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スティーブンス・ジョンソン症候群（SJS）研究
Research for Stevens-Johnson syndrome（SJS）

We explore the pathogenic mechanism of SJS with the involvement of eye symptoms caused by the consumption of cold medicine, Our aim is to identify susceptibility gene responsible for the onset of SJS through whole genome analysis.

研究背景

スティーブンス・ジョンソン症候群（SJS）は、薬剤摂取後に生ずる皮膚や粘膜の病変を特徴とする病気です。発症率は極めて低いものの、一般的な市販薬がきっかけになる場合もあるほか、死亡率が非常に高く、たいへん恐ろしい病気です。しかしながら、何らかの免疫学的な関与が示唆される一方で、発症原因はよく分かっておりません。

研究アプローチ

私たちは、京都府立医科大学眼科学教室の上田真由美博士、外園千恵博士、木下茂博士との共同研究により、ゲノムワイド関連解析（GWAS）という手法を用いて、全ゲノムに渡る網羅的なSJSの感受性遺伝子探索を実施することによって、特に感冒薬を原因とし眼症状を合併するSJSの発症メカニズムを探っています。

さらに、短時間で大量のヒトゲノムDNA配列を解読することのできる「次世代シークエンサー」を用いた全ゲノムシークエンス解析を実施することで、さらに高密度なSJS感受性遺伝子探索を実施していきます。

主な成果

これまでに実施したSJS感受性に対する候補遺伝子アプローチの結果、HLA遺伝子群がSJS感受性との非常に強い関連を示しました。
さらに、日本人のSJS患者を対象としたGWASを実施したところ、これまでに既に疾患感受性との関連が報告されているHLA遺伝子群に加え、新たにIKZF1などの多型が強い関連を示しました。

本研究に関する文献

Kawai, Yosuke, Yuki Hitomi, Mayumi Ueta, Seik-Soon Khor, Ken Nakatani, Chie Sotozono, Shigeru Kinoshita, Masao Nagasaki, and Katsushi Tokunaga. Mapping of Susceptible Variants for Cold Medicine-Related Stevens-Johnson Syndrome by Whole-Genome Resequencing. Npj Genomic Medicine 6(1):9. 2021.
Ma KS, Chung WH, Hsueh YJ, Chen SY, Tokunaga K, Kinoshita S, Ma DHK, Ueta M. Human leucocyte antigen association of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications in Han Chinese. Br J Ophthalmol. bjophthalmol-2020-317105. 2021.
Nakatani K, Ueta M, Khor SS, Hitomi Y, Okudaira Y, Masuya A, Wada Y, Sotozono C, Kinoshita S, Inoko H, Tokunaga K. Identification of HLA-A*02:06:01 as the primary disease susceptibility HLA allele in cold medicine-related Stevens-Johnson syndrome with severe ocular complications by high-resolution NGS-based HLA typing. Sci Rep. 7;9(1):16240. 2019.
Ueta M, Nakamura R, Saito Y, Tokunaga K, Sotozono C, Yabe T, Aihara M, Matsunaga K, Kinoshita S. Association of HLA class I and II gene polymorphisms with acetaminophen-related Stevens-Johnson syndrome with severe ocular complications in Japanese individuals. Hum Genome Var. 28;6:50. 2019.
Kannabiran C, Ueta M, Sangwan V, Rathi V, Basu S, Tokunaga K, Kinoshita S: Association of Human Leukocyte Antigen Class 1 genes with Stevens Johnson Syndrome with severe ocular complications in an Indian population. Sci Rep 7: 15960, 2018.
Ueta M, Hamuro J, Nishigaki H, Nakamura N, Shinomiya K, Mizushima K, Hitomi Y, Tamagawa-Mineoka R, Yokoi N, Naito Y, Tokunaga K, Katoh N, Sotozono C, Kinoshita S: Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice. Allergy 73: 395-404, 2018.
Wakamatsu TH, Ueta M, Tokunaga K, Okada Y, Loureiro RR, Costa KA, Sallum JMF, Milhomens JA, Inoue C, Sotozono C, Gomes JAP, Kinoshita S: Human Leukocyte Antigen Class I Genes Associated With Stevens-Johnson Syndrome and Severe Ocular Complications Following Use of Cold Medicine in a Brazilian Population. JAMA Ophthalmol 135: 355-360, 2017.
Ueta M, Sawai H, Shingaki R, Kawai Y, Sotozono C, Kojima K, Yoon KC, Kim MK, Seo KY, Joo CK, Nagasaki M, Kinoshita S, Tokunaga K: Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications. J Hum Genet 62: 485-489, 2017.
Ueta M, Tokunaga K, Sotozono C, Sawai H, Yoon KC, Kim MK, Seo KY, Joo CK, Tashiro K, and Kinoshita S: HLA-A*02:06 and PTGER3 polymorphism exerts additive effects in cold medicine-related Stevens Johnson syndrome with severe ocular complications. Human Genome Variation 2: 15023, 2015.
Ueta M, Sawai H, Sotozono C, Hitomi Y, Kaniwa N, Kim MK, Seo KY, Yoon KC, Joo CK, Kannabiran C, Wakamatsu TH, Sangwan V, Rathi V, Basu S, Ozeki T, Mushiroda T, Sugiyama E, Maekawa K, Nakamura R, Aihara M, Matsunaga K, Sekine A, Gomes JAP, Hamuro J, Saito Y, Kubo M, Kinoshita S, Tokunaga K: New Susceptibility Gene, IKZF1, for Cold Medicine-Related Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis with Severe Mucosal Involvements. J Allergy Clin Immunol ,135:1538-1545, 2015.
Ueta M, Kannabiran C, Wakamatsu TH, Kim MK, Yoon KC, Seo KY, Joo CK, Sangwan V, Rathi V, Basu S, Shamaila A, Lee HS, Yoon S, Sotozono C, Gomes JA, Tokunaga K, Kinoshita S. Trans-ethnic study confirmed independent associations of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe ocular surface complications. Sci Rep 4:5981, 2014.
Ueta M, Kaniwa N, Sotozono C, Tokunaga K, Saito Y, Sawai H, Miyadera H, Sugiyama E, Maekawa K, Nakamura R, Nagato M, Aihara M, Matsunaga K, Takahashi Y, Furuya H, Muramatsu M, Ikezawa Z, Kinoshita S: Independent strong association of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe mucosal involvement. Sci Rep 4:4862, 2014.
Isogai H, Miyadera H, Ueta M, Sotozono C, Kinoshita S, Tokunaga K, Hirayama N: In Silico Risk Assessment of HLA-A*02:06-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Caused by Cold Medicine Ingredients. J Toxicol 2013:514068, 2013.
Ueta M, Tokunaga K, Sotozono C, Sawai H, Tamiya G, Inatomi T, Kinoshita S: HLA-A*0206 with TLR3 polymorphisms exerts more than additive effects in Stevens-Johnson syndrome with severe ocular surface complications. PLoS One 7(8):e43650, 2012.
Ueta M, Tamiya G, Tokunaga K, Sotozono C, Ueki M, Sawai H, Inatomi T, Matsuoka T, Akira S, Narumiya S, Tashiro K, Kinoshita S: Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes. J Allergy Clin Immunol 129(5):1413-1416.e11, 2012.
Ueta M, Matsushita M, Sotozono C, Kinoshita S, Tokunaga K: Identification of a novel HLA-B allele, HLA-B*5904. Tissue Antigens 73(6):612-4, 2009.
Ueta M, Tokunaga K, Sotozono C, Inatomi T, Yabe T, Matsushita M, Mitsuishi Y, Kinoshita S: HLA class I and II gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese. Mol Vis 17;14:550-5, 2008.
Ueta M, Sotozono C, Tokunaga K, Yabe T, Kinoshita S: Strong association between HLA-A*0206 and Stevens-Johnson syndrome in the Japanese. Am J Ophthalmol 143(2):367-8, 2007.