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Interstitial lung disease (ILD) is a major complication and a prognostic factor of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).1 The prevalence of ILD is higher in Japanese AAV as compared with European populations.1 In a Japanese inception cohort study, 45.0% of patients with microscopic polyangiitis (MPA) were complicated by ILD.2 Such ethnic difference suggests a role for genetic background in the development of AAV-associated ILD (AAV-ILD).
Single nucleotide polymorphism (SNP) rs35705950(G/T) in the promotor region of MUC5B, encoding mucin 5B, is a strong genetic factor for idiopathic pulmonary fibrosis (IPF). The risk allele T was associated with overexpression of mucin 5B in the lung.3 Recently, rs35705950 has been associated with rheumatoid arthritis-associated ILD (RA-ILD).4
Here, we examined whether rs35705950 is associated with AAV-ILD in case-control and case–case association studies. About 474 Japanese patients with AAV and 842 healthy Japanese controls were recruited at rheumatology or nephrology centres based on the clinical diagnosis of AAV, and classified according to the European Medicines Agency algorithm.5 The patients were examined for the presence or absence of ILD using CT or high-resolution CT (HRCT) by site investigators. 163 patients were reported positive and 264 negative for ILD (see online supplementary table S1,S2). This study was conducted in accordance with the Declaration of Helsinki.
Genotyping was performed using TaqMan SNP Genotyping Assays (Assay ID: C___1582254_20) (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Odds ratios (ORs), 95% confidence intervals (CIs) and p values adjusted for sex were calculated by logistic regression analysis using R software, unless otherwise noted. Because of the lack of T/T genotype, dominant model for T allele was employed. Correction for multiple testing was performed using false discovery rate (FDR) method. Q values <0.05 were considered significant.
As shown in table 1, the allele frequency of rs35705950T was substantially lower in the healthy Japanese controls (0.5%) compared with Caucasian populations (~10%),3 4 and individuals with genotype T/T were not present. All patients with genotype T/G were positive for myeloperoxidase (MPO)-ANCA, but none was positive for proteinase 3 (PR3)-ANCA.
Significant association was observed in AAV-ILD, but not in AAV patients without ILD, when compared with healthy controls. Significant association was also detected when only the patients with MPO-ANCA and ILD (MPO-AAV-ILD) were compared with healthy controls.
To confirm whether the rs35705950T is associated with presence of ILD rather than AAV itself, we next compared the genotype frequencies between AAV-ILD and AAV without ILD. rs35705950T was significantly associated with AAV-ILD with the OR of 11.6 (95% CI 2.04 to 218.6, p=0.023). The association was also observed when MPO-AAV-ILD was compared with MPO-AAV without ILD (OR 9.47, 95% CI 1.65 to 178.3, p=0.037). The association was also observed when the subjects were limited to those diagnosed by HRCT (online supplementary table S3, S4).
To our knowledge, this is the first to report the association of MUC5B variant with AAV-ILD. ILD is classified into subgroups according to the histopathological and radiographic patterns. Similarly to IPF and RA-ILD, AAV-ILD most commonly exhibit usual interstitial pneumonia (UIP) pattern,1 4 while ILD in systemic sclerosis and myositis are predominantly associated with non-specific interstitial pneumonia pattern. A recent study reported that rs35705950T was more strongly associated with UIP than with ILD inconsistent with UIP.6
In addition to the small sample size, this study suffers from some limitations (online supplementary text). However, the striking observation that seven out of eight patients with AAV carrying rs35705950 exhibited ILD warrants further studies on the role of MUC5B in AAV-ILD.
The authors are indebted to Dr Pierre-Antoine Juge and Dr Philippe Dieude (Department of Rheumatology, INSERM, Université Paris Diderot, Paris, France) for the inspiring and insightful discussion and to Dr Jun Ohashi (Graduate School of Science, The University of Tokyo) for statistical advice.
Handling editor Josef S Smolen
Contributors NN, AK, NT: conceived and designed the study, performed genotyping and statistical analysis, interpreted the data and wrote the manuscript. K-eS, FH, SK, HY, HF, KS, AH, TM, KN, TSug, KY, TSum, ST: recruited patients and analysed clinical data. AS, SH: centrally evaluated HRCT images. SO, HH, HM, YA, MH: organised study groups, conceived the study and interpreted the data. All authors read and approved the manuscript.
Funding This study was supported by the grants from the Japan Agency for Medical Research and Development "The Study Group for Strategic Exploration of Drug Seeds for ANCA Associated Vasculitis and Construction of Clinical Evidence (grant number 17ek0109104h0003)”, ”The Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline (grant number 17ek0109121h0003)” and “Multitiered study to address clinical questions for management of intractable vasculitides (grant number 18ek0109360h001)", and an award grant from Japan College of Rheumatology.
Competing interests FH is employed by The Department of Lifetime Clinical Immunology of 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, with which TMDU currently pays the salary of FH. FH has also received speaking fees from Ono Pharmaceuticals, Astellas Pharma Inc. Sumitomo Dainippon Pharma and Chugai Pharmaceutical Co, Ltd. KS has received lecture fee from Chugai. HF has the following conflicts, and the following funders are supported wholly or in part by the indicated pharmaceutical companies. The Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo, the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company and the Nakatomi Foundation was established by Hisamitsu Pharmaceutical Co, Inc. The Daiwa Securities Health Foundation was established by Daiwa Securities Group Inc. and Mitsui Sumitomo Insurance Welfare Foundation was established by Mitsui Sumitomo Insurance Co, Ltd. HF was supported by research grants from Bristol-Myers Squibb Co. HF received honoraria from Ajinomoto Co, Inc., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co, Ltd. Pfizer Japan Inc, and Takeda Pharmaceutical Company, Luminex Japan Corporation Ltd, and Ayumi Pharmaceutical Corporation. ST was supported by research grants from Abbott Japan Co, Ltd, Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd. Eisai Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc. Pfizer Japan Inc, Takeda Pharmaceutical Company Limited and Teijin Pharma Limited. TSug has received honoraria from Chugai Pharmaceutical Co, Ltd. Takeda Pharmaceutical Co. Ltd, Mitsubishi-Tanabe Pharma Co, Astellas Pharma Inc, Bristol Myers Squibb K.K. Pfizer Japan Inc, UCB Japan Co. Ltd, and Abbvie Japan Co, Ltd, and has received research grant support from Takeda Pharmaceutical Co, Ltd, Astellas Pharma Inc, and Teijin Pharma Ltd. AH has received research funding from Chugai Pharmaceutical Co, Ltd. HM is a consultant for AbbVie and Teijin, receives speaker honoraria from Boehringer-Ingelheim. MH has received research grants and/or honoraria from Abbott Japan Co, Ltd. Astellas Pharma Inc; Bristol-Myers Squibb K.K. Chugai Pharmaceutical Co, Ltd. Eisai Co, Ltd. Janssen Pharmaceutical K.K. Mitsubishi Tanabe Pharma Co; Santen Pharmaceutical Co; Ltd. Takeda Pharmaceutical Co, Ltd. Teijin Pharma, Ltd. and Pfizer Japan Inc. NT has received 2015 Japan College of Rheumatology Award from Japan College of Rheumatology and 2017 Novartis Rheumatology Award from Japan Rheumatism Association with research fundings, and speaker’s honoraria from Ayumi Pharmaceutical Corporation.
Patient consent for publication Not required.
Ethics approval The study protocol was reviewed and approved by the Ethics Committees of University of Tsukuba, Tokyo Women’s Medical University, Tokyo Medical and Dental University, National Hospital Organization Sagamihara Hospital, Okayama University, and all the institutes involved in the recruitment of subjects.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data are presented in the paper and in the supplementary material.