Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea

Matsumura, Takuma; Terada, Jiro; Kinoshita, T.; Sakurai, Yoshinori; Yahaba, Misuzu; Tsushima, Kenji; Sakao, Seiichiro; Nagashima, Kengo; Ozaki, Toshinori; Kobayashi, Yoshio; Hiwasa, Takaki

doi:10.1371/journal.pone.0195015

Cited by 15 publications

(11 citation statements)

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“…CPSF proteins interact with Smad via Smicl and potentiate TGF-β/BMP-stimulated Smad-dependent transcriptional responses [ 86 , 87 ]. We previously reported the elevation of autoantibodies against SOSTDC1 and NBL1/DAN, which are the antagonists of BMP, in patients with AIS [ 48 ] and OSA [ 36 ], respectively. As such, it is possible that some, if not all, autoantibodies against TGF-β/BMP-related proteins play causal or suppressive roles in the development of atherosclerosis-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we searched for antibody markers using serological identification of antigens by cDNA expression cloning (SEREX) and the protein array method, and we reported on autoantibodies against Trop2/TACSTD2 [ 25 ], TRIM21 [ 26 ], Makorin 1 [ 27 ], and ECSA [ 28 ], for esophageal squamous cell carcinoma; FIR/PUF60 for colon cancer [ 29 ]; SH3GL1 [ 30 ] and filamin C [ 31 ] for glioma; EP300-interacting inhibitor of differentiation 3 for nonfunctional pancreatic neuroendocrine tumors [ 32 ]; proline-rich 13 for ulcerative colitis [ 33 ]; talin-1 for multiple sclerosis [ 34 ]; PSMA7 for amyotrophic lateral sclerosis [ 35 ]; NBL1/DAN [ 36 ] and SNX16 [ 37 ] for obstructive sleep apnea (OSA); and EXD2 for chronic thromboembolic pulmonary hypertension (CTEPH) [ 38 ]. We also reported on autoantibody markers for atherosclerosis-related diseases, e.g., RPA2 [ 39 ], PDCD11 [ 40 ], MMP1 [ 41 ], and DNAJC2 [ 42 ] for AIS; ASXL2 [ 43 ] for atherosclerosis; and nardilysin for acute coronary syndrome [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

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

Hiwasa

Wang

Goto

et al. 2021

BMC Med

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hiwasa

Wang

Goto

et al. 2021

BMC Med

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“…Serum samples were collected from HDs who underwent annual medical checkups at Port Square Kashiwado Clinic. We also collected serum samples from patients with SAS, as previously reported [9] [10]. Each serum sample was centrifuged at 3,000 × g for 10 min at room temperature, and then the supernatant was stored at -80°C until use (no other freeze-thaw cycles).…”

Section: Methodsmentioning

confidence: 99%

Elevated levels of autoantibodies against EXD2 and PHAX in the sera of patients with chronic thromboembolic pulmonary hypertension

et al. 2019

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While circulating autoantibodies have been detected in patients with several cardiovascular diseases, such studies have not been performed for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Here we investigated the production of certain auto-antibodies in CTEPH patients. Initial screening was performed in 5 CTEPH patients and 5 healthy donors (HDs) using a ProtoArray Human Protein Microarray v5.1 containing 9,375 human proteins, and we selected 34 antigens recognized by IgG antibodies more strongly in the sera of CTEPH patients than in the sera of HDs. In subsequent second/third analyses, we validated the auto-antibody level using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 96 CTEPH patients and 96 HDs as follows: At the second screening, we used 63 crude peptides derived from those selected 34 antigens and found that the serum levels of autoantibodies for 4 peptides seemed higher in CTEPH patients than in HDs. In third analysis, we used the purified peptides of those selected in second screening and found that serum antibodies against peptides derived from exonuclease 3'-5' domain-containing 2 (EXD2) and phosphorylated adaptor for RNA export (PHAX) were significantly higher in CTEPH patients than in HDs. The serum antibody levels to these antigens were also elevated in PAH patients. The titers against EXD2 peptide decreased after surgical treatment in CTEPH patients. These autoantibodies may be useful as biomarkers of CTEPH and PAH, and further investigations may provide novel insight into the etiology.

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“…The anti-p53 antibody is a typical antibody biomarker for cancer that has been put into practical use for diagnosing, monitoring, and predicting the prognosis of esophageal cancer (EC) and head and neck cancer [19,20]. Further application of the serological identi cation of antigens by cDNA expression cloning and the protein array method have identi ed autoantibodies against TACSTD2 [21], SLC2A1 [22], TRIM21 [23], myomegalin [24], makorin 1 [25], ECSA [26], cyclin L2 [27], and LRPAP1 [11] for EC; FIR/PUF60 for colorectal cancer (CRC) [28] and gastric cancer (GC) [29]; SH3GL1 [30] and lamin C [31] for glioma; EP300-interacting inhibitor of differentiation 3 for nonfunctional pancreatic neuroendocrine tumors [32]; and coatomer protein complex subunit epsilon/COPE [33], NBL1/DAN [34], and SNX16 [35] for obstructive sleep apnea syndrome (OSAS). Here, we report on serum antibodies against KIAA0513 (s-KIAA0513-Ab) as a broad-spectrum biomarker applicable to atherosclerosis-related diseases such as ischemic stroke, cardiovascular disease (CVD), chronic kidney disease (CKD), DM, and solid cancers.…”

Section: Introductionmentioning

confidence: 99%

Anti-KIAA0513 Antibody as a Broad-spectrum Biomarker of Mortal Atherosclerotic and Cancerous Diseases

Hiwasa¹,

Li²,

Kubota³

et al. 2021

Preprint

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Background: Numerous antibody biomarkers have been reported for cancer and atherosclerosis-related diseases. The major complications of atherosclerosis and diabetes mellitus (DM) are acute ischemic stroke (AIS), cardiovascular disease (CVD), and chronic kidney disease (CKD). Cancer development is accompanied by arterial disorders such as angiogenesis and atherosclerosis, and DM is a risk factor for certain cancers. Atherosclerosis-related diseases and cancers are therefore interrelated and could be detected by a common biomarker.Methods: We employed the protein array method for the initial screening of antigens and employed the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) to evaluate antibody levels in serum samples.Results: The protein array identified KIAA0513 as an antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. We then prepared recombinant glutathione S-transferase-fused KIAA0513 protein. AlphaLISA showed significantly higher serum antibody levels against KIAA0513 protein in patients with AIS, transient ischemic attack, DM, CVD, obstructive sleep apnea syndrome (OSAS), CKD, and solid cancers, such as esophageal, gastric, colon, lung, and breast cancer, than in healthy donors. A receiver operating characteristic (ROC) analysis revealed that the highest areas under the ROC curves of anti-KIAA0513 antibodies were for esophageal cancer, nephrosclerosis-type CKD, and DM. Spearman’s correlation analysis revealed that serum anti-KIAA0513 antibody levels were associated with maximum intima-media thickness and plaque score, which are indices of atherosclerosis and stenosis.Conclusion: Serum anti-KIAA0513 antibody markers appear to be useful for diagnosing AIS, TIA, DM, CVD, OSAS, CKD, and solid cancers and might reflect common arterial alterations leading to atherosclerotic and cancerous diseases.

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Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea

Cited by 15 publications

References 30 publications

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

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

Elevated levels of autoantibodies against EXD2 and PHAX in the sera of patients with chronic thromboembolic pulmonary hypertension

Anti-KIAA0513 Antibody as a Broad-spectrum Biomarker of Mortal Atherosclerotic and Cancerous Diseases

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