PMID- 33677398
OWN - NLM
STAT- MEDLINE
DCOM- 20220118
LR  - 20220118
IS  - 1095-9157 (Electronic)
IS  - 0896-8411 (Linking)
VI  - 119
DP  - 2021 May
TI  - Identifying the most influential gene expression profile in distinguishing 
      ANCA-associated vasculitis from healthy controls.
PG  - 102617
LID - S0896-8411(21)00025-1 [pii]
LID - 10.1016/j.jaut.2021.102617 [doi]
AB  - OBJECTIVE: Previous gene expression analyses seeking genes specific to 
      antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have been limited 
      due to crude cell separation and the use of microarrays. This study aims to 
      identify AAV-specific gene expression profiles in a way that overcomes those 
      limitations. METHODS: Blood samples were collected from 26 AAV patients and 28 
      healthy controls (HCs). Neutrophils were isolated by negative selection, whereas 
      19 subsets of peripheral blood mononuclear cells were sorted by fluorescence 
      assisted cell sorting. RNA-sequencing was then conducted for each sample, and 
      iterative weighted gene correlation network analysis (iterativeWGCNA) and random 
      forest were consecutively applied to identify the most influential gene module in 
      distinguishing AAV from HCs. Correlations of the identified module with clinical 
      parameters were evaluated, and the biological role was assessed with hub gene 
      identification and pathway analysis. Particularly, the module's association with 
      neutrophil extracellular trap formation, NETosis, was analyzed. Finally, the 
      module's overlap with GWAS-identified autoimmune disease genes (GADGs) was 
      assessed for validation. RESULTS: A neutrophil module (Neu_M20) was ranked top in 
      the random forest analysis among 255 modules created by iterativeWGCNA. Neu_M20 
      correlated with disease activity and neutrophil counts but not with the presence 
      of antineutrophil cytoplasmic antibody. The module comprised pro-inflammatory 
      genes, including those related to NETosis, supported by experimental evidence. 
      The genes in the module significantly overlapped GADGs. CONCLUSION: We identified 
      the distinct group of pro-inflammatory genes in neutrophils, which characterize 
      AAV. Further investigations are warranted to confirm our findings as they could 
      serve as novel therapeutic targets.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Yanaoka, Haruyuki
AU  - Yanaoka H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Immuno-Rheumatology Center, St. Luke's 
      International Hospital, St. Luke's International University, Tokyo, Japan.
FAU - Nagafuchi, Yasuo
AU  - Nagafuchi Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Department of Functional Genomics and 
      Immunological Diseases, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan. Electronic address: nagafuchi@g.ecc.u-tokyo.ac.jp.
FAU - Hanata, Norio
AU  - Hanata N
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Takeshima, Yusuke
AU  - Takeshima Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Department of Functional Genomics and 
      Immunological Diseases, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Ota, Mineto
AU  - Ota M
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Department of Functional Genomics and 
      Immunological Diseases, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Suwa, Yuichi
AU  - Suwa Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Shirai, Harumi
AU  - Shirai H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Sugimori, Yusuke
AU  - Sugimori Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Okubo, Mai
AU  - Okubo M
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Kobayashi, Satomi
AU  - Kobayashi S
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Hatano, Hiroaki
AU  - Hatano H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Yamada, Saeko
AU  - Yamada S
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Tsuchida, Yumi
AU  - Tsuchida Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Iwasaki, Yukiko
AU  - Iwasaki Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Sumitomo, Shuji
AU  - Sumitomo S
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Shoda, Hirofumi
AU  - Shoda H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Okada, Masato
AU  - Okada M
AD  - Immuno-Rheumatology Center, St. Luke's International Hospital, St. Luke's 
      International University, Tokyo, Japan.
FAU - Okamura, Tomohisa
AU  - Okamura T
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Department of Functional Genomics and 
      Immunological Diseases, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Yamamoto, Kazuhiko
AU  - Yamamoto K
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan; Laboratory for Autoimmune Diseases, RIKEN 
      Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Fujio, Keishi
AU  - Fujio K
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan. Electronic address: 
      FUJIOK-INT@h.u-tokyo.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210304
PL  - England
TA  - J Autoimmun
JT  - Journal of autoimmunity
JID - 8812164
RN  - 0 (Antibodies, Antineutrophil Cytoplasmic)
RN  - 0 (Biomarkers)
SB  - IM
MH  - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/*diagnosis/*etiology
MH  - Antibodies, Antineutrophil Cytoplasmic/adverse effects/immunology
MH  - *Biomarkers
MH  - Case-Control Studies
MH  - Computational Biology
MH  - *Disease Susceptibility
MH  - Extracellular Traps/immunology/metabolism
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation
MH  - Gene Regulatory Networks
MH  - Genome-Wide Association Study
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Immunophenotyping
MH  - Neutrophils/immunology/metabolism
MH  - *Transcriptome
OTO - NOTNLM
OT  - ANCA-associated vasculitis
OT  - Iterative WGCNA
OT  - NETosis
OT  - RNA-equencing
OT  - Random forest
EDAT- 2021/03/08 06:00
MHDA- 2022/01/19 06:00
CRDT- 2021/03/07 20:38
PHST- 2021/01/01 00:00 [received]
PHST- 2021/02/10 00:00 [revised]
PHST- 2021/02/12 00:00 [accepted]
PHST- 2021/03/08 06:00 [pubmed]
PHST- 2022/01/19 06:00 [medline]
PHST- 2021/03/07 20:38 [entrez]
AID - S0896-8411(21)00025-1 [pii]
AID - 10.1016/j.jaut.2021.102617 [doi]
PST - ppublish
SO  - J Autoimmun. 2021 May;119:102617. doi: 10.1016/j.jaut.2021.102617. Epub 2021 Mar 
      4.