New Susceptibility Gene IKZF1 for Cold Medicine-Related Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis with Severe Mucosal Involvement. M. UETA1,2, H. Sawai3, C. Sotozono1, Y. Hitomi3, N. Kaniwa4, MK. Kim5, KY. Seo6, KC. Yoon7, CK. Joo8, C. Kannabiran9, TH. Wakamatsu10, V. Sangwan11, V. Rathi11, S. Basu11, T. Ozeki12, T. Mushiroda12, E. Sugiyama4, K. Maekawa4, R. Nakamura4, M. Aihara13, K. Matsunaga14, A. Sekine15, JAP. Gomes10, J. Hamuro1, Y. Saito4, M. Kubo12, S. Kinoshita1, K. Tokunaga2 1) Kyoto Prefectural University of Medicine, Kyoto, Japan; 2) Research Center for Inflammation and Regenerative Medicine, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan; 3) Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 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. Marys Hospital, College of Medicine, The 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.
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 and infectious agents. To identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI), a genome-wide association study (GWAS) was performed in 808 Japanese individuals (117 cases and 691 controls). We found that the HLA-A region showed the strongest association with susceptibility to CM-SJS/TEN with SMI. Outside of the HLA region, there were 60 SNPs with p < 10-3 in the GWAS. In the 11 SNPs that were p < 10-5, loci IKZF1 and TSHZ2 showed especially low p-values. The 10 SNPs of the 11 SNPs with p < 10-5, which functional TaqMan probes were available, were studied in a subsequent replication analysis by using an independent set of 208 Japanese samples (20 cases and 188 controls). In this first replication study, there were no SNPs with a significant association after applying the Bonferroni correction because of the relatively small sample size. However, the ORs of 9 SNPs of the 10 SNPs showed the same direction of association as those in the GWAS. Moreover, we genotyped these 10 SNPs in samples from the Korean population (34 cases and 90 controls), which is genetically close to the Japanese population. Although the number of Korean cases was small, we found a significant association between Korean CM-SJS/TEN with SMI and IKZF1. Furthermore, the meta-analysis with Japanese and Korean samples showed a genome-wide significant association with IKZF1. Moreover, in Indian samples (26 case and 56 controls), we also genotyped the SNP of IKZF1. Although the Indian population is genetically close to the European population and the sample size was small, we found significant associations between Indian CM-SJS/TEN with SMI and IKZF1. Furthermore, the meta-analysis with Japanese, Korean and Indian samples showed a genome-wide significant association between CM-SJS/TEN with SMI and IKZF1 (p = 7.6×10-11) . Furthermore, quantitative ratios of IKZF1 alternative splicing isoforms, Ik1 and Ik2, were significantly associated with the genotypes. These results indicate that the ratio of Ik2/Ik1 may be influenced by IKZF1 SNPs, which were significantly associated with susceptibility to CM-SJS/TEN with SMI.