CN110646617B - Aortic dissection diagnostic marker and application thereof - Google Patents
Aortic dissection diagnostic marker and application thereof Download PDFInfo
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- CN110646617B CN110646617B CN201910854716.0A CN201910854716A CN110646617B CN 110646617 B CN110646617 B CN 110646617B CN 201910854716 A CN201910854716 A CN 201910854716A CN 110646617 B CN110646617 B CN 110646617B
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/535—Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
- G01N2800/329—Diseases of the aorta or its branches, e.g. aneurysms, aortic dissection
Abstract
The present application discloses an aortic dissection diagnostic marker comprising at least one of protein inhibitor 16 and fibrinogen-like protein 1. The aortic dissection diagnosis marker is applied to the diagnosis of aortic dissection. The aortic dissection diagnostic marker is applied to the production of diagnostic products for diagnosing aortic dissection. The aortic dissection diagnostic marker is applied to distinguishing aortic dissection from acute coronary syndrome. The aortic dissection diagnostic marker is applied to the production of diagnostic products for distinguishing aortic dissection from acute coronary syndrome. The aortic dissection diagnosis marker is obtained by screening through a proteomics principle, and can effectively improve the diagnosis rate of the aortic dissection and the diagnosis rate of distinguishing the aortic dissection from acute coronary syndrome through the verification of a large number of samples.
Description
Technical Field
The application relates to the technical field of biological detection, in particular to an aortic dissection diagnosis marker and application thereof.
Background
The aortic dissection refers to a state that blood in an aortic cavity enters an aortic media from a torn part of an aortic intima to separate the media, and expands along the major axis direction of the aorta to form true and false separation of two cavities of the aortic wall. 65-70% of the disease die from cardiac tamponade, arrhythmia and the like in an acute stage, and early diagnosis and treatment are very necessary. The current common examination such as echocardiography, CT, MRI and the like is very helpful for establishing the diagnosis of aortic dissection, and aorta angiography or IVUS examination can be considered for the therapist who performs the operation. However, the aortic dissection is fast in onset, and the patients can tear the aorta after a few hours of onset to cause final death. On one hand, because the diagnosis mode of CT or aorta angiography takes a long time, on the other hand, the symptom of the aortic dissection is similar to the symptom of other cardiovascular diseases, such as acute coronary syndrome and aortic aneurysm, the patient often has broken arteries or even dies when the diagnosis is unknown, and at present, no quick diagnosis molecular marker can be used for assisting the differential diagnosis and risk assessment of the patient temporarily.
Disclosure of Invention
The object of the present application is to overcome the drawbacks of the prior art by providing a diagnostic marker for aortic dissection with relatively high specificity and sensitivity, and to provide the use of the diagnostic marker for aortic dissection.
In order to achieve the technical purpose, the technical scheme adopted by the application is as follows:
an aortic dissection diagnostic marker comprising at least one of a protein inhibitor 16 and fibrinogen-like protein 1.
Further, the aortic dissection diagnostic marker further comprises at least one of photopolymerizing protein and matrix metalloproteinase.
In particular, the markers are differentially expressed in the subject sample compared to the control sample.
More specifically, the marker is increased in expression in the subject sample as compared to the control sample.
Preferably, the control sample and the subject sample are derived from serum.
Preferably, the expression level of the marker is verified by an enzyme-linked immunosorbent assay.
The aortic dissection diagnosis marker is applied to the diagnosis of aortic dissection.
The aortic dissection diagnostic marker is applied to the production of diagnostic products for diagnosing aortic dissection.
The aortic dissection diagnostic marker is applied to distinguishing aortic dissection from acute coronary syndrome.
The aortic dissection diagnostic marker is applied to the production of diagnostic products for distinguishing aortic dissection from acute coronary syndrome.
Compared with the prior art, the method has the following advantages:
(1) the aortic dissection diagnostic marker is screened out by the proteomics principle, and has higher specificity and sensitivity when being used as a molecular marker;
(2) the aortic dissection diagnostic marker is verified by a large number of samples, and the specificity and the sensitivity are proved;
(3) the aortic dissection diagnosis marker can be obtained from serum, can be rapidly verified through ELISA, realizes rapid diagnosis of the aortic dissection, and also improves the diagnosis accuracy of the aortic dissection.
Drawings
FIG. 1 is a high throughput screening process of aortic dissection diagnostic markers in the present application and application thereof.
FIG. 2 shows the results of ELISA verification of protein expression levels obtained from 9 primary screens in the aortic dissection diagnostic markers and their applications.
FIG. 3 shows the results of ROC curve comparison of the expression levels of 4 target proteins in the aortic dissection diagnostic marker and the application thereof.
Detailed Description
The present application is described in further detail below with reference to the attached drawings and the detailed description.
One, high throughput screening process
Referring to fig. 1, before high throughput screening of molecular markers for aortic dissection, a test sample is screened, which comprises the following steps:
(1) 5997 clinically diagnosed chest pain patients were enrolled from clinical cases;
(2) after 846 patients with stable angina and 859 patients with abdominal aortic aneurysm were excluded, 4292 patients with acute coronary syndrome and aortic dissection remained;
(3) further excluding 77 aortal dissection patients and 73 patients with acute coronary syndrome after the age of less than 18 years, pregnant women and patients with severe hepatorenal dysfunction;
(4) 15 of 77 aortic dissection patients were selected, and 15 of 73 patients with acute coronary syndrome were selected.
Furthermore, the serum of 15 selected aortal dissection patients and 15 selected acute coronary syndrome patients is subjected to differential protein screening by adopting the combined technology of an isotope labeling relative and absolute quantitative method (iTRAQ) and a non-standard quantitative method (LABEL-FREE). Wherein, a sample of a patient with acute coronary syndrome is taken as a control sample, and a sample of a patient with aortic dissection is taken as a test sample.
Isotope labeling relative and absolute quantitation (iTRAQ) methods rely on iTRAQ reagents, which are amine-labeled isobaric elements that can be linked to amino acid terminal amino groups and lysine side chain amino groups in mass spectra, where any of the iTRAQ reagents labels the same protein in different samples to exhibit the same mass-to-charge ratio, in tandem mass spectra, signal examples are represented as peaks of different mass-to-charge ratios (114-121), and thus, based on the height and area of the peak, proteins can be identified and quantitative information can be analyzed for different treatments of the same protein. The iTRAQ technology has high sensitivity and low detection limit, and can detect low-abundance proteins; the separation capacity is strong, the analysis range is wide, and the protein identification method can identify any type of protein, including high molecular weight protein, acidic protein and alkaline protein, membrane protein and insoluble protein, and the protein with the KD of less than 10KD or more than 200KD is also applicable; the high flux can simultaneously analyze 8 samples, improve the experimental flux and simultaneously analyze proteins at a plurality of time points or processed differently; the result is reliable, the qualitative and quantitative analysis results are more reliable, and the molecular weight and rich structural information of each component can be simultaneously given during qualitative analysis; the method has the advantages of high automation degree, combination of liquid chromatography and mass spectrometry, automatic operation, high analysis speed and good separation effect.
The method of non-standard quantification (LABEL-FREE) analyzes the quantity change of different source sample proteins by comparing the number of mass spectrum analysis times or mass spectrum peak intensity, and considers that the frequency of the peptide segment captured and detected in the mass spectrum is in positive correlation with the abundance of the peptide segment in the mixture, so that the protein abundance is reflected by the counting of the mass spectrum detection of the protein, and the mass spectrum detection counting and the protein quantity can be related by a proper mathematical formula, thereby quantifying the protein. The technology does not need expensive isotope labels as internal standards, and improves the detection efficiency of low-abundance proteins and the accuracy of protein quantification.
The method comprises the following steps of respectively detecting differential proteins (including expression quantity difference of the same protein and whether the same protein is expressed) in sera of two groups of patients (aortic dissection and acute coronary syndrome) by using an iTRAQ combined Label-free technology, searching markers related to aortic dissection diagnosis in a wider range, selecting the protein with the maximum correlation after carrying out two overlapping in a large range, simultaneously giving out the protein which only appears in an aortic dissection patient and the protein which only appears in a control group by Label-free, carrying out cluster analysis by using a patch software, and carrying out protein interaction analysis to screen out the serum protein markers with the maximum possibility of 9 candidates: photopolymerized protein (Lumican), protein inhibitor 16(PI16), fibrinogen-like protein 1(FGL1), matrix metalloproteinase-9 (MMP9), fibrillar protein 1 antigen (FBN1), platelet factor 4(PF4), Von Willebrand Factor (VWF), matrix metalloproteinase-2 (MMP-2), and polyprotein 1(MMRN 1).
Second, ELISA verification Process
Enzyme-linked immunosorbent assay (ELISA) refers to a qualitative and quantitative method in which an immune reaction is carried out by adsorbing a soluble antigen or antibody onto a solid-phase carrier such as polystyrene. The enzyme-labeled antigen used by the method has high enzyme catalytic activity, so that the reaction effect can be greatly amplified, and the determination method can achieve high sensitivity, therefore, the ELISA serum verification is the most widely, most convenient and most rapid method for clinical application at present. If the selected serum protein marker is screened through high throughput, the specificity and sensitivity of the selected serum protein marker can be shown in the verification of ELISA, and the clinical application of the selected serum protein marker is facilitated.
Performing serum ELISA validation of a large number of samples on the 9 serum protein markers found in the high-throughput screening process, specifically referring to FIG. 1, performing ELISA validation of the 9 serum protein markers on the sera of the previously selected 77 patients with aortic dissection and 73 patients with acute coronary syndrome, using the Acute Coronary Syndrome (ACS) sample as a control group and the aortic dissection (AAD) sample as an experimental group, and sorting the data of each serum protein marker into a box chart (see FIG. 2).
In FIG. 2, A is a comparison of the expression levels of Lumican in the AAD sample and the ACS sample, respectively. B is the comparison of the expression level of PI16 in the AAD sample and ACS sample. C is the comparison of the expression level of MMP9 in the AAD sample and the ACS sample. D is the comparison of the expression level of FGL1 in the AAD sample and ACS sample. E is the comparison of the expression level of FBN1 in the AAD sample and ACS sample. F is the comparison of the expression level of MMP2 in the AAD sample and the ACS sample. G is the comparison of the expression level of PF4 in the AAD sample and the ACS sample. H is a comparison of the expression levels of VWF in the AAD sample and the ACS sample, respectively. I is the comparison of the expression level of MMRN1 in AAD sample and ACS sample. According to statistical analysis, the data of Lumican, PI16, FGL1 and MMP9 reflect significant differences (group marked with "#" in fig. 2, p <0.05), which indicates that the expression levels of the 4 serum protein markers in ACS and AAD are significantly different, and can be used for distinguishing ACS from AAD; the data for FBN1, PF4, VWF, MMP2 and MMRN1 reflect non-significant differences (group labeled "&" in figure 2, p >0.05), suggesting that the 5 serum protein markers are not significantly different in the amount of expression in ACS and AAD, and that ACS and AAD cannot be distinguished by validating the 5 serum protein markers.
Thus, after further performing large sample size serum ELISA validation, 4 significantly elevated serum protein markers were obtained in aortic dissection patients' serum as Lumican, PI16, FGL1, and MMP9, respectively. And finally, collecting the aortic tissues of two groups of patients (the aortic dissection needs to replace the ascending aorta of the patient with the normal donated organ) for immunofluorescence and protein electrophoresis verification, wherein the target protein is actually obviously increased in the aortic dissection tissues. Finally, the conclusion is obtained: by detecting the content of the 4 protein markers (Lumican, PI16, FGL1 and MMP9) in serum, the diagnosis rate of aortic dissection can be rapidly improved, or the diagnosis rate of differentiating ACS and AAD can be rapidly improved.
Third, accuracy verification process
Further, ROC curves were plotted reflecting the sensitivity and specificity of the 4 serum protein markers for diagnosing aortic dissection. ROC curves are often used in the medical field to analyze the ability of any boundary value of an index to identify a disease. The ROC curve takes a true positive rate (sensitivity) as an ordinate and a false positive rate (1-specificity) as an abscissa, the closer the ROC curve is to the upper left corner, the higher the accuracy of the test related to the index is, the point of the ROC curve closest to the upper left corner is the best threshold with the least errors, and the occurrence of false positives and false negatives is the least. The ROC curve can also be used for comparing two or more than two diagnostic methods or diagnostic indexes of the same disease, the ROC curve of each test is drawn into the same coordinate, the advantages and disadvantages of the diagnostic methods or diagnostic indexes can be visually distinguished, the Area (AUC) under the ROC curve of each test can be respectively calculated for comparison, and the diagnostic method or diagnostic index with the highest AUC has the best diagnostic value.
Referring to fig. 3, panel a is a set of ROC curves of the 4 serum protein markers (Lumican, PI16, FGL1, and MMP9) respectively counted after ELISA verification, wherein PI16 shows the highest diagnostic accuracy with aortic dissection, AUC is 0.739, sensitivity is 55.8%, and specificity is 78.1%.
The B diagram of fig. 3 carries out integrated statistics on PI16 in combination with data of other 3 serum protein markers (Lumican, FGL1, and MMP9), respectively, wherein AUC of ROC curve of PI16 in combination with Lumican is 0.742, sensitivity is 90.9%, and specificity is 43.8%; the AUC of the ROC curve of PI16 in combination with Lumican and FGL1 was 0.78, the sensitivity was 67.5%, and the specificity was 76.7%. The results show that the combined use of the serum protein markers can optimize the diagnosis accuracy of aortic dissection more than the single use, wherein the scheme of diagnosing aortic dissection by taking PI16 as a main part and combining other serum protein markers with high correlation degree is more excellent, and the scheme by combining PI16 with Lumican and FGL1 is optimal.
In summary, the aortic dissection diagnostic marker is obtained by screening according to the proteomics principle, and can effectively improve the diagnosis rate of aortic dissection and the diagnosis rate of distinguishing aortic dissection from acute coronary syndrome through the verification of a large number of samples.
The above embodiments are only preferred embodiments of the present application, but not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present application should be construed as equivalents and are included in the scope of the present application.
Claims (5)
1. Use of an aortic dissection diagnostic marker in the manufacture of a serum test product for differentiating between aortic dissection and acute coronary syndrome, wherein the marker consists of protein inhibitor 16, fibrinogen-like protein 1, photopolymerisable protein and matrix metalloproteinase-9.
2. Use of an aortic dissection diagnostic marker as claimed in claim 1 in the manufacture of a serum test product for differentiating aortic dissection from acute coronary syndrome, wherein the marker is differentially expressed in a test sample compared to a control sample.
3. Use of an aortic dissection diagnostic marker as claimed in claim 2 in the manufacture of a serum test product for differentiating aortic dissection from acute coronary syndrome, wherein the marker is expressed in an increased amount in a sample from a subject as compared to a control sample.
4. Use of the aortic dissection diagnostic marker of claim 2 in the manufacture of a serum test product for differentiating aortic dissection from acute coronary syndrome, wherein the control sample and the subject sample are derived from serum.
5. Use of the aortic dissection diagnostic marker of claim 2 in the manufacture of a serum test product for differentiating aortic dissection from acute coronary syndrome, wherein the expression level of the marker is verified by enzyme linked immunosorbent assay.
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