IKZF1, a new susceptibility gene for cold medicine–related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement
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...
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| Published in | Journal of allergy and clinical immunology Vol. 135; no. 6; pp. 1538 - 1545.e17 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.06.2015
Elsevier Limited |
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| Abstract | 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.
We sought to identify susceptibility loci for cold medicine–related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI).
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).
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.
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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| AbstractList | 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 identifiedIKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs T]; odds ratio, 0.5;P = 8.5 x 10-11). Furthermore, quantitative ratios of theIKZF1alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes. Conclusion We identifiedIKZF1as 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 byIKZF1single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI. 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. We sought to identify susceptibility loci for cold medicine–related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). 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). 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. 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. 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. 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. 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. We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI). 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). 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. 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. 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.BACKGROUNDStevens-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.We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI).OBJECTIVEWe sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI).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).METHODSA 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).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.RESULTSIn 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.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.CONCLUSIONWe 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 | Wakamatsu, Tais Hitomi Joo, Choun-Ki Sawai, Hiromi Hitomi, Yuki Kim, Mee Kum Seo, Kyoung Yul Maekawa, Keiko Kubo, Michiaki Saito, Yoshiro Matsunaga, Kayoko Gomes, José Álvaro Pereira Kinoshita, Shigeru Sotozono, Chie Kaniwa, Nahoko Ozeki, Takeshi Mushiroda, Taisei Hamuro, Junji Sangwan, Virender Ueta, Mayumi Rathi, Varsha Kannabiran, Chitra Sekine, Akihiro Tokunaga, Katsushi Nakamura, Ryosuke Yoon, Kyung-Chul Sugiyama, Emiko Aihara, Michiko Basu, Sayan |
| Author_xml | – sequence: 1 givenname: Mayumi surname: Ueta fullname: Ueta, Mayumi email: mueta@koto.kpu-m.ac.jp organization: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan – sequence: 2 givenname: Hiromi surname: Sawai fullname: Sawai, Hiromi organization: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan – sequence: 3 givenname: Chie surname: Sotozono fullname: Sotozono, Chie organization: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan – sequence: 4 givenname: Yuki surname: Hitomi fullname: Hitomi, Yuki organization: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan – sequence: 5 givenname: Nahoko surname: Kaniwa fullname: Kaniwa, Nahoko organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 6 givenname: Mee Kum surname: Kim fullname: Kim, Mee Kum organization: Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea – sequence: 7 givenname: Kyoung Yul surname: Seo fullname: Seo, Kyoung Yul organization: Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea – sequence: 8 givenname: Kyung-Chul surname: Yoon fullname: Yoon, Kyung-Chul organization: Department of Ophthalmology, Chonnam National University, Gwangju, Korea – sequence: 9 givenname: Choun-Ki surname: Joo fullname: Joo, Choun-Ki organization: Department of Ophthalmology & Visual Science, Seoul St Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea – sequence: 10 givenname: Chitra surname: Kannabiran fullname: Kannabiran, Chitra organization: Prof Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India – sequence: 11 givenname: Tais Hitomi surname: Wakamatsu fullname: Wakamatsu, Tais Hitomi organization: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil – sequence: 12 givenname: Virender surname: Sangwan fullname: Sangwan, Virender organization: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India – sequence: 13 givenname: Varsha surname: Rathi fullname: Rathi, Varsha organization: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India – sequence: 14 givenname: Sayan surname: Basu fullname: Basu, Sayan organization: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India – sequence: 15 givenname: Takeshi surname: Ozeki fullname: Ozeki, Takeshi organization: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan – sequence: 16 givenname: Taisei surname: Mushiroda fullname: Mushiroda, Taisei organization: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan – sequence: 17 givenname: Emiko surname: Sugiyama fullname: Sugiyama, Emiko organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 18 givenname: Keiko surname: Maekawa fullname: Maekawa, Keiko organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 19 givenname: Ryosuke surname: Nakamura fullname: Nakamura, Ryosuke organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 20 givenname: Michiko surname: Aihara fullname: Aihara, Michiko organization: Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan – sequence: 21 givenname: Kayoko surname: Matsunaga fullname: Matsunaga, Kayoko organization: Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan – sequence: 22 givenname: Akihiro surname: Sekine fullname: Sekine, Akihiro organization: EBM Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan – sequence: 23 givenname: José Álvaro Pereira surname: Gomes fullname: Gomes, José Álvaro Pereira organization: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil – sequence: 24 givenname: Junji surname: Hamuro fullname: Hamuro, Junji organization: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan – sequence: 25 givenname: Yoshiro surname: Saito fullname: Saito, Yoshiro organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 26 givenname: Michiaki surname: Kubo fullname: Kubo, Michiaki organization: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan – sequence: 27 givenname: Shigeru surname: Kinoshita fullname: Kinoshita, Shigeru organization: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan – sequence: 28 givenname: Katsushi surname: Tokunaga fullname: Tokunaga, Katsushi email: tokunaga@m.u-tokyo.ac.jp organization: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25672763$$D View this record in MEDLINE/PubMed |
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| Copyright | 2015 American Academy of Allergy, Asthma & Immunology American Academy of Allergy, Asthma & Immunology Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. Copyright Elsevier Limited Jun 2015 |
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| Issue | 6 |
| Keywords | Stevens-Johnson syndrome GWAS OR alternative splicing severe mucosal involvement NSAID cold medicine IKZF1 SMI toxic epidermal necrolysis CM-SJS/TEN SNP genome-wide association study TLR IRF TEN SJS KPUM Cold medicine–related SJS/TEN Toll-like receptor Nonsteroidal anti-inflammatory drug Odds ratio Single nucleotide polymorphism Interferon regulatory factor Kyoto Prefectural University of Medicine |
| Language | English |
| License | https://www.elsevier.com/tdm/userlicense/1.0 Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. |
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| Snippet | Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous... Background Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin... |
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| SubjectTerms | Adolescent Adult Aged Allergy and Immunology Alternative Splicing Anti-Inflammatory Agents, Non-Steroidal - adverse effects Asian Continental Ancestry Group Case-Control Studies cold medicine Colleges & universities European Continental Ancestry Group Female Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Genomes Genotype & phenotype HLA-A Antigens - genetics HLA-A Antigens - immunology Humans Ikaros Transcription Factor - genetics Ikaros Transcription Factor - immunology IKZF1 Male Medical personnel Medical treatment Medicine Middle Aged Mortality Mouth Mucosa - drug effects Mouth Mucosa - pathology Multi-Ingredient Cold, Flu, and Allergy Medications - adverse effects Nonsteroidal anti-inflammatory drugs Odds Ratio Polymorphism, Single Nucleotide Protein Isoforms - genetics Protein Isoforms - immunology Quality control severe mucosal involvement Stevens-Johnson syndrome Stevens-Johnson Syndrome - ethnology Stevens-Johnson Syndrome - etiology Stevens-Johnson Syndrome - genetics Stevens-Johnson Syndrome - pathology toxic epidermal necrolysis |
| Title | IKZF1, a new susceptibility gene for cold medicine–related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement |
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