. 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.

PubMed Disclaimer

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.

Cited by

Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review.
Kadura S, Raghu G. Kadura S, et al. Eur Respir Rev. 2021 Nov 8;30(162):210123. doi: 10.1183/16000617.0123-2021. Print 2021 Dec 31. Eur Respir Rev. 2021. PMID: 34750115 Free PMC article. Review.
Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Update: Genetic Pathogenesis.
Li W, Huang H, Cai M, Yuan T, Sheng Y. Li W, et al. Front Immunol. 2021 Mar 26;12:624848. doi: 10.3389/fimmu.2021.624848. eCollection 2021. Front Immunol. 2021. PMID: 33841406 Free PMC article. Review.
MPO-ANCA positive interstitial pneumonia: Current knowledge and future perspectives.
Bando M, Homma S, Harigai M. Bando M, et al. Sarcoidosis Vasc Diffuse Lung Dis. 2022;38(4):e2021045. doi: 10.36141/svdld.v38i4.11808. Epub 2022 Jan 13. Sarcoidosis Vasc Diffuse Lung Dis. 2022. PMID: 35115752 Free PMC article. Review.
Association between the AKT1 single nucleotide polymorphism (rs2498786, rs2494752 and rs5811155) and microscopic polyangiitis risk in a Chinese population.
Li L, Rao J, Lan J, Zhu Y, Gong A, Chu L, Feng F, Xue C. Li L, et al. Mol Genet Genomics. 2023 May;298(3):767-776. doi: 10.1007/s00438-023-02012-6. Epub 2023 Apr 7. Mol Genet Genomics. 2023. PMID: 37029297 Free PMC article.
Association of a Single Nucleotide Variant in TERT with Airway Disease in Japanese Rheumatoid Arthritis Patients.
Higuchi T, Oka S, Furukawa H, Shimada K, Tsunoda S, Ito S, Okamoto A, Fujimori M, Nakamura T, Katayama M, Saisho K, Shinohara S, Matsui T, Migita K, Nagaoka S, Tohma S. Higuchi T, et al. Genes (Basel). 2023 Nov 16;14(11):2084. doi: 10.3390/genes14112084. Genes (Basel). 2023. PMID: 38003027 Free PMC article.

See all "Cited by" articles

References

1. Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the pathogenesis of ANCA-associated vasculitis. Kidney Dis. 2016;1:205–215. doi: 10.1159/000442323. - DOI - PMC - PubMed
1. 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 U.K. Rheumatology. 2011;50:1916–1920. doi: 10.1093/rheumatology/ker205. - DOI - PubMed
1. Alba MA, Flores-Suárez LF, Henderson AG, Xiao H, Hu P, Nachman PH, et al. Interstital lung disease in ANCA vasculitis. Autoimmun Rev. 2017;16:722–729. doi: 10.1016/j.autrev.2017.05.008. - DOI - PMC - PubMed
1. Furuta S, Chaudhry AN, Hamano Y, Fujimoto S, Nagafuchi H, Makino H, et al. Comparison of phenotype and outcome in microscopic polyangiitis between Europe and Japan. J Rheumatol. 2014;41:325–333. doi: 10.3899/jrheum.130602. - DOI - PubMed
1. Lyons PA, Rayner TF, Trvedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367:214–223. doi: 10.1056/NEJMoa1108735. - DOI - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous