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.
  
  
  CONCLUSIONS
  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: 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.
authors: Mayumi
authors: M
authors: Ueta
authors: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Hiromi
authors: H
authors: Sawai
authors: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Chie
authors: C
authors: Sotozono
authors: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Yuki
authors: Y
authors: Hitomi
authors: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors: Nahoko
authors: N
authors: Kaniwa
authors: Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.
authors: Mee Kum
authors: MK
authors: Kim
authors: Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.
authors: Kyoung Yul
authors: KY
authors: Seo
authors: Department of Ophthalmology, Chonnam National University, Gwangju, Korea.
authors: Kyung-Chul
authors: KC
authors: Yoon
authors: Department of Ophthalmology & Visual Science, Seoul St Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea.
authors: Choun-Ki
authors: CK
authors: Joo
authors: Prof Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India.
authors: Chitra
authors: C
authors: Kannabiran
authors: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors: Tais Hitomi
authors: TH
authors: Wakamatsu
authors: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India.
authors: Virender
authors: V
authors: Sangwan
authors: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India.
authors: Varsha
authors: V
authors: Rathi
authors: Cornea and Anterior Segment Services, L V Prasad Eye Institute, Hyderabad, India.
authors: Sayan
authors: S
authors: Basu
authors: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors: Takeshi
authors: T
authors: Ozeki
authors: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors: Taisei
authors: T
authors: Mushiroda
authors: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors: Emiko
authors: E
authors: Sugiyama
authors: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors: Keiko
authors: K
authors: Maekawa
authors: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors: Ryosuke
authors: R
authors: Nakamura
authors: Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Michiko
authors: M
authors: Aihara
authors: Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Kayoko
authors: K
authors: Matsunaga
authors: EBM Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Akihiro
authors: A
authors: Sekine
authors: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors: José Álvaro Pereira
authors: JÁ
authors: Gomes
authors: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Junji
authors: J
authors: Hamuro
authors: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors: Yoshiro
authors: Y
authors: Saito
authors: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Shigeru
authors: S
authors: Kinoshita
authors: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: tokunaga@m.u-tokyo.ac.jp.
authors: Katsushi
authors: K
authors: Tokunaga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D044466:Asian People; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects* / Q000473:pathology; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications / Q000009:adverse effects*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D013262:Stevens-Johnson Syndrome / Q000208:ethnology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D044465:White People
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015234:HLA-A Antigens; C497239:IKZF1 protein, human; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor
keywords: IKZF1; Stevens-Johnson syndrome; alternative splicing; cold medicine; genome-wide association study; severe mucosal involvement; toxic epidermal necrolysis