ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1955

Association of TERT and DSP Polymorphisms with Susceptibility to Myeloperoxidase-ANCA-Associated Vasculitis

Aya Kawasaki1, Natsumi Namba 1, Ken-ei Sada 2, Fumio Hirano 3, Shigeto Kobayashi 4, Hidehiro Yamada 5, Hiroshi Furukawa 6, Kenji Nagasaka 7, Takahiko Sugihara 8, Aika Suzuki 9, Kunihiro Yamagata 10, Takayuki Sumida 11, Shigeto Tohma 12, Sakae Homma 13, Shoichi Ozaki 14, Hiroshi Hashimoto 15, Hirofumi Makino 16, Yoshihiro Arimura 17, Masayoshi Harigai 18 and Naoyuki Tsuchiya 1, 1Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, 2Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kitaku, Okayama, Japan, 3Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan, 4Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan, 5Center for Rheumatic diseases, Seirei Yokohama Hospital, Kawasaki, Japan, 6Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan, 7Department of Rheumatology, Ome Municipal General Hospital, Tokyo, 8Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan, 9Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan, 10Department of Nephrology, University of Tsukuba, Tsukuba, Ibaraki, Japan, 11Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, 12National Hospital Organization Tokyo National Hospital, Kiyose, Japan, 13Department of Advanced and Integrated Interstitial Lung Diseases Research, School of Medicine, Toho University, Tokyo, Japan, 14St. Marianna University School of Medicine, Kawasaki, Japan, 15Juntendo University School of Medicine, Tokyo, Japan, 16Okayama University, Okayama, Japan, 17Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan, 18Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: , ,

Session Information

Date: Tuesday, November 12, 2019

Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Epidemiology of ANCA-associated vasculitis (AAV) is substantially different between East Asian and European populations. Microscopic polyangiitis (MPA) and MPO-ANCA positive AAV (MPO-AAV) are prevalent in Japan, while granulomatosis with polyangiitis (GPA) and PR3-ANCA positive AAV (PR3-AAV) are dominant in Europe. In addition, high prevalence of interstitial lung disease (ILD), a severe complication and a prognostic factor in AAV, is a striking feature in the Japanese population, suggesting a role for genetic background in the development and clinical features of AAV.
A proportion of patients with idiopathic pulmonary fibrosis (IPF) are positive for MPO-ANCA, and some of these patients develop MPA, suggesting that ILD in AAV and IPF may share some pathogenic processes. Recently, we reported that 5% of MPO-AAV patients with ILD carry MUC5B single nucleotide variant (SNV) rs35705950T, the risk allele for IPF, as compared with 1% among healthy controls, indicating that MUC5B is a shared susceptibility gene between IPF and MPO-AAV associated ILD (Namba et al, Ann Rheum Dis 2019). However, the allele frequency of rs35705950T is much lower in general Japanese population as compared with European populations, and does not account for high prevalence of ILD in Japanese AAV. In this study, we performed association study of other IPF susceptibility genes, TERT and DSP, to examine whether these are associated with ILD in AAV patients.

Methods: The members of Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) and Research Committee of Progressive Renal Disease, Ministry of Health, Labour, and Welfare of Japan contributed to this study.
Five hundred and twenty-three patients including 315 MPA, 108 GPA, 68 eosinophilic granulomatosis with polyangiitis (EGPA) and 32 unclassifiable AAV (412 MPO-ANCA positive [MPO-AAV] and 66 PR3-ANCA positive [PR3-AAV]) and 4394 controls were examined. Among MPO-AAV, 163 were positive for ILD and 264 were negative. Genotyping for TERT rs2736100 and DSP rs2076295 was performed by TaqMan SNP Genotyping Assays. Association was tested by chi-squared test.

Results: Allele frequencies of TERT rs2736100A and DSP rs2076295G were not significantly different between MPO-AAV with ILD and MPO-AAV without ILD (Table 1). However, when the association of TERT was tested in MPO-AAV regardless of the presence/absence of ILD, rs2736100A was significantly increased in MPO-AAV as compared with healthy controls (P=4.3E-05, Pc=5.2E-04, odds ratio [OR] 1.37). This association was also observed in MPA (P=2.2E-04, Pc=0.0013, OR 1.38). Similarly, DSP rs2076295G is increased in MPA (P=0.0029, Pc=0.0086, OR 1.28) and MPO-AAV (P=0.0026, Pc=0.0086, OR 1.25) as compared with healthy controls. Other AAV phenotypes were not significantly associated with both SNVs after correction for multiple testing, although a trend for association was observed between EGPA and TERT and between PR3-AAV and DSP.

Conclusion: TERT and DSP SNVs were found to be associated with MPO-AAV and MPA for the first time. These results suggest that some susceptibility genes to IPF may be associated with AAV regardless of the presence of ILD.

Disclosure: A. Kawasaki, None; N. Namba, None; K. Sada, Chugai Pharmaceutical Co, Ltd., 8; F. Hirano, Chugai Pharmaceutical Co, Ltd., 2, 8, Ono Pharmaceuticals, 2, 8, CSL Behring, 2, Towa Pharmaceutical Co, Ltd., 2, Abbvie Japan Co, Ltd., 2, Japan Blood Products Organization, 2, Ayumi Pharmaceutical Co, 2, Nippon Kayaku Co, Ltd., 2, Astellas Pharma Inc., 8, Sumitomo Dainippon Pharma, 8, UCB Japan, 2; S. Kobayashi, None; H. Yamada, None; H. Furukawa, Ajinomoto Co., Inc., 8, Ayumi Pharmaceutical Corporation, 8, Bristol-Myers Squibb Co., 2, Daiichi Sankyo Co., Ltd., 8, Dainippon Sumitomo Pharma Co., Ltd., 8, Daiwa Securities Health Foundation, 2, Japan Research Foundation for Clinical Pharmacology, 2, Kato Memorial Trust for Nambyo Research, 2, Luminex Japan Corporation Ltd., 8, Mitsui Sumitomo Insurance Welfare Foundation, 2, Nakatomi Foundation, 2, Pfizer Japan Inc., 8, Takeda Pharmaceutical Company, 8, Takeda Science Foundation, 2, The Nakatomi Foundation, 2; K. Nagasaka, Bristol-Myers Squibb Co. Ltd., 8, Chugai Pharmaceutical Co, Ltd., 8, Teijin Pharma, Ltd., 8; T. Sugihara, None; A. Suzuki, None; K. Yamagata, None; T. Sumida, None; S. Tohma, Abbott Japan Co, Ltd., 2, Abbott Japan Co., Ltd., 2, AbbVie GK., 8, Asahi Kasei Pharma Corporation, 8, Astellas Pharma Inc, 2, Astellas Pharma Inc., 2, 8, Chugai Pharmaceutical Co, Ltd., 2, Chugai Pharmaceutical Co., Ltd., 2, 8, Eisai Co, Ltd., 2, Eisai Co., Ltd., 2, Merck Sharp and Dohme Inc., 2, Mitsubishi Tanabe Pharma Corporation, 2, 8, Ono Pharmaceutical Co., Ltd., 8, Pfizer Japan Inc, 2, Pfizer Japan Inc., 2, 8, Takeda Pharmaceutical Company Limited, 2, Teijin Pharma Limited, 2; S. Homma, None; S. Ozaki, None; H. Hashimoto, None; H. Makino, AbbVie, 5, Teijin, 5, Boehringer-Ingelheim, 5; Y. Arimura, None; M. Harigai, AbbVie Japan GK, 2, 8, Ayumi Pharmaceutical Co. Ltd., 2, Bristol Meyers Squib, 2, 5, 8, Bristol-Myers Squibb Co. Ltd, 2, 5, 8, Chugai Pharmaceutical Co. Ltd., 2, 5, 8, Chugai Pharmaceutical Co., Ltd., 2, 5, 8, Eisai Co. Ltd., 2, Eisai Co., Ltd., 2, Eli Lilly, 5, 8, Mitsubishi Tanabe Pharma Co., 2, Mitsubishi Tanabe Pharma Corp., 2, Nippon Kayaku Co. Ltd., 2, Taisho Toyama Pharmaceutical Co. Ltd., 2, Takeda Pharmaceutical Co., 2, Takeda Pharmaceutical Co., Ltd., 2, Teijin Pharma Ltd., 2, 8, Teijin Pharma, Ltd., 2, 8; N. Tsuchiya, Ayumi Pharmaceutical Corporation, 8, Bristol-Myers Squibb, 2, Bristol-Myers Squibb Co. Ltd, 2, Japan College of Rheumatology, 2, Japan Rheumatism Foundation, 2.

To cite this abstract in AMA style:

Kawasaki A, Namba N, Sada K, Hirano F, Kobayashi S, Yamada H, Furukawa H, Nagasaka K, Sugihara T, Suzuki A, Yamagata K, Sumida T, Tohma S, Homma S, Ozaki S, Hashimoto H, Makino H, Arimura Y, Harigai M, Tsuchiya N. Association of TERT and DSP Polymorphisms with Susceptibility to Myeloperoxidase-ANCA-Associated Vasculitis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/association-of-tert-and-dsp-polymorphisms-with-susceptibility-to-myeloperoxidase-anca-associated-vasculitis/. Accessed .

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