CN116287207B - Use of biomarkers in diagnosing cardiovascular related diseases - Google Patents
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Abstract
The invention discloses application of a biomarker in diagnosing cardiovascular related diseases, and provides application of a reagent for detecting the biomarker NTNG1 in a sample to be detected in preparing a product for diagnosing and/or assisting in diagnosing the cardiovascular related diseases, and verification results of the invention show that NTNG1 has better diagnosis efficiency, can diagnose whether a subject has cardiovascular related diseases or risk of cardiovascular related diseases according to the NTNG1, and has better clinical application value.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to application of a biomarker in diagnosing cardiovascular related diseases.
Background
Cardiovascular and cerebrovascular diseases are manifestations of systemic vascular lesions or systemic vascular lesions in the heart and brain. Its etiology has mainly 4 aspects. The blood components are respectively vascular factors such as atherosclerosis, hypertensive arteriosclerotic arteriosclerosis, arteritis and the like, hemodynamic factors such as hypertension and the like, blood rheology anomalies such as hyperlipidemia, diabetes and the like, blood component factors such as leukemia, anemia, thrombocytosis and the like.
Coronary artery expansion refers to the localized or diffuse expansion of the coronary artery over 1.5 times or more its adjacent normal coronary artery caliber due to various causes. Coronary artery expansion involves multiple blood vessels, with more men than women. Both coronary artery dilation (Corinary Artery Ectasia) and coronary artery neoplasia (Coronary artery aneurysm) belong to the neoplasia-like dilation (aneurysmal dilatation) of the coronary artery. In the current literature, aneurysmal coronary artery disease is defined artificially, and coronary aneurysms are commonly used to describe focal expansions, which are defined as diameters 1.5 times larger than adjacent normal coronary arteries, whereas coronary expansion is used to describe more diffuse arterial lesions, accumulating over 50% of the coronary length. Coronary aneurysms are further classified into cystic (transverse greater than longitudinal) and clostridial (longitudinal greater than transverse). Stable angina is the most common symptom, and malignant arrhythmias and even sudden death can occur when spontaneous interlayer forms. Few patients have aneurysm rupture, causing acute cardiac tamponade, and the symptoms are sudden chest distress, dyspnea, pale complexion or cyanosis, and the like, which endanger the life of the patients.
Disclosure of Invention
In order to make up the defects of the prior art, the invention provides the following technical scheme:
the invention provides application of an agent for detecting NTNG1 expression level in preparing a product for diagnosing whether a subject suffers from cardiovascular related diseases.
Further, the cardiovascular-related disease includes coronary artery dilation.
Further, the NTNG1 is under-expressed in the patient.
Further, the reagent for detecting the expression level of NTNG1 includes a reagent for detecting the expression level of NTNG1 protein and/or the expression level of NTNG1 mRNA.
Further, the reagent for detecting the expression amount of the NTNG1 protein includes a reagent used in the following method: enzyme-linked immunosorbent assay, western blot, radioimmunoassay, sandwich assay, immunohistochemical staining, mass spectrometry, immunoprecipitation assay, complement fixation assay, flow cytometry and protein chip method.
Further, the reagent for detecting the expression amount of NTNG1 mRNA includes reagents used in the following methods: PCR-based detection methods, southern hybridization methods, northern hybridization methods, dot hybridization methods, fluorescent in situ hybridization methods, DNA microarray methods, ASO methods, high throughput sequencing methods.
Further, reagents for collecting and/or processing a sample are included in the reagent.
Further, the sample comprises primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, peripheral blood, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, tissue culture fluid, tissue extracts, homogenized tissue, tumor tissue, cell extracts.
Further, the sample is peripheral blood.
The invention also provides a product for diagnosing whether a subject suffers from cardiovascular-related diseases, the product comprising the reagent for detecting the NTNG1 expression level in a sample.
Further, the product comprises a kit, a chip, test paper and a membrane strip.
Further, the kit comprises qRCR kit, immunoblotting detection kit, immunochromatography detection kit, flow cytometry analysis kit, immunohistochemical detection kit, ELISA kit and electrochemiluminescence detection kit.
Further, the sample comprises primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, peripheral blood, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, tissue culture fluid, tissue extracts, homogenized tissue, tumor tissue, cell extracts.
Further, the sample is peripheral blood.
Further, the reagent for detecting the NTNG1 expression level in the sample comprises a primer for specifically amplifying NTNG1, a probe for specifically recognizing NTNG1, and a binding agent for specifically binding to a protein encoded by NTNG1.
The invention also provides a pharmaceutical composition for treating cardiovascular-related diseases, which comprises an agent for promoting the expression amount of NTNG1.
Further, the pharmaceutical composition comprises an accelerator or inhibitor that accelerates or inhibits the expression level of the biomarker.
Further, the promoter promotes the expression level of a biomarker whose expression is down-regulated in cardiovascular-related diseases, and the inhibitor inhibits the expression level of a biomarker whose expression is up-regulated in cardiovascular-related diseases.
Further, the cardiovascular-related disease includes coronary artery dilation.
The invention also provides application of the biomarker in constructing a calculation model for diagnosing cardiovascular related diseases, wherein the biomarker comprises NTNG1.
The present invention provides a system or device for diagnosing whether a subject has a cardiovascular-related disease or is at risk for developing a cardiovascular-related disease,
comprising the following steps:
a processor:
the input module is used for inputting the level of a biomarker in a biological sample, wherein the biomarker is NTNG1;
a computer readable medium containing instructions which, when executed by the processor, perform a first algorithm at an input level of a gene and/or an expression product thereof; and
and an output module: it provides a marker based on the input level of the gene and/or its expression product, wherein the marker indicates the presence of a cardiovascular-related disease in the subject.
Further, the system includes an agent for the biomarker.
Further, the cardiovascular-related disease includes coronary artery dilation.
Drawings
FIG. 1 is a diagram of a protein interaction network;
fig. 2 is a ROC graph of NTNG1 diagnosing coronary artery dilation.
Detailed Description
For the purpose of further detailed description of the present invention, it is to be understood and appreciated that the description is intended to illustrate the invention, and not to limit the scope of the invention.
The term "expression level" as used herein refers to determining the amount or presence of an RNA transcript of an intrinsic gene or its expression product. Methods of detecting the expression of an intrinsic gene of the present disclosure, i.e., gene expression profiling, include methods based on polynucleotide hybridization analysis, methods based on polynucleotide sequencing, immunohistochemical methods, and methods based on proteomics. These methods typically detect the expression product (e.g., mRNA) of an intrinsic gene described herein. In preferred embodiments, PCR-based methods, such as reverse transcription PCR (RT-PCR), and array-based methods, such as microarrays, are used.
In a specific embodiment of the invention, the agents may be administered simultaneously or sequentially, or may be administered by separate varying regimens and by different routes. The agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and provided together in the form of an optional kit with instructions for their use.
The reagent for detecting the NTNG1 protein is a specific binding agent of the NTNG1 protein. The specific binding agent is, for example, a receptor for protein NTNG1, a lectin that binds protein NTNG1, an antibody to protein NTNG1, a peptide antibody to protein NTNG1, a bispecific dual binding agent, or a bispecific antibody format. Examples of specific binding agents are peptides, peptidomimetics, aptamer, spiegelmer, darpin, ankyrin repeat proteins, kunitz-type domains, antibodies, single domain antibodies and monovalent antibody fragments.
The term "binding agent" in the present invention is meant to include any naturally occurring, synthetic or genetically engineered agent, such as a protein, that binds an antigen or a target protein or peptide. The binding agent may be derived from naturally occurring antibodies or synthetically engineered. Binding proteins or agents can function similarly to antibodies by binding to a particular antigen to form a complex and elicit a biological response (e.g., agonize or antagonize a particular biological activity). The binding agent or binding protein may include isolated fragments, an "Fv" fragment consisting of the variable regions of the heavy and light chains of an antibody, a recombinant single chain polypeptide molecule ("ScFv protein") in which the light and heavy chain variable regions are linked by a peptide linker, and a minimal recognition unit consisting of amino acid residues that mimic the hypervariable region. As used herein, the term binding agent may also include antibody fragments produced by whole antibody modification or synthesized de novo using recombinant DNA methods. In some embodiments, the antibody is a single chain antibody, e.g., a single chain Fv (scFv) antibody in which a variable heavy chain and a variable light chain are joined together (either directly or via a peptide linker) to form a continuous polypeptide. Single chain Fv (scFv) polypeptides are covalently linked VH:VL heterodimers that can be expressed from nucleic acids comprising VH-and VL-encoding sequences that are either directly bound or bound via a peptide-encoding linker (see, e.g., huston et al (1988) Proc.Nat. Acad. Sci. USA,85:5879-5883, the entire contents of which are incorporated herein by reference). There are many structures for converting naturally polymerized but chemically separated polypeptide light and heavy chains from the antibody V region into scFv molecules that will fold into a three-dimensional structure substantially similar to the structure of the antigen binding site.
The term "biomarker" as used herein refers to a gene that is differentially present (i.e., increased or decreased) in a biological sample from a subject or group of subjects having a first phenotype (e.g., having a disease) as compared to a biological sample from a subject or group of subjects having a second phenotype (e.g., having no disease). The term generally refers to the concentration, content, or concentration, content of one gene or two or more genes.
In a specific embodiment of the invention, the biomarker is NTNG1.
In the present invention, the biomarker NTNG1 (geng ID: 22854) includes a gene and its encoded protein and its homolog, mutation, and isoform. The term encompasses full length, unprocessed biomarkers, as well as any form of biomarker derived from processing in a cell. The term encompasses naturally occurring variants (e.g., splice variants or allelic variants) of the biomarker.
The terms "patient," "subject," and "individual" are used interchangeably herein and refer to an animal, particularly a human, for which it is desirable to analyze a biological sample obtained therefrom for the presence of immune system-stimulating microorganisms. In some embodiments, the subject is in need of diagnosis of a disease or disorder, e.g., diagnosis of inflammatory bowel disease, wherein a biological sample is analyzed using the assays and methods described herein. The term "subject" or "patient" as used herein also refers to human and non-human animals. The term "non-human animal" includes all vertebrates, for example, mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any domestic animals or pets; and non-mammals such as chickens, amphibians, reptiles, and the like. In one embodiment, the subject is a human.
Methods for detecting molecules such as nucleic acids, proteins, etc., in a subject to detect, diagnose, monitor, predict, or assess cardiovascular-related disease states or outcomes are described herein.
The terms "sample", "sample" as used herein refer to a composition obtained or derived from a subject (e.g., an individual of interest) that comprises cells and/or other molecular entities to be characterized and/or identified according to, for example, physical, biochemical, chemical and/or physiological characteristics. For example, the phrase "disease sample" or variant thereof refers to any sample obtained from a subject of interest that is expected or known to comprise the cell and/or molecular entity to be characterized. Samples include, but are not limited to, tissue samples (e.g., tumor tissue samples), primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph, synovial fluid, follicular fluid (fluid), semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebral spinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture fluid (tissue culture medium), tissue extracts such as homogenized tissue, tumor tissue, cell extracts, and combinations thereof.
In some embodiments of the invention, the sample is obtained from the subject by the same party that subsequently obtained biomarker data from the sample.
In some embodiments, the sample is received from another entity that collects the sample from a subject, such as a physician, nurse, phlebotomist, or medical care-giver.
In some specific embodiments, the sample is obtained from the subject by a medical professional under the direction of an isolated entity, and then provided to the entity, such as a testing laboratory. In some embodiments, the sample is collected by the subject or a caretaker of the subject at home and provided to a party who obtains biomarker data from the sample.
In some embodiments of the invention, the data may represent the amount or concentration of a biomarker. In other words, the data may be data of expression levels of nucleic acids, proteins or polypeptides. The expression level data of the biomarkers described herein may be expression level data of a protein or polypeptide, which may be measured by protein array, proteomics, expression proteomics, mass spectrometry, multiple reaction monitoring, selective reaction monitoring, 2D PAGE, 3D PAGE, electrophoresis, proteomic chip, proteomic microarray, edman degradation, direct or indirect ELISA, immunoadsorption assay, immuno PCR, proximity extension assay, luminex assay or homogeneous assay, time resolved fluorescence resonance energy transfer, time Resolved Fluorescence (TRF), fluorescent Oxygen Channel Immunoassay (FOCI), or luminescent oxygen channel immunoassay.
In some embodiments, the methods, products, devices/systems described herein utilize various sandwich, competitive or non-competitive assay formats of the marker molecules to determine the expression levels of the biomarkers described herein. Such methods produce a signal that is related to the presence or amount of one or more proteins described herein. Suitable assay formats also include chromatography, mass spectrometry and western "blotting". In addition, certain methods and devices, such as biosensors, optical immunoassays, immunoadsorption assays, and enzyme immunoassays, can be used to determine the presence or quantity of an analyte without the need for a labeled molecule. Examples of Enzyme Immunoassays (EIA) include chemiluminescent enzyme immunoassays, electrochemiluminescent immunoassays (ECLIA) and enzyme linked immunosorbent assays (ELISA).
In some embodiments, the methods, products, devices/systems described herein utilize any reliable method to measure the level or amount in a sample. In general, detection and quantification from a sample can be accomplished by a variety of known methods for mRNA, including, for example, amplification-based methods, hybridization-based methods, and sequencing-based methods. Other exemplary techniques include Ribonuclease Protection Assay (RPA) and mass spectrometry.
In some embodiments, the present disclosure provides an assay kit for assaying any one of the set of biomarkers included herein for detecting cardiovascular-related disease. In certain instances, the assay kit comprises one or more detection reagents. Such detection reagents include, but are not limited to, probes, primers, antibodies.
The term "primer" as used in the present invention refers to a fragment that recognizes a target gene sequence, and includes forward and reverse primer pairs, preferably, primer pairs that provide an analysis result with specificity and sensitivity. The nucleic acid sequence of the primer is a sequence that is not identical to a non-target sequence present in the sample, and can impart high specificity when it is a primer that amplifies only a target gene sequence including a complementary primer binding site and does not induce non-specific amplification.
The term "probe" in the present invention refers to a molecule that is capable of binding to a specific sequence or subsequence or other portion of another molecule. Unless otherwise indicated, the term "probe" generally refers to a polynucleotide probe that is capable of binding to another polynucleotide (often referred to as a "target polynucleotide") by complementary base pairing. Depending on the stringency of the hybridization conditions, the probe is able to bind to a target polynucleotide that lacks complete sequence complementarity with the probe. Probes may be labeled directly or indirectly, and include primers. Hybridization means, including, but not limited to: solution phase, solid phase, mixed phase or in situ hybridization assays.
In general, in real-time fluorescent quantitative PCR detection, the probe will be designed to have a melting temperature exceeding 10℃for the forward and reverse primers, which allows complete binding of the probe to the PCR product during annealing and extension. Typically, for example, a Taqman probe will hydrolyze during extension by a DNA polymerase having 5'-3' exonuclease activity, so that the fluorescent groups and quenching groups in the probe are far away, and resonance energy transfer between the fluorescent groups and quenching groups is destroyed, so that fluorescence emitted by the fluorescent groups can be detected by an instrument, and at the same time, as the PCR product increases gradually, the fluorescence signal will exhibit an exponential level rise over a certain period of time, and finally an "S" -shaped amplification curve is presented on a fluorescent quantitative PCR instrument. Reagents for real-time fluorescent quantitative PCR include, but are not limited to: forward and reverse primers for target sequence of target gene, taqman fluorescent probe, optimized PCR buffer, deoxynucleotide triphosphate, DNA polymerase with 5'-3' exonuclease activity, etc.
In the present invention, the pharmaceutical composition may be prepared using various additives such as buffers, stabilizers, bacteriostats, isotonic agents, chelating agents, pH controlling agents and surfactants. The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or by an implanted reservoir. Oral administration or injection administration is preferred. The pharmaceutical compositions of the present invention may contain any of the usual non-toxic pharmaceutically acceptable carriers, adjuvants or excipients. In some cases, a pharmaceutically acceptable acid, base or buffer may be used to adjust the pH of the formulation to improve the stability of the formulated compound or dosage form thereof.
The term "area under the curve" or "AUC" as used in the present invention refers to the area under the curve of a subject's working characteristics (ROC) curve, both of which are well known in the art. AUC measurements are useful for comparing classifier accuracy across the entire data range. Classifiers with higher AUC have a higher ability to correctly classify between two target groups (e.g., ovarian cancer samples and normal or control samples) is not known. ROC curves are useful for characterizing the performance of a particular feature (e.g., any biomarker described herein and/or any entry of additional biomedical information) when distinguishing between two populations (e.g., individuals responding to a therapeutic agent and not responding). Typically, feature data is selected across the entire population (e.g., cases and controls) in ascending order based on the values of individual features. Then, for each value of the feature, the true and false positive rates of the data are calculated. The true positive rate is determined by counting the number of cases above the value of the feature and dividing by the total number of cases. False positive rates were determined by counting the number of controls above the value of the feature and dividing by the total number of controls. Although the definition refers to the case where the characteristic is increased in the case compared to the control, the definition also applies to the case where the characteristic is lower in the case compared to the control (in this case, a sample below the value of the characteristic will be counted). The ROC curve may be generated with respect to individual features and may be generated with respect to other individual outputs, for example, a combination of two or more features may be mathematically combined (e.g., added, subtracted, multiplied, etc.) to provide an individual sum value, and the individual sum value may be plotted in the ROC curve. In addition, any combination of features, the combination of which results from separate output values, may be plotted in the ROC curve. These combinations of features may include testing. ROC curves are plots of true positive rate (sensitivity) of the test versus false positive rate (1-specificity) of the test.
Example 1 screening for biomarkers associated with coronary artery dilation
1. Screening method
(1) Data for screening and preprocessing
To screen biomarkers for coronary artery dilation diagnosis, common gene expression data associated with coronary artery dilation is downloaded from a gene expression integrated database (GEO). The dataset GSE87016 is downloaded from the GEO database (http:// www.ncbi.nlm.nih.gov/GEO /).
The data downloaded from the gene expression integrated database (GEO) also requires further processing:
1) The data set selected must be genome-wide DNA methylation data;
2) These data are from coronary artery dilation and control blood samples;
3) The study considered either the normalized or the original dataset.
(2) High throughput transcriptome data and pretreatment
A large amount of sample double-ended sequencing data was obtained by the Illumina platform. In view of the influence of the data error rate on the result, the trimmonic software is adopted to carry out quality preprocessing on the original data, and the numbers of reads in the whole quality control process are statistically summarized.
The specific steps and the sequence are as follows:
(1) A dehiscence (adapter);
(2) Removing low quality reads;
(3) Removing low-quality bases from the 3 'and 5' ends in a different manner;
(4) Counting the original sequencing quantity, the effective sequencing quantity, Q30 and GC content, and carrying out comprehensive evaluation.
And carrying out data quantity statistics on the sequence after data quality control.
(3) mRNA Gene expression level analysis
And (3) using known reference gene sequences and annotation files as databases, and adopting a sequence similarity comparison method to identify the expression abundance of each protein coding gene in each sample. The number of reads aligned to the protein-encoding gene in each sample was obtained using the htseq-count software. After the counts are obtained by comparison, the protein coding genes need to be filtered to remove the genes with the reads of zero number. The number of genes detected in each sample is shown in Table 1, and the statistical partial results of the number of genes detected in Table 1 are shown
The FPKM method can eliminate the influence of the difference of the length and the sequencing quantity of the protein coding gene on the expression of the calculated protein coding gene, and the calculated gene expression quantity is high or low in reaction expression.
(4) Differential analysis of mRNA
Firstly, filtering genes according to the counts mean value, and only keeping the genes with counts mean value larger than 2 for further analysis. And (3) carrying out standardization treatment on the count number of each sample gene by using DESeq2 (using BaseMean value to estimate the expression quantity), calculating a difference multiple, carrying out difference significance test by using NB (negative binomial distribution test), and finally screening the difference protein coding genes according to the difference multiple and the difference significance test result. The condition for screening the difference is p <0.05 +|log2foldchange| >1.
(5) Differential methylation analysis
GSE87016 dataset containing 23 samples of methylation data (NOR: cae=12:11) was downloaded from GEO database and differential methylation analysis was performed on methylation data using the CHAMP package. The set screening criteria is p.value <0.05.
(6) Protein interaction analysis of aberrant methylation modified differentially expressed genes
To investigate the protein interaction relationship between the screened aberrant methylation modified differentially expressed genes we constructed PPI networks of the screened 20 aberrant methylation modified differentially expressed genes using the online database sting.
2. Results
And (3) carrying out standardization treatment on the count number of each sample gene by using DESeq2 (using BaseMean value to estimate the expression quantity), calculating a difference multiple, carrying out difference significance test by using NB (negative binomial distribution test), and finally screening the difference protein coding genes according to the difference multiple and the difference significance test result. Analysis of high throughput sequenced transcriptome mRNA gave 152 differentially expressed genes, including 93 up-regulated and 59 down-regulated.
GSE87016 dataset containing 23 samples of methylation data (NOR: cae=12:11) was downloaded from GEO database and differential methylation analysis was performed on methylation data using the CHAMP package. The set screening criteria were p.value <0.05, yielding 9377 differential methylation sites, 4318 total differential methylation genes, including 2289 hypermethylation genes, 2029 hypomethylation genes.
Intersection of the mRNA differential expression gene and the differential methylation gene to obtain differential expression genes with abnormal methylation regulation, and 9 genes with downregulated expression with hypermethylation modification and 11 genes with upregulated expression with hypomethylation modification are obtained.
To investigate the protein interaction relationship between the screened aberrant methylation modified differentially expressed genes we constructed PPI networks of the screened 20 aberrant methylation modified differentially expressed genes using the online database sting. FIG. 1 shows PPI networks of 20 aberrant methylation-modified differentially expressed genes constructed using the STRING database.
Next we import the results obtained in the STRING database into the Cytoscape software (http:// www.cytoscape.org /), and use the CytoHubba plug-in to screen the core genes. We used a total of 3 algorithms, and screened a total of 10 core genes after crossing the first 10 genes of each algorithm (table 2).
Table 23 screening of HUB Gene of aberrant methylation modified differential expression Gene
Example 2 coronary artery dilation biomarker NTNG1 diagnostic efficacy validation analysis
Based on the result of high-throughput transcriptome data integration analysis, NTNG1 is screened as a candidate gene, coronary artery expansion patient blood and control blood (15 cases) are collected, RNA samples are extracted, and fluorescent quantitative PCR (qRT-PCR) is utilized to verify the differential expression of the candidate gene in a disease group and a control group.
Drawing a ROC curve graph of NTNG1 for diagnosing coronary artery expansion, as shown in FIG. 2, NTNG1 shows higher diagnosis efficacy in coronary artery expansion diagnosis, AUC value is 0.798, sensitivity is 0.846, specificity is 0.750, and NTNG1 is indicated to be capable of diagnosing coronary artery expansion with diagnosis efficacy.
The above description of the embodiments is only for the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principle of the invention, and these improvements and modifications will fall within the scope of the claims of the invention.
Claims (4)
1. Use of an agent for detecting the amount of expression of NTNG1 in a subject in the manufacture of a product for diagnosing whether the subject has coronary artery expansion, said NTNG1 being under-expressed in a patient suffering from coronary artery expansion.
2. The use according to claim 1, wherein the reagent for detecting the expression level of NTNG1 is a reagent for detecting the expression level of NTNG1 protein.
3. The use according to claim 1, wherein the reagent for detecting the expression level of NTNG1 is a reagent for detecting the expression level of NTNG1 mRNA.
4. The use of a reagent for detecting the expression level of a biomarker in the blood of a subject in the construction of a computational model for diagnosing coronary artery expansion, wherein the biomarker is NTNG1, and wherein NTNG1 is low-expressed in a coronary artery expansion patient.
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