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

and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article number218
JournalArthritis Research and Therapy
Volume19
Issue number1
DOIs
Publication statusPublished - 2017 Sep 29

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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Antineutrophil Cytoplasmic Antibodies
Vasculitis
Transketolase
Proteomics
Biomarkers
Tissue Inhibitor of Metalloproteinase-1
Tenascin
Kidney
Serum
C-Reactive Protein
Peroxidase
Cohort Studies
Inflammation
Matrix Metalloproteinase 9
Leucine
Liquid Chromatography
Communicable Diseases
Blood Proteins
Mass Spectrometry

Keywords

  • Antineutrophil cytoplasmic antibody-associated vasculitis
  • Biomarkers
  • Eosinophilic granulomatosis with polyangiitis
  • Granulomatosis with polyangiitis
  • Microscopic polyangiitis
  • Targeted proteomics

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan (2017). Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Research and Therapy, 19(1), [218]. https://doi.org/10.1186/s13075-017-1429-3

Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. / and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan.

In: Arthritis Research and Therapy, Vol. 19, No. 1, 218, 29.09.2017.

Research output: Contribution to journalArticle

and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan 2017, 'Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis', Arthritis Research and Therapy, vol. 19, no. 1, 218. https://doi.org/10.1186/s13075-017-1429-3
and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan. Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Research and Therapy. 2017 Sep 29;19(1). 218. https://doi.org/10.1186/s13075-017-1429-3
and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan. / Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. In: Arthritis Research and Therapy. 2017 ; Vol. 19, No. 1.
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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.",
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T1 - Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

AU - and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan

AU - Ishizaki, Jun

AU - Takemori, Ayako

AU - Suemori, Koichiro

AU - Matsumoto, Takuya

AU - Akita, Yoko

AU - Sada, Ken ei

AU - Yuzawa, Yukio

AU - Amano, Koichi

AU - Takasaki, Yoshinari

AU - Harigai, Masayoshi

AU - Arimura, Yoshihiro

AU - Makino, Hirofumi

AU - Yasukawa, Masaki

AU - Takemori, Nobuaki

AU - Hasegawa, Hitoshi

AU - Murakawa, Yohko

AU - Muso, Eri

AU - Komatsuda, Atsushi

AU - Ito, Satoshi

AU - Fujii, Takao

AU - Kawakami, Atsushi

AU - Nakaya, Izaya

AU - Saito, Takao

AU - Ito, Takafumi

AU - Hirawa, Nobuhito

AU - Yamamura, Masahiro

AU - Nakano, Masaaki

AU - Nitta, Kosaku

AU - Ogura, Makoto

AU - Naniwa, Taio

AU - Ozaki, Shoichi

AU - Hirahashi, Junichi

AU - Ogawa, Noriyoshi

AU - Hosoya, Tatsuo

AU - Wada, Takashi

AU - Horikoshi, Satoshi

AU - Kawaguchi, Yasushi

AU - Hayashi, Taichi

AU - Yoshida, Masaharu

AU - Watanabe, Tsuyoshi

AU - Inaguma, Daijo

AU - Tsuruya, Kazuhiko

AU - Homma, Noriyuki

AU - Takeuchi, Tsutomu

AU - Nakagawa, Naoki

AU - Takeda, Shinichi

AU - Katabuchi, Ritsuko

AU - Iwano, Masayuki

AU - Atsumi, Tatsuya

AU - Fujimoto, Shoichi

PY - 2017/9/29

Y1 - 2017/9/29

N2 - 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.

AB - 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.

KW - Antineutrophil cytoplasmic antibody-associated vasculitis

KW - Biomarkers

KW - Eosinophilic granulomatosis with polyangiitis

KW - Granulomatosis with polyangiitis

KW - Microscopic polyangiitis

KW - Targeted proteomics

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