and Katsushi Tokunaga",
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journal = "Journal of Allergy and Clinical Immunology",
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Ueta, M, Sawai, H, Sotozono, C, Hitomi, Y, Kaniwa, N, Kim, MK, Seo, KY, Yoon, KC, Joo, CK, Kannabiran, C, Wakamatsu, TH, Sangwan, V, Rathi, V, Basu, S, Ozeki, T, Mushiroda, T, Sugiyama, E, Maekawa, K, Nakamura, R, Aihara, M, Matsunaga, K, Sekine, A, Gomes, JÁP, Hamuro, J, Saito, Y, Kubo, M, Kinoshita, S & Tokunaga, K 2015, 'IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement', Journal of Allergy and Clinical Immunology, vol. 135, no. 6, pp. 1538-1545.e17. https://doi.org/10.1016/j.jaci.2014.12.1916

IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement. / Ueta, Mayumi; Sawai, Hiromi; Sotozono, Chie; Hitomi, Yuki; Kaniwa, Nahoko; Kim, Mee Kum; Seo, Kyoung Yul; Yoon, Kyung Chul; Joo, Choun Ki; Kannabiran, Chitra; Wakamatsu, Tais Hitomi; Sangwan, Virender; Rathi, Varsha; Basu, Sayan; Ozeki, Takeshi; Mushiroda, Taisei; Sugiyama, Emiko; Maekawa, Keiko; Nakamura, Ryosuke; Aihara, Michiko; Matsunaga, Kayoko; Sekine, Akihiro; Gomes, José Álvaro Pereira; Hamuro, Junji; Saito, Yoshiro; Kubo, Michiaki; Kinoshita, Shigeru; Tokunaga, Katsushi.

In: Journal of Allergy and Clinical Immunology, Vol. 135, No. 6, 01.06.2015, p. 1538-1545.e17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement

AU - Ueta, Mayumi

AU - Sawai, Hiromi

AU - Sotozono, Chie

AU - Hitomi, Yuki

AU - Kaniwa, Nahoko

AU - Kim, Mee Kum

AU - Seo, Kyoung Yul

AU - Yoon, Kyung Chul

AU - Joo, Choun Ki

AU - Kannabiran, Chitra

AU - Wakamatsu, Tais Hitomi

AU - Sangwan, Virender

AU - Rathi, Varsha

AU - Basu, Sayan

AU - Ozeki, Takeshi

AU - Mushiroda, Taisei

AU - Sugiyama, Emiko

AU - Maekawa, Keiko

AU - Nakamura, Ryosuke

AU - Aihara, Michiko

AU - Matsunaga, Kayoko

AU - Sekine, Akihiro

AU - Gomes, José Álvaro Pereira

AU - Hamuro, Junji

AU - Saito, Yoshiro

AU - Kubo, Michiaki

AU - Kinoshita, Shigeru

AU - Tokunaga, Katsushi

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Background Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes, including the ocular surface, oral cavity, and genitals. These reactions are very rare but are often associated with inciting drugs, infectious agents, or both. Objective We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). Methods A genome-wide association study was performed in 808 Japanese subjects (117 patients with CM-SJS/TEN with SMI and 691 healthy control subjects), and subsequent replication studies were performed in 204 other Japanese subjects (16 cases and 188 control subjects), 117 Korean subjects (27 cases and 90 control subjects), 76 Indian subjects (20 cases and 56 control subjects), and 174 Brazilian subjects (39 cases and 135 control subjects). Results In addition to the most significant susceptibility region, HLA-A, we identified IKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs T]; odds ratio, 0.5; P = 8.5 × 10-11). Furthermore, quantitative ratios of the IKZF1 alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes. Conclusion We identified IKZF1 as a susceptibility gene for CM-SJS/TEN with SMI not only in Japanese subjects but also in Korean and Indian subjects and showed that the Ik2/Ik1 ratio might be influenced by IKZF1 single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI.

AB - Background Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes, including the ocular surface, oral cavity, and genitals. These reactions are very rare but are often associated with inciting drugs, infectious agents, or both. Objective We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). Methods A genome-wide association study was performed in 808 Japanese subjects (117 patients with CM-SJS/TEN with SMI and 691 healthy control subjects), and subsequent replication studies were performed in 204 other Japanese subjects (16 cases and 188 control subjects), 117 Korean subjects (27 cases and 90 control subjects), 76 Indian subjects (20 cases and 56 control subjects), and 174 Brazilian subjects (39 cases and 135 control subjects). Results In addition to the most significant susceptibility region, HLA-A, we identified IKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs T]; odds ratio, 0.5; P = 8.5 × 10-11). Furthermore, quantitative ratios of the IKZF1 alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes. Conclusion We identified IKZF1 as a susceptibility gene for CM-SJS/TEN with SMI not only in Japanese subjects but also in Korean and Indian subjects and showed that the Ik2/Ik1 ratio might be influenced by IKZF1 single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI.

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U2 - 10.1016/j.jaci.2014.12.1916

DO - 10.1016/j.jaci.2014.12.1916

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VL - 135

SP - 1538-1545.e17

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

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