ETS proto-oncogene 1, transcription factor (ETS1) is involved in various immune responses. Genome-wide association studies on systemic lupus erythematosus in Chinese populations identified the association of ETS1 polymorphism in 3′ untranslated region, rs1128334A, which was associated with lower ETS1 expression. In view of substantial sharing of susceptibility genes across multiple autoimmune diseases, we examined whether ETS1 is associated with a rare autoimmune rheumatic disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Association of rs1128334 was tested in 466 Japanese patients with AAV and 1099 healthy controls by logistic regression analysis under the additive model. AAV patients were classified into 285 microscopic polyangiitis (MPA), 92 granulomatosis with polyangiitis (GPA), 56 eosinophilic GPA, and 33 unclassifiable AAV, according to the European Medicines Agency (EMEA) algorithm. Among the patients, 376 were positive for MPO–ANCA and 62 for PR3–ANCA. When the patients were classified according to the EMEA classification, rs1128334A allele was significantly increased in GPA (P = 0.0060, P c = 0.030, odds ratio (OR), 1.54; 95% confidence interval (CI), 1.13–2.10). With respect to the ANCA specificity, significant association was observed in PR3–ANCA positive AAV (P = 0.0042, P c = 0.021, OR, 1.72; 95% CI, 1.19–2.49). In conclusion, ETS1 polymorphism was suggested to be associated with GPA and PR3–ANCA positive AAV in a Japanese population.
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Kallenberg CG, Heeringa P, Stegeman CA. Mechanisms of disease: pathogenesis and treatment of ANCA-associated vasculitides. Nat Clin Pract Rheumatol. 2006;2:661–70.
Fujimoto S, Watts RA, Kobayashi S, Suzuki K, Jayne DR, Scott DG, et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK. Rheumatology. 2011;50:1916–20.
Sada KE, Yamamura M, Harigai M, Fujii T, Dobashi H, Takasaki Y, et al. Classification and characteristics of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study. Arthritis Res Ther. 2014;16:R101; https://doi.org/10.1186/ar4550.
Kawasaki A, Hasebe N, Hidaka M, Hirano F, Sada KE, Kobayashi S, et al. Protective role of HLA-DRB1*13:02 against microscopic polyangiitis and MPO-ANCA-positive vasculitides in a Japanese population: a case-control study. PLoS ONE. 2016;11:e0154393; https://doi.org/10.1371/journal.pone.0154393.
Heckmann M, Holle JU, Arning L, Knaup S, Hellmich B, Nothnagel M, et al. The Wegener’s granulomatosis quantitative trait locus on chromosome 6p21.3 as characterized by tagSNP genotyping. Ann Rheum Dis. 2008;67:972–9.
Gonzalez-Galarza FF, Takeshita LY, Santos EJ, Kempson F, Maia MH, da Silva AL, et al. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res. 2015;43:D784–D788.
Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367:214–23.
Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, et al. Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 2013;65:2457–68.
Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J, et al. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol. 2017;69:1054–66.
Mahr AD, Edberg JC, Stone JH, Hoffman GS, St Clair EW, Specks U, et al. Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener’s granulomatosis. Arthritis Rheum. 2010;62:3760–7.
Teruel M, Alarcon-Riquelme ME. The genetic basis of systemic lupus erythematosus: what are the risk factors and what have we learned. J Autoimmun. 2016;74:161–75.
Kawasaki A, Kyogoku C, Ohashi J, Miyashita R, Hikami K, Kusaoi M, et al. Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms. Arthritis Rheum. 2008;58:826–34.
Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, et al. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. Arthritis Res Ther. 2008;10:R113; https://doi.org/10.1186/ar2516.
Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M, Ohashi J, Kawamoto M, et al. Association of the FAM167A-BLK region with systemic sclerosis. Arthritis Rheum. 2010;62:890–5.
Shimane K, Kochi Y, Horita T, Ikari K, Amano H, Hirakata M, et al. The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population. Arthritis Rheum. 2010;62:574–9.
Shimane K, Kochi Y, Suzuki A, Okada Y, Ishii T, Horita T, et al. An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes. Rheumatology. 2013;52:1172–82.
Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M, et al. Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes. 2002;51:545–51.
Furukawa H, Kawasaki A, Oka S, Ito I, Shimada K, Sugii S, et al. Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03. PLoS ONE. 2014;9:e87792; https://doi.org/10.1371/journal.pone.0087792.
Oka S, Furukawa H, Kawasaki A, Shimada K, Sugii S, Hashimoto A, et al. Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients. PLoS ONE. 2014;9:e99453; https://doi.org/10.1371/journal.pone.0099453.
Furukawa H, Oka S, Kawasaki A, Shimada K, Sugii S, Matsushita T, et al. Human leukocyte antigen and systemic sclerosis in Japanese: the sign of the four independent protective alleles, DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01. PLoS ONE. 2016;11:e0154255; https://doi.org/10.1371/journal.pone.0154255.
Dittmer J. The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol. 2015;35:20–38.
Garrett-Sinha LA. Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci. 2013;70:3375–90.
Russell L, Garrett-Sinha LA. Transcription factor Ets-1 in cytokine and chemokine gene regulation. Cytokine. 2010;51:217–26.
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41:1234–7.
Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010;6:e1000841; https://doi.org/10.1371/journal.pgen.1000841.
Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta ML, Gunnarsson I, et al. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet. 2013;21:994–9.
Shan S, Dang J, Li J, Yang Z, Zhao H, Xin Q, et al. ETS1 variants confer susceptibility to ankylosing spondylitis in Han Chinese. Arthritis Res Ther. 2014;16:R87; https://doi.org/10.1186/ar4530.
Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007;66:222–7.
Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D, Matsumoto I, et al. Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. Arthritis Res Ther. 2010;12:R174; https://doi.org/10.1186/ar3134.
Chung SA, Xie G, Roshandel D, Sherva R, Edberg JC, Kravitz M, et al. Meta-analysis of genetic polymorphisms in granulomatosis with polyangiitis (Wegener’s) reveals shared susceptibility loci with rheumatoid arthritis. Arthritis Rheum. 2012;64:3463–71.
Lu X, Zoller EE, Weirauch MT, Wu Z, Namjou B, Williams AH, et al. Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression. Am J Hum Genet. 2015;96:731–9.
Wilde B, Thewissen M, Damoiseaux J, Hilhorst M, van Paassen P, Witzke O, et al. Th17 expansion in granulomatosis with polyangiitis (Wegener’s): the role of disease activity, immune regulation and therapy. Arthritis Res Ther. 2012;14:R227; https://doi.org/10.1186/ar4066.
Abdulahad WH, Stegeman CA, Limburg PC, Kallenberg CG. Skewed distribution of Th17 lymphocytes in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 2008;58:2196–205.
Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol. 2005;17:1179–91.
Yamaguchi-Kabata Y, Nakazono K, Takahashi A, Saito S, Hosono N, Kubo M, et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am J Hum Genet. 2008;83:445–56.
The authors are grateful to the patients and healthy donors who participated in this study, and to the doctors who recruited patients to the projects of the Research Committee on intractable vasculitides and the Japanese RPGN Study Group of progressive renal disease, Ministry of Health, Labor and Welfare of Japan (including remission induction therapy in Japanese patients with ANCA-associated vasculitides (RemIT-JAV), remission induction therapy in Japanese patients with ANCA-associated vasculitides and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), and Japanese patients with MPO ANCA-associated vasculitis (JMAAV)) and directly to this study. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant numbers 25461467 and 16K09886), Japan Agency for Medical Research and Development (AMED) “The Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline (Grant numbers 16ek0109121h0002 and 17ek0109121s0403)” and “The Study Group for Strategic Exploration of Drug Seeds for ANCA-Associated Vasculitis and Construction of Clinical Evidence (Grant number 16ek0109104h0002 and 17ek0109104s0203)”, the Japan Rheumatism Foundation, the Japan College of Rheumatology, and the SENSHIN Medical Research Foundation.
Conflict of interest
FH is employed by the Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University (TMDU), which has received unrestricted research grants from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceuticals, Mitsubishi Tanabe Pharma Co., UCB Japan, CSL Behring, Towa Pharmaceutical Co., Ltd., Abbvie Japan Co., Ltd., Japan Blood Products Organization, Ayumi Pharmaceutical Co., and Nippon Kayaku Co., Ltd. TS received honoraria for lectures from Mitsubishi Tanabe Pharma Co., Ltd., and research grants from Mitsubishi Tanabe Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Co., Ltd., and Ono Pharmaceutical Co., Ltd. ST received honoraria for lectures from Pfizer, and a research grant from Chugai Pharmaceutical Co., Ltd. HM serves as a consultant for Abbvie Japan Co., Ltd. and Teijin Pharma Ltd. MH has received a research grant from Abbvie. Tokyo Women’s Medical University (TWMU), particularly the Division of Epidemiology and Pharmacoepidemiology in Rheumatic Diseases, has received unrestricted research grants from Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Teijin Pharma Ltd., with which TWMU paid the salary of MH. NT received 2017 Novartis—Japan Rheumatism Foundation Rheumatology Prize. The remaining authors declare no conflict of interest.
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Kawasaki, A., Yamashita, K., Hirano, F. et al. Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population. J Hum Genet 63, 55–62 (2018). https://doi.org/10.1038/s10038-017-0362-2
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