. 2020 Oct 16;22(1):246.

doi: 10.1186/s13075-020-02347-0.

Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study

Aya Kawasaki^{1

2}, Natsumi Namba^{3

4}, Ken-Ei Sada^{5

6}, Fumio Hirano^{7

8}, Shigeto Kobayashi⁹, Kenji Nagasaka¹⁰, Takahiko Sugihara^{7

8}, Nobuyuki Ono¹¹, Takashi Fujimoto¹², Makio Kusaoi¹³, Naoto Tamura¹³, Kunihiro Yamagata¹⁴, Takayuki Sumida¹⁵, Hiroshi Hashimoto¹⁶, Shoichi Ozaki¹⁷, Hirofumi Makino¹⁸, Yoshihiro Arimura^{19

20}, Masayoshi Harigai²¹, Naoyuki Tsuchiya^{22

23}

Affiliations

¹ Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. a-kawasaki@umin.net.
² School of Medical Sciences, University of Tsukuba, Tsukuba, Japan. a-kawasaki@umin.net.
³ Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
⁴ School of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
⁵ Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
⁶ Department of Clinical Epidemiology, Kochi Medical School, Kochi University, Nankoku, Japan.
⁷ Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan.
¹⁰ Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan.
¹¹ Department of Rheumatology, Saga University, Saga, Japan.
¹² The Center for Rheumatic Diseases, Nara Medical University, Kashihara, Japan.
¹³ Department of Internal Medicine and Rheumatology, School of Medicine, Juntendo University, Tokyo, Japan.
¹⁴ Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁵ Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁶ School of Medicine, Juntendo University, Tokyo, Japan.
¹⁷ Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁸ Okayama University, Okayama, Japan.
¹⁹ Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Mitaka, Japan.
²⁰ Department of Internal Medicine, Kichijoji Asahi Hospital, Musashino, Japan.
²¹ Department of Rheumatology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
²² Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. tsuchiya-tky@umin.net.
²³ School of Medical Sciences, University of Tsukuba, Tsukuba, Japan. tsuchiya-tky@umin.net.

PMID: 33076992
PMCID: PMC7574242
DOI: 10.1186/s13075-020-02347-0

Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study

Aya Kawasaki et al. Arthritis Res Ther. 2020.

. 2020 Oct 16;22(1):246.

doi: 10.1186/s13075-020-02347-0.

Authors

Affiliations

¹ Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. a-kawasaki@umin.net.
² School of Medical Sciences, University of Tsukuba, Tsukuba, Japan. a-kawasaki@umin.net.
³ Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
⁴ School of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
⁵ Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
⁶ Department of Clinical Epidemiology, Kochi Medical School, Kochi University, Nankoku, Japan.
⁷ Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan.
¹⁰ Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan.
¹¹ Department of Rheumatology, Saga University, Saga, Japan.
¹² The Center for Rheumatic Diseases, Nara Medical University, Kashihara, Japan.
¹³ Department of Internal Medicine and Rheumatology, School of Medicine, Juntendo University, Tokyo, Japan.
¹⁴ Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁵ Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁶ School of Medicine, Juntendo University, Tokyo, Japan.
¹⁷ Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁸ Okayama University, Okayama, Japan.
¹⁹ Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Mitaka, Japan.
²⁰ Department of Internal Medicine, Kichijoji Asahi Hospital, Musashino, Japan.
²¹ Department of Rheumatology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
²² Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. tsuchiya-tky@umin.net.
²³ School of Medical Sciences, University of Tsukuba, Tsukuba, Japan. tsuchiya-tky@umin.net.

PMID: 33076992
PMCID: PMC7574242
DOI: 10.1186/s13075-020-02347-0

Abstract

Background: Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD.

Methods: Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test.

Results: When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10^-4, P_c = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10^-4, P_c = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10^-4, P_c = 0.0015, OR 1.33; DSP P = 0.0011, P_c = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD.

Conclusions: Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Keywords: Microscopic polyangiitis; Myeloperoxidase-ANCA; Polymorphism; Single nucleotide variant; Susceptibility; Vasculitis.

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Conflict of interest statement

Dr. Sada has received speaker’s honoraria from Chugai Pharmaceutical Co. Ltd.

Dr. Hirano has received research grants and/or speaker’s honoraria from Chugai Pharmaceutical Co. Ltd., Ono Pharmaceuticals, CSL Behring, Towa Pharmaceutical Co. Ltd., Abbvie Japan Co. Ltd., Japan Blood Products Organization, Ayumi Pharmaceutical Co., Nippon Kayaku Co. Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma, and UCB Japan.

Dr. Nagasaka has received speaker’s honoraria from Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Teijin Pharma Ltd.

Dr. Makino is a consultant for AbbVie, Teijin, and Boehringer-Ingelheim.

Dr. Harigai has received research grants and/or honoraria from AbbVie Japan Co. Ltd., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Ono Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Ayumi Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., and Pfizer Japan Inc. Dr. Harigai serves as a consultant for Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co. Ltd., CIMIC Co. Ltd., Kissei Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc.

Dr. Tsuchiya has received research fund from H.U. Group Research Institute G.K. for a collaborative research unrelated to this study, and research grants from Bristol-Myers Squibb, 2015 Japan College of Rheumatology Award from Japan College of Rheumatology, 2017 Novartis Rheumatology Award from Japan Rheumatism Association with research funding, and speaker’s honoraria from Teijin.

Other authors declare no potential conflict of interest.

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Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study

Affiliations

Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study

Authors

Affiliations

Abstract

Conflict of interest statement

References

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LinkOut - more resources

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Research Materials

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