{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:29:37Z","timestamp":1761611377046},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T00:00:00Z","timestamp":1439424000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T00:00:00Z","timestamp":1439424000000},"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>Complement is involved in many immune-mediated diseases. However, the association of its copy number variations (CNVs) and polymorphisms with Behcet\u2019s disease (BD) and Vogt-Koyanagi-Harada syndrome (VKH) is unknown. We examined copy number and mRNA expression by real-time PCR. Cytokine production by stimulated peripheral blood mononuclear cells (PBMCs) in genotyped individuals was measured by ELISA. The frequencies of having more than two copies of C3 were significantly increased in BD and VKH, whereas CNV of C5 was only associated with BD. Increased frequencies of the GG genotype of C3 rs408290 and C5 rs2269067 were found in BD. No association was observed between C3 and C5 SNPs and VKH. mRNA expression in the high CNV group and GG cases of C3 and C5 was significantly higher compared to other genotypes. Increased interleukin-17 and IFN-\u03b3 was observed in the high CNV group and GG genotype cases of C3. Interleukin-17 but not IFN-\u03b3 was increased in the high CNV group and GG genotype cases of C5. No effect of C3 or C5 genetic variants was seen on the production of TNF-\u03b1, IL-10, IL-1\u03b2, MCP-1, IL-6 and IL-8. Our study thus provides further evidence for a role of complement in the pathogenesis of uveitis.<\/jats:p>","DOI":"10.1038\/srep12989","type":"journal-article","created":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T09:39:08Z","timestamp":1439458748000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Copy number variations and gene polymorphisms of Complement components in ocular Behcet\u2019s disease and Vogt-Koyanagi-Harada syndrome"],"prefix":"10.1038","volume":"5","author":[{"given":"Dengfeng","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengping","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanni","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aize","family":"Kijlstra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peizeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,13]]},"reference":[{"key":"BFsrep12989_CR1","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1136\/bjo.80.9.844","volume":"80","author":"MS Suttorp-Schulten","year":"1996","unstructured":"Suttorp-Schulten, M. S. & Rothova, A. The possible impact of uveitis in blindness: a literature survey. The British journal of ophthalmology. 80, 844\u2013848 (1996).","journal-title":"The British journal of ophthalmology."},{"key":"BFsrep12989_CR2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s10384-006-0383-4","volume":"51","author":"H Goto","year":"2007","unstructured":"Goto, H. et al. Epidemiological survey of intraocular inflammation in Japan. Japanese journal of ophthalmology. 51, 41\u201344 (2007).","journal-title":"Japanese journal of ophthalmology."},{"key":"BFsrep12989_CR3","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1080\/02713680500263606","volume":"30","author":"P Yang","year":"2005","unstructured":"Yang, P. et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Current eye research. 30, 943\u2013948 (2005).","journal-title":"Current eye research."},{"key":"BFsrep12989_CR4","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1056\/NEJM199910213411707","volume":"341","author":"T Sakane","year":"1999","unstructured":"Sakane, T., Takeno, M., Suzuki, N. & Inaba, G. Behcet\u2019s disease. The New England journal of medicine. 341, 1284\u20131291 (1999).","journal-title":"The New England journal of medicine."},{"key":"BFsrep12989_CR5","first-page":"S6","volume":"19","author":"A Gul","year":"2001","unstructured":"Gul, A. Behcet\u2019s disease: an update on the pathogenesis. Clinical and experimental rheumatology. 19, S6\u201312 (2001).","journal-title":"Clinical and experimental rheumatology."},{"key":"BFsrep12989_CR6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/S0039-6257(05)80105-5","volume":"39","author":"RS Moorthy","year":"1995","unstructured":"Moorthy, R. S., Inomata, H. & Rao, N. A. Vogt-Koyanagi-Harada syndrome. Survey of ophthalmology. 39, 265\u2013292 (1995).","journal-title":"Survey of ophthalmology."},{"key":"BFsrep12989_CR7","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S0002-9394(14)73884-X","volume":"119","author":"AR Rutzen","year":"1995","unstructured":"Rutzen, A. R., Ortega-Larrocea, G., Schwab, I. R. & Rao, N. A. Simultaneous onset of Vogt-Koyanagi-Harada syndrome in monozygotic twins. American journal of ophthalmology. 119, 239\u2013240 (1995).","journal-title":"American journal of ophthalmology."},{"key":"BFsrep12989_CR8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1136\/ard.57.1.45","volume":"57","author":"I Fresko","year":"1998","unstructured":"Fresko, I. et al. Genetic anticipation in Behcet\u2019s syndrome. Annals of the rheumatic diseases. 57, 45\u201348 (1998).","journal-title":"Annals of the rheumatic diseases."},{"key":"BFsrep12989_CR9","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1146\/annurev.genom.9.081307.164217","volume":"10","author":"F Zhang","year":"2009","unstructured":"Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease and evolution. Annual review of genomics and human genetics. 10, 451\u2013481 (2009).","journal-title":"Annual review of genomics and human genetics."},{"key":"BFsrep12989_CR10","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrg2149","volume":"8","author":"JS Beckmann","year":"2007","unstructured":"Beckmann, J. S., Estivill, X. & Antonarakis, S. E. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature reviews. Genetics. 8, 639\u2013646 (2007).","journal-title":"Nature reviews. Genetics."},{"key":"BFsrep12989_CR11","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1146\/annurev.bi.57.070188.001541","volume":"57","author":"HJ Muller-Eberhard","year":"1988","unstructured":"Muller-Eberhard, H. J. Molecular organization and function of the complement system. Annual review of biochemistry. 57, 321\u2013347 (1988).","journal-title":"Annual review of biochemistry."},{"key":"BFsrep12989_CR12","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s00281-008-0110-y","volume":"30","author":"NS Bora","year":"2008","unstructured":"Bora, N. S., Jha, P. & Bora, P. S. The role of complement in ocular pathology. Seminars in immunopathology. 30, 85\u201395 (2008).","journal-title":"Seminars in immunopathology."},{"key":"BFsrep12989_CR13","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1016\/j.molimm.2007.06.145","volume":"44","author":"P Jha","year":"2007","unstructured":"Jha, P., Bora, P. S. & Bora, N. S. The role of complement system in ocular diseases including uveitis and macular degeneration. Molecular immunology. 44, 3901\u20133908 (2007).","journal-title":"Molecular immunology."},{"key":"BFsrep12989_CR14","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1167\/iovs.05-1062","volume":"47","author":"P Jha","year":"2006","unstructured":"Jha, P. et al. The complement system plays a critical role in the development of experimental autoimmune anterior uveitis. Investigative ophthalmology & visual science. 47, 1030\u20131038 (2006).","journal-title":"Investigative ophthalmology & visual science."},{"key":"BFsrep12989_CR15","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/ng1750","volume":"38","author":"B Gold","year":"2006","unstructured":"Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature genetics. 38, 458\u2013462 (2006).","journal-title":"Nature genetics."},{"key":"BFsrep12989_CR16","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/0198-8859(88)90032-8","volume":"21","author":"D Wakefield","year":"1988","unstructured":"Wakefield, D. et al. Association of complement allotype C4B2 with anterior uveitis. Human immunology. 21, 233\u2013237 (1988).","journal-title":"Human immunology."},{"key":"BFsrep12989_CR17","doi-asserted-by":"publisher","first-page":"2963","DOI":"10.1002\/art.38116","volume":"65","author":"S Hou","year":"2013","unstructured":"Hou, S. et al. Copy number variations of complement component C4 are associated with Behcet\u2019s disease but not with ankylosing spondylitis associated with acute anterior uveitis. Arthritis and rheumatism. 65, 2963\u20132970 (2013).","journal-title":"Arthritis and rheumatism."},{"key":"BFsrep12989_CR18","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1136\/bjophthalmol-2014-305596","volume":"98","author":"S Hou","year":"2014","unstructured":"Hou, S. et al. High C4 gene copy numbers protects against Vogt-Koyanagi-Harada syndrome in Chinese Han. The British journal of ophthalmology. 98, 1733\u20131737 (2014).","journal-title":"The British journal of ophthalmology."},{"key":"BFsrep12989_CR19","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.exer.2005.07.011","volume":"82","author":"RW Read","year":"2006","unstructured":"Read, R. W., Szalai, A. J., Vogt, S. D., McGwin, G. & Barnum, S. R. Genetic deficiency of C3 as well as CNS-targeted expression of the complement inhibitor sCrry ameliorates experimental autoimmune uveoretinitis. Experimental eye research. 82, 389\u2013394 (2006).","journal-title":"Experimental eye research."},{"key":"BFsrep12989_CR20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/j.1365-2249.2009.04070.x","volume":"159","author":"DA Copland","year":"2010","unstructured":"Copland, D. A. et al. Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. Clinical and experimental immunology. 159, 303\u2013314 (2010).","journal-title":"Clinical and experimental immunology."},{"key":"BFsrep12989_CR21","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1038\/ng.2741","volume":"45","author":"JM Seddon","year":"2013","unstructured":"Seddon, J. M. et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature genetics. 45, 1366\u20131370 (2013).","journal-title":"Nature genetics."},{"key":"BFsrep12989_CR22","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1093\/rheumatology\/kem321","volume":"47","author":"H Miyagawa","year":"2008","unstructured":"Miyagawa, H. et al. Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology (Oxford). 47, 158\u2013164 (2008).","journal-title":"Rheumatology (Oxford)."},{"key":"BFsrep12989_CR23","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/gene.2009.23","volume":"10","author":"B Rhodes","year":"2009","unstructured":"Rhodes, B. et al. The heritability and genetics of complement C3 expression in UK SLE families. Genes and immunity. 10, 525\u2013530 (2009).","journal-title":"Genes and immunity."},{"key":"BFsrep12989_CR24","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1056\/NEJMoa072618","volume":"357","author":"JR Yates","year":"2007","unstructured":"Yates, J. R. et al. Complement C3 variant and the risk of age-related macular degeneration. The New England journal of medicine. 357, 553\u2013561 (2007).","journal-title":"The New England journal of medicine."},{"key":"BFsrep12989_CR25","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.exer.2012.01.005","volume":"96","author":"SJ Kim","year":"2012","unstructured":"Kim, S. J., Lee, S. J., Kim, N. R. & Chin, H. S. Association of polymorphisms in C2, CFB and C3 with exudative age-related macular degeneration in a Korean population. Experimental eye research. 96, 42\u201347 (2012).","journal-title":"Experimental eye research."},{"key":"BFsrep12989_CR26","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1038\/ejhg.2009.23","volume":"17","author":"J Bergeron-Sawitzke","year":"2009","unstructured":"Bergeron-Sawitzke, J. et al. Multilocus analysis of age-related macular degeneration. European journal of human genetics: EJHG. 17, 1190\u20131199 (2009).","journal-title":"European journal of human genetics: EJHG."},{"key":"BFsrep12989_CR27","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1080\/02713680903003484","volume":"34","author":"XT Pei","year":"2009","unstructured":"Pei, X. T. et al. Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a chinese population. Current eye research. 34, 615\u2013622 (2009).","journal-title":"Current eye research."},{"key":"BFsrep12989_CR28","doi-asserted-by":"publisher","first-page":"e28847","DOI":"10.1371\/journal.pone.0028847","volume":"6","author":"S Yanagisawa","year":"2011","unstructured":"Yanagisawa, S. et al. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population. PloS one. 6, e28847 (2011).","journal-title":"PloS one."},{"key":"BFsrep12989_CR29","doi-asserted-by":"publisher","first-page":"e1000107","DOI":"10.1371\/journal.pgen.1000107","volume":"4","author":"M Chang","year":"2008","unstructured":"Chang, M. et al. A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2. PLoS genetics. 4, e1000107 (2008).","journal-title":"PLoS genetics."},{"key":"BFsrep12989_CR30","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.ophtha.2009.08.032","volume":"117","author":"DC Baas","year":"2010","unstructured":"Baas, D. C. et al. The complement component 5 gene and age-related macular degeneration. Ophthalmology. 117, 500\u2013511 (2010).","journal-title":"Ophthalmology."},{"key":"BFsrep12989_CR31","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/ejhg.2008.140","volume":"17","author":"JA Fagerness","year":"2009","unstructured":"Fagerness, J. A. et al. Variation near complement factor I is associated with risk of advanced AMD. European journal of human genetics: EJHG. 17, 100\u2013104 (2009).","journal-title":"European journal of human genetics: EJHG."},{"key":"BFsrep12989_CR32","doi-asserted-by":"publisher","first-page":"5158","DOI":"10.4049\/jimmunol.181.7.5158","volume":"181","author":"A Ghannam","year":"2008","unstructured":"Ghannam, A. et al. Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells and regulatory T cells. J Immunol. 181, 5158\u20135166 (2008).","journal-title":"J Immunol."},{"key":"BFsrep12989_CR33","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1111\/j.1365-2249.2010.04093.x","volume":"160","author":"T Sugihara","year":"2010","unstructured":"Sugihara, T. et al. The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease. Clinical and experimental immunology. 160, 386\u2013393 (2010).","journal-title":"Clinical and experimental immunology."},{"key":"BFsrep12989_CR34","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/j.jaci.2007.01.010","volume":"119","author":"W Chi","year":"2007","unstructured":"Chi, W. et al. IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. The Journal of allergy and clinical immunology. 119, 1218\u20131224 (2007).","journal-title":"The Journal of allergy and clinical immunology."},{"key":"BFsrep12989_CR35","doi-asserted-by":"publisher","first-page":"6434","DOI":"10.1167\/iovs.12-10398","volume":"53","author":"Y Tian","year":"2012","unstructured":"Tian, Y. et al. Effect of 1, 25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behcet\u2019s disease. Investigative ophthalmology & visual science. 53, 6434\u20136441 (2012).","journal-title":"Investigative ophthalmology & visual science."},{"key":"BFsrep12989_CR36","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/sj.bjp.0707332","volume":"152","author":"PN Monk","year":"2007","unstructured":"Monk, P. N., Scola, A. M., Madala, P. & Fairlie, D. P. Function, structure and therapeutic potential of complement C5a receptors. British journal of pharmacology. 152, 429\u2013448 (2007).","journal-title":"British journal of pharmacology."},{"key":"BFsrep12989_CR37","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1002\/art.38237","volume":"66","author":"C Kessel","year":"2014","unstructured":"Kessel, C. et al. A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis. Arthritis Rheumatol. 66, 610\u2013621 (2014).","journal-title":"Arthritis Rheumatol."},{"key":"BFsrep12989_CR38","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/ni.1926","volume":"11","author":"S Lajoie","year":"2010","unstructured":"Lajoie, S. et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nature immunology. 11, 928\u2013935 (2010).","journal-title":"Nature immunology."},{"key":"BFsrep12989_CR39","first-page":"81","volume":"4","author":"A Gul","year":"2005","unstructured":"Gul, A. Behcet\u2019s disease as an autoinflammatory disorder. Current drug targets. Inflammation and allergy. 4, 81\u201383 (2005).","journal-title":"Inflammation and allergy."},{"key":"BFsrep12989_CR40","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.autrev.2013.01.004","volume":"12","author":"A Greco","year":"2013","unstructured":"Greco, A. et al. Vogt-Koyanagi-Harada syndrome. Autoimmunity reviews. 12, 1033\u20131038 (2013).","journal-title":"Autoimmunity reviews."},{"key":"BFsrep12989_CR41","doi-asserted-by":"crossref","unstructured":"Criteria for diagnosis of Behcet\u2019s disease. International Study Group for Behcet\u2019s Disease. Lancet. 335, 1078\u20131080 (1990).","DOI":"10.1016\/0140-6736(90)92643-V"},{"key":"BFsrep12989_CR42","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/S0002-9394(01)00925-4","volume":"131","author":"RW Read","year":"2001","unstructured":"Read, R. W. et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. American journal of ophthalmology. 131, 647\u2013652 (2001).","journal-title":"American journal of ophthalmology."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep12989.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12989","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12989.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T23:48:21Z","timestamp":1672962501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep12989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,13]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,10,16]]}},"alternative-id":["BFsrep12989"],"URL":"https:\/\/doi.org\/10.1038\/srep12989","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,13]]},"assertion":[{"value":"10 February 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12989"}}