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

Arthritis Research & Therapy

Naoto Tamura¹  Makio Kusaoi¹  Takayuki Sumida²  Shigeto Kobayashi³  Shoichi Ozaki⁴  Yoshihiro Arimura⁵  Kunihiro Yamagata⁶  Ken-ei Sada⁷  Takahiko Sugihara⁸  Fumio Hirano⁸  Kenji Nagasaka⁹  Nobuyuki Ono^1,10  Masayoshi Harigai^1,11  Aya Kawasaki^1,12  Natsumi Namba^1,12  Naoyuki Tsuchiya^1,12  Hirofumi Makino^1,13  Hiroshi Hashimoto^1,14  Takashi Fujimoto^1,15 

[1]Department of Internal Medicine and Rheumatology, School of Medicine, Juntendo University, Tokyo, Japan

[2]Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

[3]Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan

[4]Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

[5]Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Mitaka, Japan

[6]Department of Internal Medicine, Kichijoji Asahi Hospital, Musashino, Japan

[7]Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

[8]Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

[9]Department of Clinical Epidemiology, Kochi Medical School, Kochi University, Nankoku, Japan

[10]Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

[11]Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

[12]Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan

[13]Department of Rheumatology, Saga University, Saga, Japan

[14]Department of Rheumatology, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan

[15]Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan

[16]School of Medical Sciences, University of Tsukuba, Tsukuba, Japan

[17]Okayama University, Okayama, Japan

[18]School of Medicine, Juntendo University, Tokyo, Japan

[19]The Center for Rheumatic Diseases, Nara Medical University, Kashihara, Japan

关键词: Myeloperoxidase-ANCA;    Vasculitis;    Microscopic polyangiitis;    Susceptibility;    Single nucleotide variant;    Polymorphism;   

DOI  :  10.1186/s13075-020-02347-0

来源: Springer

【 摘 要 】

BackgroundInterstitial 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.MethodsFive 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.ResultsWhen 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, Pc = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10−4, Pc = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10−4, Pc = 0.0015, OR 1.33; DSP P = 0.0011, Pc = 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.ConclusionsUnexpectedly, 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.

【 授权许可】

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