Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

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Abstract

Background

Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Methods

A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples ( n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study).

Results

Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers).

Conclusions

We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-017-1429-3) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Jun Ishizaki: ishizaki@m.ehime-u.ac.jp

Ayako Takemori: ayakot@m.ehime-u.ac.jp

Koichiro Suemori: suemori@m.ehime-u.ac.jp

Takuya Matsumoto: takuya-m@m.ehime-u.ac.jp

Yoko Akita: akita.yoko.fp@ehime-u.ac.jp

Ken-ei Sada: sadakenn@okayama-u.ac.jp

Yukio Yuzawa: yukio-y@fujita-hu.ac.jp

Koichi Amano: amanokoi@saitama-med.ac.jp

Yoshinari Takasaki: tyoshi@med.juntendo.ac.jp

Masayoshi Harigai: harigai.masayoshi@twmu.ac.jp

Yoshihiro Arimura: arimuray@ks.kyorin-u.ac.jp

Hirofumi Makino: makino@okayama-u.ac.jp

Masaki Yasukawa: yasukawa@m.ehime-u.ac.jp

Nobuaki Takemori: +81-89-960-5499 , takemori@m.ehime-u.ac.jp

Hitoshi Hasegawa:

ORCID: http://orcid.org/0000-0003-3902-2066

+81-89-960-5296 , hitoshih@m.ehime-u.ac.jp

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 29 September 2017

Publication date PMC-release: 29 September 2017

Publication date (Print): 2017

Volume: 19

Electronic Location Identifier: 218

Affiliations

[1 ]ISNI 0000 0001 1011 3808, GRID grid.255464.4, Department of Hematology, Clinical Immunology, and Infectious Diseases, , Ehime University Graduate School of Medicine, ; Toon, Ehime 791-0295 Japan

[2 ]ISNI 0000 0001 1011 3808, GRID grid.255464.4, Division of Proteomics Research, Proteo-Science Center, , Ehime University, ; Toon, Ehime 791-0295 Japan

[3 ]ISNI 0000 0001 1302 4472, GRID grid.261356.5, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, ; Okayama, Japan

[4 ]ISNI 0000 0004 1761 798X, GRID grid.256115.4, Department of Nephrology, , Fujita Health University School of Medicine, ; Aichi, Japan

[5 ]ISNI 0000 0004 0467 0255, GRID grid.415020.2, Department of Rheumatology and Clinical Immunology, , Saitama Medical Center, Saitama Medical University, ; Saitama, Japan

[6 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Rheumatology, , Juntendo University Koshigaya Hospital, ; Saitama, Japan

[7 ]ISNI 0000 0001 0720 6587, GRID grid.410818.4, Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, , Institute of Rheumatology, Tokyo Women’s Medical University, ; Tokyo, Japan

[8 ]ISNI 0000 0000 9340 2869, GRID grid.411205.3, Nephrology and Rheumatology, First Department of Internal Medicine, , Kyorin University School of Medicine, ; Tokyo, Japan

[9 ]ISNI 0000 0004 0631 9477, GRID grid.412342.2, Okayama University Hospital, ; Okayama, Japan

Author information

Hitoshi Hasegawa http://orcid.org/0000-0003-3902-2066

Article

Publisher ID: 1429

DOI: 10.1186/s13075-017-1429-3

PMC ID: 5622475

PubMed ID: 28962592

SO-VID: 61cf57aa-a8bf-4b41-8e9e-eebda41f8622

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 May 2017

Date accepted : 15 September 2017

Funding

Funded by: Ehime University (JP)

Award ID: XA49003

Award Recipient : Nobuaki Takemori

Funded by: The Research Committee of Intractable Vasculitis Syndrome and Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of Japan

Funded by: strategic exploration of drug seeds for ANCA-associated vasculitis and construction of clinical evidence from Japan Agency for Medical Research and development, AMED

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: antineutrophil cytoplasmic antibody-associated vasculitis,biomarkers,targeted proteomics,microscopic polyangiitis,granulomatosis with polyangiitis,eosinophilic granulomatosis with polyangiitis

Data availability:

ScienceOpen disciplines: Orthopedics

Keywords: antineutrophil cytoplasmic antibody-associated vasculitis, biomarkers, targeted proteomics, microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis

Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

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Background

Methods

Results

Conclusions

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Most cited references 38

S100A8/A9: From basic science to clinical application.

The role of tenascin-C in tissue injury and tumorigenesis

A simplified disease activity index for rheumatoid arthritis for use in clinical practice.

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