Mayumi Ueta1, Hiromi Sawai2, Chie Sotozono3, Yuki Hitomi2, Nahoko Kaniwa4, Mee Kum Kim5, Kyoung Yul Seo6, Kyung-Chul Yoon7, Choun-Ki Joo8, Chitra Kannabiran9, Tais Hitomi Wakamatsu10, Virender Sangwan11, Varsha Rathi11, Sayan Basu11, Takeshi Ozeki12, Taisei Mushiroda12, Emiko Sugiyama4, Keiko Maekawa4, Ryosuke Nakamura4, Michiko Aihara13, Kayoko Matsunaga14, Akihiro Sekine15, José Álvaro Pereira Gomes10, Junji Hamuro3, Yoshiro Saito4, Michiaki Kubo12, Shigeru Kinoshita3, Katsushi Tokunaga16. 1. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Research Center for Inflammation and Regenerative Medicine, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan; Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: mueta@koto.kpu-m.ac.jp. 2. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 3. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. 4. Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan. 5. Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea. 6. Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea. 7. Department of Ophthalmology, Chonnam National University, Gwangju, Korea. 8. Department of Ophthalmology & Visual Science, Seoul St Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea. 9. Prof Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India. 10. Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil. 11. Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India. 12. Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 13. Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 14. Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan. 15. EBM Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. 16. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: tokunaga@m.u-tokyo.ac.jp.
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.
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.
Authors: Tais H Wakamatsu; Mayumi Ueta; Katsushi Tokunaga; Yukinori Okada; Renata R Loureiro; Karita A Costa; Juliana Maria F Sallum; José Arthur Milhomens; Chikara Inoue; Chie Sotozono; José Álvaro P Gomes; Shigeru Kinoshita Journal: JAMA Ophthalmol Date: 2017-04-01 Impact factor: 7.389
Authors: Hajirah N Saeed; Charles Bouchard; Christine Shieh; Elizabeth Phillips; James Chodosh Journal: Ocul Surf Date: 2019-11-27 Impact factor: 5.033