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01-12-2021 | Stroke | Research article

Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke

Authors: Takaki Hiwasa, Hao Wang, Ken-ichiro Goto, Seiichiro Mine, Toshio Machida, Eiichi Kobayashi, Yoichi Yoshida, Akihiko Adachi, Tomoo Matsutani, Mizuki Sata, Kazumasa Yamagishi, Hiroyasu Iso, Norie Sawada, Shoichiro Tsugane, Mitoshi Kunimatsu, Ikuo Kamitsukasa, Masahiro Mori, Kazuo Sugimoto, Akiyuki Uzawa, Mayumi Muto, Satoshi Kuwabara, Yoshio Kobayashi, Mikiko Ohno, Eiichiro Nishi, Akiko Hattori, Masashi Yamamoto, Yoshiro Maezawa, Kazuki Kobayashi, Ryoichi Ishibashi, Minoru Takemoto, Koutaro Yokote, Hirotaka Takizawa, Takashi Kishimoto, Kazuyuki Matsushita, Sohei Kobayashi, Fumio Nomura, Takahiro Arasawa, Akiko Kagaya, Tetsuro Maruyama, Hisahiro Matsubara, Minako Tomiita, Shinsaku Hamanaka, Yushi Imai, Tomoo Nakagawa, Naoya Kato, Jiro Terada, Takuma Matsumura, Yusuke Katsumata, Akira Naito, Nobuhiro Tanabe, Seiichiro Sakao, Koichiro Tatsumi, Masaaki Ito, Fumiaki Shiratori, Makoto Sumazaki, Satoshi Yajima, Hideaki Shimada, Mikako Shirouzu, Shigeyuki Yokoyama, Takashi Kudo, Hirofumi Doi, Katsuro Iwase, Hiromi Ashino, Shu-Yang Li, Masaaki Kubota, Go Tomiyoshi, Natsuko Shinmen, Rika Nakamura, Hideyuki Kuroda, Yasuo Iwadate

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS.

Methods

Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay.

Results

The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297–311 of DIDO1, 426–440 of FOXJ2, and 607–621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case–control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS.

Conclusions

Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.

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Title: Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke
Authors: Takaki Hiwasa
Hao Wang
Ken-ichiro Goto
Seiichiro Mine
Toshio Machida
Eiichi Kobayashi
Yoichi Yoshida
Akihiko Adachi
Tomoo Matsutani
Mizuki Sata
Kazumasa Yamagishi
Hiroyasu Iso
Norie Sawada
Shoichiro Tsugane
Mitoshi Kunimatsu
Ikuo Kamitsukasa
Masahiro Mori
Kazuo Sugimoto
Akiyuki Uzawa
Mayumi Muto
Satoshi Kuwabara
Yoshio Kobayashi
Mikiko Ohno
Eiichiro Nishi
Akiko Hattori
Masashi Yamamoto
Yoshiro Maezawa
Kazuki Kobayashi
Ryoichi Ishibashi
Minoru Takemoto
Koutaro Yokote
Hirotaka Takizawa
Takashi Kishimoto
Kazuyuki Matsushita
Sohei Kobayashi
Fumio Nomura
Takahiro Arasawa
Akiko Kagaya
Tetsuro Maruyama
Hisahiro Matsubara
Minako Tomiita
Shinsaku Hamanaka
Yushi Imai
Tomoo Nakagawa
Naoya Kato
Jiro Terada
Takuma Matsumura
Yusuke Katsumata
Akira Naito
Nobuhiro Tanabe
Seiichiro Sakao
Koichiro Tatsumi
Masaaki Ito
Fumiaki Shiratori
Makoto Sumazaki
Satoshi Yajima
Hideaki Shimada
Mikako Shirouzu
Shigeyuki Yokoyama
Takashi Kudo
Hirofumi Doi
Katsuro Iwase
Hiromi Ashino
Shu-Yang Li
Masaaki Kubota
Go Tomiyoshi
Natsuko Shinmen
Rika Nakamura
Hideyuki Kuroda
Yasuo Iwadate
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Stroke
Myocardial Infarction
Arterial Occlusive Disease
Diabetes
Chronic Kidney Disease
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02001-9

At a glance: The STEP trials

Springer Medicine

Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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