Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population

Abstract

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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Acknowledgments

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.

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Correspondence to Naoyuki Tsuchiya.

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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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