CN112961912A - Exosome miRNA (micro ribonucleic acid) serving as molecular marker for diagnosing coronary heart disease and application of exosome miRNA - Google Patents
Exosome miRNA (micro ribonucleic acid) serving as molecular marker for diagnosing coronary heart disease and application of exosome miRNA Download PDFInfo
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Abstract
The invention belongs to the technical field of molecular diagnosis, and particularly relates to exosome miRNA serving as a molecular marker for diagnosing coronary heart disease and application thereof. The miRNA is any one or a combination of more than two molecular markers of miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p, and the specific nucleic acid sequence of the exosome miRNA is shown in SEQ NO.4, 8, 2, 13, 5 and 1. The invention proves that the six plasma exosome miRNA can be used as a molecular diagnosis marker of coronary heart disease; the miRNA is prepared into a kit, a microarray or a biochip for diagnosing the coronary heart disease, and the coronary heart disease can be rapidly diagnosed and judged by detecting the expression quantity of the plasma exosome miRNA of a subject.
Description
Technical Field
The invention belongs to the technical field of molecular diagnosis, and particularly relates to exosome miRNA serving as a molecular marker for diagnosing coronary heart disease and application thereof.
Background
Cardiovascular disease has a high incidence and mortality worldwide. The Chinese cardiovascular disease report 2017 shows that the number of patients with cardiovascular diseases in China is as high as 2.9 hundred million, wherein the patients with coronary heart disease are 1100 million. However, the clinical diagnosis of coronary heart disease still has great defects at present, the diagnosis of patients suspected of coronary heart disease is not standard and not comprehensive, so that the misdiagnosis rate and the missed diagnosis rate of coronary heart disease are both high, and the early discovery, early diagnosis and early treatment of coronary heart disease patients are very important, so that the development and prognosis of the disease are related. At present, the gold standard for clinical coronary heart disease diagnosis is coronary artery angiography, but because the characteristics of high cost, invasiveness and examination risk exist defects, the development of a noninvasive, rapid, sensitive and low-cost molecular diagnosis method is imperative.
Exosomes are microvesicles secreted from cells, have a diameter of about 30-200nm, have a double-layer membrane structure, and naturally exist in biological fluids such as blood, urine, saliva, breast milk, cell culture media, and the like. Almost all types of cells (immune cells, neural cells, stem cells), including tumor cells, can produce and release exosomes. Exosomes can carry liposomes, proteins, mRNA and miRNA to target tissues and can be involved in cellular communication, immune responses, and tumor growth and migration.
Recent studies have shown that miRNA in exosomes changes in content, size, type, etc. under disease conditions, and measurement of exosome miRNA as a biomarker has many advantages over miRNA free in blood. The exosome membrane can effectively protect the inclusion from nuclease degradation, thereby maintaining the integrity and functionality of exosome miRNA in circulating blood, so that the exosome miRNA can be used for detecting the disease development of coronary heart disease by the characteristics, and can be used as an effective index for diagnosing the coronary heart disease.
Disclosure of Invention
The invention aims to provide an exosome miRNA as a molecular marker for diagnosing coronary heart disease and an effective diagnostic tool for diagnosing the coronary heart disease.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the miRNA is any one or a combination of more than two molecular markers of miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p, and the specific nucleic acid sequence of the miRNA is shown in SEQ NO.4, 8, 2, 13, 5 and 1.
Preferably, the miRNA is miR-15a-3p, miR-155-5p and miR-210-3 p.
Preferably, the exosomes are plasma exosomes.
The exosome miRNA is applied to preparation of a kit, a microarray or a biochip for diagnosing coronary heart disease.
The application of the substance for detecting the expression quantity of the exosome miRNA in preparing a product for diagnosing coronary heart disease.
Preferably, the substance for detecting the expression level of the exosome miRNA is a primer or a probe.
A primer combination for fluorescence quantitative detection of the exosome miRNA is shown as follows:
(1) primers for miR-15a-3 p: 5'-AACACGCCAGGCCATATTGTG-3'
(1) Primers for miR-155-5 p: 5'-AAGCGACCTTAATGCTAATCGTGA-3'
(2) Primers for miR-210-3 p: 5'-AACAAGCTGTGCGTGTGACA-3'
The invention discloses a molecular marker for diagnosing coronary heart disease based on plasma exosome miRNA and application thereof. The qRT-PCR result shows that six kinds of human plasma exosome miRNAs such as miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p are differentially expressed between patients with coronary heart disease and healthy control groups. The ROC curve is used for analyzing the efficacy of six plasma exosome miRNAs in diagnosing patients with coronary heart disease, and the results show that the AUC values of the six exosome miRNAs are 0.897, 0.885, 0.952, 0.813, 0.774 and 0.976 respectively. The exosomes miR-15a-3P, miR-155-5P and miR-210-3P with higher AUC values are used as molecular marker combinations to be investigated, and the result of the efficiency analysis shows that the AUC value of the molecular marker combination reaches 0.992, P is less than 0.001 and is higher than a single index; the sensitivity and specificity were 100% and 92.9%, respectively.
The invention proves that the six plasma exosome miRNA can be used as a molecular diagnosis marker of coronary heart disease. The kit, microarray or biochip for diagnosing coronary heart disease is prepared, and the coronary heart disease is rapidly diagnosed and judged by detecting the expression quantity of plasma exosome miRNA of a subject: when the expression quantity of at least one miRNA in exosomes miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p is down-regulated, or the expression quantities of miR-15a-3p, miR-155-5p and miR-210-3p are all down-regulated, the fact that the subject suffers from coronary heart disease is prompted, and the clinical application value is important.
Drawings
FIG. 1 TEM images (scale bar, 100nm) of plasma exosomes of healthy control group and coronary heart disease patients;
FIG. 2 plasma exosome particle size analysis curves for healthy control group and coronary heart disease patients;
FIG. 3 Western blot of three representative exosome-specific markers; CTR in the figure, healthy control group; IHD, ischemic coronary disease group;
FIG. 4 is a schematic diagram showing the relative expression of six plasma exosome miRNAs with statistical significance in healthy control group and coronary heart disease patients; CTR in the figure, healthy control group; IHD, ischemic coronary disease group;
FIG. 5 ROC curve analysis of six plasma exosome miRNA expression levels;
FIG. 6 ROC curve analysis of combined models of plasma exosomes miR-15a-3p, miR-155-5p and miR-210-3 p.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
1) Test reagent
Plasma samples of healthy control group and coronary heart disease patients of the present invention were obtained from the first subsidiary hospital of zheng zhou university. Other reagents or consumables used are commonly available or available to those skilled in the art via public routes.
2) Test method
Collecting human peripheral blood with EDTA anticoagulant blood collection tube, centrifuging at 2500g for 15min, collecting upper layer plasma in 2ml sterile tube, and freezing at-80 deg.C. Taking out plasma from a refrigerator, thawing in a water bath at 25 ℃, transferring to a centrifuge tube, centrifuging at 4 ℃ for 10min at 3000g, and removing cell debris in a sample; the cell debris-removed centrifugation supernatant was transferred to a new centrifuge tube and centrifuged at 10000g for 20min at 4 ℃ to remove impurities in the sample. 1.6ml of the supernatant was added with 0.4ml of Exoquick reagent (System Biosciences) and allowed to stand at 4 ℃ for 30 minutes. Centrifuging (3000g × 30 min), and discarding the supernatant, centrifuging again (3000g × 5 min), and discarding the supernatant to obtain the precipitate as exosome.
Exosomes were extracted using the Exoquick kit (System Biosciences). Mu.l of the resulting exosome suspension was applied to a Formvar-carbon loaded copper mesh, washed with PBS, placed on 50. mu.l of 1% glutaraldehyde solution for 5min, and then placed on 100. mu.l ddH2O wash for 2 minutes. Dyeing with uranyl oxalate solution and methylcellulose solution, absorbing excessive liquid on filter paper, drying in air for 5min, and identifying the obtained exosome form with JEOL-1230 transmission electron microscope. And analyzing and identifying the obtained exosome particle size and specific markers by using a ZetaView PMX 110 particle tracker and Western blotting.
3) Analytical method
Performing statistical analysis and mapping by using Graphpad Prism 8 software, expressing continuous variables conforming to normal distribution by mean +/-standard deviation (mean +/-SD), and comparing data between two groups by using an independent sample t test;
the diagnostic efficacy of exosome mirnas was evaluated using SPSS 22.0 software to calculate and map the area under the curve. P <0.05 is statistically significant for differences.
Examples
Plasma from 14 healthy controls and 18 coronary heart disease patients was collected and stored at-80 ℃ in time. The basic clinical characteristics of the collector are shown in table 1;
TABLE 1 basic clinical characteristics
Note: continuous variables are mean ± standard deviation (mean ± SE) and categorical variables are expressed as percentages. CTR, healthy control; IHD, ischemic coronary heart disease.
Extracting exosomes from the plasma sample by using an Exoquick kit (System Biosciences), fixing the obtained exosomes on a sample-carrying copper net, dyeing and drying, and identifying the morphology of the obtained exosomes by using a JEOL-1230 transmission electron microscope; and analyzing and identifying the obtained exosome particle size and specific markers by using a ZetaView PMX 110 particle tracker and Western blotting. Wherein, the TEM image is shown in FIG. 1; the Nanoparticle Tracking Analysis (NTA) results are shown in fig. 2; the western blot results are shown in fig. 3(Alix, CD 63 and Hsp 70). The results of fig. 1 to 3 show that the extracted vesicles are consistent with exosome characteristics in morphology, particle size distribution and specific marker labeling.
Previous studies suggest that 13 exosome mirnas have relevance to coronary heart disease, which are: miR-301a-5p, miR-19a-3p, miR-133a-3p, miR-155-5p, miR-26a-5p, miR-20a-5p, miR-181b-5p, miR-15a-3p, miR-18a-5p, miR-30e-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3 p; the specific nucleic acid sequence is shown as SEQ NO. 1-13; the method is verified by utilizing qRT-PCR, and the specific process is as follows:
1. extraction of total RNA of plasma exosomes
An appropriate amount of exosome was taken out into a 1.5ml EP tube, 800ul Trizol reagent (Invitrogen corporation) was added thereto, mixed well, lysed for 10min, and centrifuged at 12000rpm for 10min to take the supernatant. Shaking and mixing, standing at 4 deg.C for 10min, adding 200ul chloroform, shaking and mixing, standing at 4 deg.C for 10min, and centrifuging at 12000rpm (10 min); collecting supernatant, adding isopropanol with the same volume as the supernatant, adding glycogen with a certain volume, standing overnight at-20 deg.C, centrifuging at 12000rpm at 4 deg.C for 10min, and discarding the supernatant; adding 1ml of 70% ethanol, and centrifuging again at 12000rpm at 4 ℃; when the RNA just becomes transparent, adding a proper amount of nucleic-free water, carrying out water bath at 55 ℃ for 5min to completely dissolve the RNA, and carrying out ultraviolet analysis to determine the concentration of the extracted RNA.
Reverse transcription of RNA into cDNA
Using PrimeScriptTMRT (Takara) kit reverse transcription of RNA into cDNA. Firstly, preparing reaction mixed liquor on ice according to the table 2 to eliminate genome in RNA, in order to ensure the accuracy of the preparation of the reaction liquor, preparing MasterMix according to the quantity of the reaction number +2 in each reaction, then subpackaging in each reaction tube, and finally adding an RNA sample. Then incubated at 42 ℃ for 2 minutes and stored at 4 ℃.
TABLE 2 genome Elimination in RNA
The reverse transcription reaction system and reaction conditions are shown in tables 3 and 4;
TABLE 3 reverse transcription reaction System
TABLE 4 reverse transcription reaction conditions
qRT-PCR detection
Exosome mirnas were analyzed using a Stepone plus fluorescent quantitative PCR instrument (Applied Biosystems) with three replicates per sample. Table 5 shows the nucleic acid sequences of 13 miRNAs and cel-miR-39 and the forward primer sequences thereof, and the sequence of the universal reverse primer is 5'-GTCGTATCCAGTGCAGGGT-3'. Primer pairs were designed and synthesized by Umibio corporation and NCBI blast comparison was used to analyze the sensitivity and specificity of the primers. Tables 6 and 7 show the qRT-PCR reaction system and reaction conditions, respectively, in which
Premix Ex Taq (Tli RNaseH Plus) was purchased from Takara. Taking cel-miR-39 as an external reference, Log2 (2-delta. CT) represents the relative expression level of the target gene.
TABLE 5 exosome miRNA nucleic acid sequences and their forward primer sequences
TABLE 6 qRT-PCR detection reaction System
TABLE 7 qRT-PCR detection reaction conditions
4. Results and analysis:
the qRT-PCR detection result shows that miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p are differentially expressed in patients with coronary heart disease and healthy control groups: compared with a healthy control group, the expression level of at least one of the six miRNAs of the coronary heart disease patient is reduced, and the difference between the two groups has statistical significance. The specific expression results of the six miRNAs in the coronary heart disease patients and the healthy control group are shown in FIG. 4.
Statistical analysis and mapping were performed using Graphpad Prism 8 software, and the diagnostic potency of exosome mirnas was evaluated using SPSS 22.0 software to calculate the area under the curve. ROC curve analysis of miRNA expression levels for six plasma exosomes is shown in figure 5.
The results show that the diagnosis efficacy of miR-15a-3P, miR-18a-5P, miR-155-5P, miR-92a-2-5P, miR-181a-5P and miR-210-3P on coronary heart disease, namely the area under the ROC curve (AUC) is 0.897, 0.885, 0.952, 0.813, 0.774 and 0.976 respectively, and the P value is less than 0.05. Wherein the AUC value of the miRNA of the three exosomes of miR-15a-3p, miR-155-5p and miR-210-3p is maximum.
The three exosome miRNAs are used as a combined model for diagnosing coronary heart disease. The diagnosis efficiency of the above 3 exosome miRNA combinations on coronary heart disease was evaluated by selecting the above 14 healthy controls and 18 coronary heart diseases and calculating the area under the curve using SPSS 22.0 software, and the results are shown in fig. 6.
The results show AUC values for the three marker combinations of 0.992(0.971, 1), P <0.001, higher than single index; the detection specificity and sensitivity are 92.9% and 100%, respectively. The exosome miRNA combination can be used as a molecular marker for diagnosing coronary heart disease: if the expression levels of miR-15a-3p, miR-155-5p and miR-210-3p in plasma exosomes of the subject are all reduced, the subject is suggested to suffer from coronary heart disease.
SEQUENCE LISTING
<110> first subsidiary Hospital of Zhengzhou university
<120> exosome miRNA (micro ribonucleic acid) serving as molecular marker for diagnosing coronary heart disease and application thereof
<130> NONE
<160> 14
<170> PatentIn version 3.5
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Claims (7)
1. The exosome miRNA is used as a molecular marker for diagnosing coronary heart disease, and is characterized in that:
the exosome miRNA is one or a combination of more than two molecular markers of miR-15a-3p, miR-18a-5p, miR-155-5p, miR-92a-2-5p, miR-181a-5p and miR-210-3p, and the specific nucleic acid sequence of the exosome miRNA is shown in SEQ NO.4, 8, 2, 13, 5 and 1.
2. The molecular marker of claim 1, wherein: the exosome miRNA is miR-15a-3p, miR-155-5p and miR-210-3 p.
3. The molecular marker of any one of claims 1 to 2, wherein: the exosome is a plasma exosome.
4. Application of exosome miRNA in preparation of kit, microarray or biochip for diagnosing coronary heart disease.
5. And the application of the substance for detecting the expression quantity of the exosome miRNA in the preparation of products for diagnosing coronary heart disease.
6. The use of claim 5, wherein: the substance for detecting the expression quantity of the exosome miRNA is a primer or a probe.
7. A primer combination for fluorescence quantitative detection of the exosome miRNA is characterized in that the primer combination is as follows:
(1) primers for miR-15a-3 p: 5'-AACACGCCAGGCCATATTGTG-3'
(2) Primers for miR-155-5 p: 5'-AAGCGACCTTAATGCTAATCGTGA-3'
(3) Primers for miR-210-3 p: 5'-AACAAGCTGTGCGTGTGACA-3' are provided.
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| CN114058693A (en) * | 2021-11-22 | 2022-02-18 | 中国人民解放军总医院第二医学中心 | Coronary heart disease marker PRKAB2 and application thereof |
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