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

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 6; pp. 1538 - 1545.e17
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2015; Elsevier Limited
• Subjects: 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; 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
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.12.1916

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.