{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T19:40:34Z","timestamp":1765827634839},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T00:00:00Z","timestamp":1511222400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T00:00:00Z","timestamp":1511222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Stevens Johnson syndrome (SJS) is part of a spectrum of adverse drug reactions resulting in the destruction of skin, mucous membranes, and the ocular surface. A similar, more severe form of the disorder included in this spectrum is toxic epidermal necrolysis (TEN). Approximately 35% of patients suffer chronic sequelae such as vascularization, corneal scarring, conjunctival inversion to the cornea, keratinization, symblepharon, scarring of the palpebral conjunctiva, trichiasis, and severe dry eye. We focused on 80 Indian patients with SJS\/TEN with severe ocular complications (SOC) and investigated the association of alleles at <jats:italic>HLA -A, HLA-B<\/jats:italic> and <jats:italic>HLA-C<\/jats:italic> loci; the controls were 50 healthy Indian volunteers. Genotyping at <jats:italic>HLA-A, HLA-B<\/jats:italic>, and <jats:italic>HLA-C<\/jats:italic> loci showed a significant positive association with <jats:italic>HLA-A*33:03<\/jats:italic>, <jats:italic>HLA-B*44:03<\/jats:italic>, and <jats:italic>HLA-C*07:01<\/jats:italic> alleles, and a significant negative association with <jats:italic>HLA-B*57:01<\/jats:italic> and <jats:italic>HLA-C*06:02<\/jats:italic>. This indicates that <jats:italic>HLA-A*33:03<\/jats:italic>, <jats:italic>HLA-B*44:03<\/jats:italic> and <jats:italic>HLA-C*07:01<\/jats:italic> are risk alleles, and <jats:italic>HLA-B*57:01<\/jats:italic> and <jats:italic>HLA-C*06:02<\/jats:italic> are protective alleles in this population. We also found that the haplotypes consisting of <jats:italic>HLA-B*44:03<\/jats:italic> and <jats:italic>HLA-C*07:01<\/jats:italic> were strongly associated with SJS\/TEN with SOC in our Indian population (p\u2009=\u20091.1\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>, odds ratio\u2009=\u200911.0). Describing the association of the haplotype could facilitate the understanding of increased risk factors for developing SJS\/TEN with SOC.<\/jats:p>","DOI":"10.1038\/s41598-017-15965-7","type":"journal-article","created":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T15:37:14Z","timestamp":1510760234000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Association of Human Leukocyte Antigen Class 1 genes with Stevens Johnson Syndrome with severe ocular complications in an Indian population"],"prefix":"10.1038","volume":"7","author":[{"given":"Chitra","family":"Kannabiran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayumi","family":"Ueta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virender","family":"Sangwan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varsha","family":"Rathi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayan","family":"Basu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Kinoshita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,11,21]]},"reference":[{"key":"15965_CR1","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.2217\/pgs.12.108","volume":"13","author":"R Pavlos","year":"2012","unstructured":"Pavlos, R., Mallal, S. & Phillips, E. HLA and pharmacogenetics of drug hypersensitivity. Pharmacogenomics. \n                           13, 1285\u20131306 (2012).","journal-title":"Pharmacogenomics."},{"key":"15965_CR2","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1056\/NEJM199512143332404","volume":"333","author":"JC Roujeau","year":"1995","unstructured":"Roujeau, J. C., Kelly, J. P. & Naldi, L. et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. The New England journal of medicine. \n                           333, 1600\u20131607 (1995).","journal-title":"The New England journal of medicine."},{"key":"15965_CR3","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1097\/00007611-198005000-00015","volume":"73","author":"JZ Yetiv","year":"1980","unstructured":"Yetiv, J. Z., Bianchine, J. R. & Owen, J. A. Etiologic factors of the Stevens-Johnson syndrome. South Med J. \n                           73, 599\u2013602 (1980).","journal-title":"South Med J."},{"key":"15965_CR4","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.ophtha.2008.12.048","volume":"116","author":"C Sotozono","year":"2009","unstructured":"Sotozono, C., Ueta, M. & Koizumi, N. et al. Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology. \n                           116, 685\u2013690 (2009).","journal-title":"Ophthalmology."},{"key":"15965_CR5","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ajo.2015.05.002","volume":"160","author":"C Sotozono","year":"2015","unstructured":"Sotozono, C., Ueta, M. & Nakatani, E. et al. Predictive Factors Associated With Acute Ocular Involvement in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. American journal of ophthalmolog. \n                           160, 228\u2013237 e222 (2015).","journal-title":"American journal of ophthalmolog."},{"key":"15965_CR6","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1016\/j.ophtha.2006.10.029","volume":"114","author":"C Sotozono","year":"2007","unstructured":"Sotozono, C., Ang, L. P. & Koizumi, N. et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Ophthalmology. \n                           114, 1294\u20131302 (2007).","journal-title":"Ophthalmology."},{"key":"15965_CR7","doi-asserted-by":"publisher","first-page":"e25209","DOI":"10.1371\/journal.pone.0025209","volume":"6","author":"M Ueta","year":"2011","unstructured":"Ueta, M., Sotozono, C., Yokoi, N., Inatomi, T. & Kinoshita, S. Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders. PloS one. \n                           6, e25209 (2011).","journal-title":"PloS one."},{"key":"15965_CR8","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.preteyeres.2012.05.003","volume":"31","author":"M Ueta","year":"2012","unstructured":"Ueta, M. & Kinoshita, S. Ocular surface inflammation is regulated by innate immunity. Prog Retin Eye Res. \n                           31, 551\u2013575 (2012).","journal-title":"Prog Retin Eye Res."},{"key":"15965_CR9","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1001\/jamaophthalmol.2017.0074","volume":"135","author":"TH Wakamatsu","year":"2017","unstructured":"Wakamatsu, T. H., Ueta, M. & Tokunaga, K. et al. 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 ophthalmology. \n                           135, 355\u2013360 (2017).","journal-title":"JAMA ophthalmology."},{"key":"15965_CR10","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1001\/archopht.1982.01030040431012","volume":"100","author":"BJ Mondino","year":"1982","unstructured":"Mondino, B. J., Brown, S. I. & Biglan, A. W. HLA antigens in Stevens-Johnson syndrome with ocular involvement. Archives of ophthalmology. \n                           100, 1453\u20131454 (1982).","journal-title":"Archives of ophthalmology."},{"key":"15965_CR11","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1016\/S0161-6420(96)30491-0","volume":"103","author":"WJ Power","year":"1996","unstructured":"Power, W. J., Saidman, S. L. & Zhang, D. S. et al. HLA typing in patients with ocular manifestations of Stevens-Johnson syndrome. Ophthalmology. \n                           103, 1406\u20131409 (1996).","journal-title":"Ophthalmology."},{"key":"15965_CR12","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1001\/archderm.1987.01660330082014","volume":"123","author":"JC Roujeau","year":"1987","unstructured":"Roujeau, J. C. et al. Genetic susceptibility to toxic epidermal necrolysis. Archives of dermatology. \n                           123, 1171\u20131173 (1987).","journal-title":"Archives of dermatology."},{"key":"15965_CR13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.ajo.2006.09.029","volume":"143","author":"M Ueta","year":"2007","unstructured":"Ueta, M., Sotozono, C., Tokunaga, K., Yabe, T. & Kinoshita, S. Strong Association Between HLA-A*0206 and Stevens-Johnson Syndrome in the Japanese. American journal of ophthalmology. \n                           143, 367\u2013368 (2007).","journal-title":"American journal of ophthalmology."},{"key":"15965_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/srep04862","volume":"4","author":"M Ueta","year":"2014","unstructured":"Ueta, M., Kaniwa, N. & Sotozono, C. et al. 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. \n                           4, 4862 (2014).","journal-title":"Sci Rep."},{"key":"15965_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/srep05981","volume":"4","author":"M Ueta","year":"2014","unstructured":"Ueta, M., Kannabiran, C. & Wakamatsu, T. H. et al. 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. \n                           4, 5981 (2014).","journal-title":"Sci Rep."},{"key":"15965_CR16","doi-asserted-by":"publisher","first-page":"4134","DOI":"10.1073\/pnas.0409500102","volume":"102","author":"SI Hung","year":"2005","unstructured":"Hung, S. I., Chung, W. H. & Liou, L. B. et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA \n                           102, 4134\u20134139 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"15965_CR17","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1097\/FPC.0b013e3282f3ef9c","volume":"18","author":"C Lonjou","year":"2008","unstructured":"Lonjou, C., Borot, N. & Sekula, P. et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenetics and genomics. \n                           18, 99\u2013107 (2008).","journal-title":"Pharmacogenetics and genomics."},{"key":"15965_CR18","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/tpj.2011.41","volume":"13","author":"M Tohkin","year":"2013","unstructured":"Tohkin, M., Kaniwa, N. & Saito, Y. et al. A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. The pharmacogenomics journal. \n                           13, 60\u201369 (2013).","journal-title":"The pharmacogenomics journal."},{"key":"15965_CR19","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/428486a","volume":"428","author":"WH Chung","year":"2004","unstructured":"Chung, W. H., Hung, S. I. & Hong, H. S. et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. \n                           428, 486 (2004).","journal-title":"Nature."},{"key":"15965_CR20","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1097\/ICO.0000000000000708","volume":"35","author":"HS Lee","year":"2016","unstructured":"Lee, H. S., Ueta, M. & Kim, M. K. et al. Analysis of Ocular Manifestation and Genetic Association of Allopurinol-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in South Korea. Cornea. \n                           35, 199\u2013204 (2016).","journal-title":"Cornea."},{"key":"15965_CR21","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/jhg.2016.160","volume":"62","author":"M Ueta","year":"2017","unstructured":"Ueta, M., Sawai, H. & Shingaki, R. et al. 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. Journal of human genetics. \n                           62, 485\u2013489 (2017).","journal-title":"Journal of human genetics."},{"key":"15965_CR22","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1016\/j.jaci.2014.12.1916","volume":"135","author":"M Ueta","year":"2015","unstructured":"Ueta, M., Sawai, H. & Sotozono, C. et al. IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome\/toxic epidermal necrolysis with severe mucosal involvement. The Journal of allergy and clinical immunology. \n                           135, 1538\u20131545 e1517 (2015).","journal-title":"The Journal of allergy and clinical immunology."},{"key":"15965_CR23","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1136\/bjo.2006.113449","volume":"91","author":"M Ueta","year":"2007","unstructured":"Ueta, M., Sotozono, C. & Inatomi, T. et al. Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. The British journal of ophthalmology. \n                           91, 962\u2013965 (2007).","journal-title":"The British journal of ophthalmology."},{"key":"15965_CR24","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/j.jaci.2010.08.007","volume":"126","author":"M Ueta","year":"2010","unstructured":"Ueta, M., Sotozono, C. & Nakano, M. et al. Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study. The Journal of allergy and clinical immunology. \n                           126, 1218\u20131225 e1210 (2010).","journal-title":"The Journal of allergy and clinical immunology."},{"key":"15965_CR25","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1167\/iovs.07-1401","volume":"49","author":"M Ueta","year":"2008","unstructured":"Ueta, M. et al. Association of combined IL-13\/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest Ophthalmol Vis Sci. \n                           49, 1809\u20131813 (2008).","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"15965_CR26","first-page":"550","volume":"14","author":"M Ueta","year":"2008","unstructured":"Ueta, M., Tokunaga, K. & Sotozono, C. et al. HLA class I and II gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese. Mol Vis. \n                           14, 550\u2013555 (2008).","journal-title":"Mol Vis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15965-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15965-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15965-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T13:49:36Z","timestamp":1671803376000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15965-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,21]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["15965"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-15965-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,21]]},"assertion":[{"value":"23 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15960"}}