CN111621562B - Application of non-coding RNA in preparation of osteoarthritis early diagnosis detection product - Google Patents

Application of non-coding RNA in preparation of osteoarthritis early diagnosis detection product Download PDF

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CN111621562B
CN111621562B CN202010551605.5A CN202010551605A CN111621562B CN 111621562 B CN111621562 B CN 111621562B CN 202010551605 A CN202010551605 A CN 202010551605A CN 111621562 B CN111621562 B CN 111621562B
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CN111621562A (en
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李恒
闵继康
唐慧斌
袁永健
豆晓杰
翁伟
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First Peoples Hospital of Huzhou
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Abstract

The invention discloses application of non-coding RNA in preparation of an early diagnosis and detection product of osteoarthritis, in particular to application of non-coding RNA in preparation of NONHSAT016936.2, DANCR and miR-146a-3p genes, and results show that the non-coding RNA has guiding significance for diagnosis of patients with OA, and combined diagnosis of the non-coding RNA, the DANCR and miR-146a-3p genes has a superposition effect, so that the product and means for early diagnosis of osteoarthritis are provided.

Description

Application of non-coding RNA in preparation of osteoarthritis early diagnosis detection product
Technical Field
The invention relates to the technical field of biological medicine, and relates to application of non-coding RNA in preparation of an early diagnosis product of osteoarthritis, in particular to application of non-coding RNA in preparation of an early diagnosis product of osteoarthritis, wherein the non-coding RNA is NONHSAT016936.2, DANCR or miR-146a-3p gene.
Background
Osteoarthritis is a degenerative disease, which is commonly seen in middle-aged and elderly people, and is caused by degeneration and injury of articular cartilage, reactive hyperplasia of joint margin and subchondral bone, which are caused by factors such as age, obesity, strain, wound, etc. The main symptom of osteoarthritis is joint pain, which often occurs in the morning and is relieved after movement, but if the movement is excessive, the pain can be aggravated.
At present, the diagnosis of osteoarthritis mainly depends on X-ray examination, but the diagnosis is detection of the advanced irreversible structural damage of osteoarthritis, but is not suitable for early diagnosis of osteoarthritis.
Disclosure of Invention
The invention mainly aims to provide the application of the product in the early diagnosis and detection of the osteoarthritis, which has important significance for early patients of the osteoarthritis to find out and take corresponding treatment modes in time and for slowing down the progress of the patient.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
use of non-coding RNA, which is a NONHSAT016936.2, DANCR or miR-146a-3p gene, in the preparation of an early diagnosis and detection product for osteoarthritis.
When the NONHSAT016936.2 gene expression level is high and the DANCR and miR-146a-3p gene expression levels are low, the sample has a higher risk of osteoarthritis.
Preferably, the detection product is a detection of the expression level of the NONHSAT016936.2, DANCR or miR-146a-3p gene in the sample by reverse transcription PCR, fluorescent quantitative PCR, in situ hybridization, chip or high-throughput sequencing platform.
Preferably, the detection product comprises primers and/or probes capable of specifically amplifying the NONHSAT016936.2, DANCR or miR-146a-3p genes.
Preferably, the primer pair sequence for specifically amplifying the NONHSAT016936.2 gene is SQ1:5'-CGCCCAGGAACATGGTAACAC-3', SQ2:5'-GCCAAGGCTGTGACACAAGAG-3'.
Preferably, the primer set sequence for specifically amplifying the DANCR gene is SQ3:5'-AGCGCAGGTTGACAACTACAG-3' or 5'-AGCGCAGAGTTTCATCACCTC-3', SQ4:5'-CTGCAGCTTGGGTGTGTATTC-3'.
Preferably, the primer pair sequence for specifically amplifying the miR-146a-3p gene is as follows: SQ5:5'-GACGGGCCTCTGAAATTCAG-3', SQ6:5'-CAGTGCAGGGTCCGAGGTAT-3'.
Preferably, the test sample is peripheral blood.
Preferably, the detection product comprises a chip, a kit, a test paper or a high-throughput sequencing platform.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses non-coding genes NONHSAT016936.2, DANCR or miR-146a-3p related to osteoarthritis, and discovers that when the NONHSAT016936.2 gene expression level is high and the DANCR and miR-146a-3p gene expression levels are low, a sample has higher risk of suffering from osteoarthritis, and the gene expression level of NONHSAT016936.2 gradually increases along with the deepening of the inflammatory degree of osteoarthritis, and the DANCR and miR-146a-3p gene expression levels obviously decrease, so that the method has important significance for early diagnosis of osteoarthritis.
The foregoing is merely an overview of the present invention, and for the purpose of providing a better understanding of the present invention, the present invention is further described below with reference to the accompanying drawings.
Drawings
FIG. 1 is a diagram showing peripheral blood expression of NONHSAT016936.2, DANCR and miR-146a-3p genes in a healthy control group and an OA patient group.
Detailed Description
For an understanding of the present invention, the present invention will be further described with reference to the drawings and examples. The experimental procedures, which are not explicitly stated in the examples, are carried out according to conventional strips, such as those described in Sambrook et al, molecular cloning, a laboratory Manual, or according to the recommendations of the manufacturer of the reagents or products.
Example 1 clinical case selection
(1) Group entry criteria:
1: age 45-70 years;
2: patients diagnosed with osteoarthritis of the knee or complaining of knee pain for more than 3 months;
3: and signing an informed consent form.
(2) Exclusion criteria:
1: the patients who failed to take blood and joint fluid specimens on time during treatment according to the requirements of the study;
2: complications affect the joint sufferer;
3: patients with serious diseases such as heart, brain, liver, kidney and hematopoietic system;
4: pregnancy, women in pregnancy or lactation, psychotic patients, etc.; patient with scar skin;
5: patients who are participating in other clinical trials;
6: a history of alcohol, drug abuse is suspected or confirmed;
7: other diseases or conditions, such as frequent changes in working environment and unstable living environment, which are likely to cause missed visits, are considered by researchers to reduce the possibility of using the group or complicate the group.
(3) The selected cases were grouped according to diagnostic classification criteria established by the international society of osteoarthritis:
1: 36 healthy control groups;
2: 115 cases of patients with knee joint OA were diagnosed;
115 cases of patients with knee joint OA were diagnosed by X-ray film;
3: group of high risk group 42
The patient suffering from OA, which is mainly complained of knee pain for more than 3 months without obvious imaging change and eliminates other related diseases such as rheumatism, rheumatoid and the like.
EXAMPLE 2 preparation of RNA samples
(1) Peripheral blood mononuclear cell isolation:
1ml of elbow normal venous blood is extracted from 36 healthy control groups and 115 OA patient groups and placed in a heparin anticoagulation tube, the mixture is shaken uniformly, and the blood is diluted 1 to 2 times by PH7.2 to 7.6Hank's liquid;
taking 3-4 ml of LTS1077 polysucrose-diatrizoic amine layering liquid, and placing the layering liquid into a 15X 150mm test tube;
sucking diluted blood by a capillary tube, gradually adding the diluted blood along the tube wall at a position 1cm away from the layering liquid to enable the diluted blood to be overlapped on the layering liquid, wherein the volume ratio of the diluted blood to the layering liquid is about 2:1, a step of;
centrifuging at 2000rpm for 30min with horizontal centrifuge, separating the tube content into 3 layers, wherein the upper layer is plasma and Hank's liquid, the middle layer is layering liquid, and the bottom layer is erythrocyte and polynuclear leukocyte.
A single nuclear cell layer which is milky and turbid (white cloud layer narrow band) and mainly comprises single nuclear cells is visible at the interface of the upper liquid layer and the middle liquid layer, capillary vessels are used for lightly inserting the single nuclear cells into the cloud layer, the single nuclear cells of the interface layer are sucked along the periphery of a test tube, and the single nuclear cells are placed into another test tube;
adding 5 times of Ca-free volume 2+ 、Mg 2+ Is mixed uniformly, 1500rpm for 10min, the supernatant is discarded, and the cells are washed twice repeatedly;
after the last centrifugation, the supernatant was discarded, 0.2ml of a 20% small Niu Xiejiang Hank's solution was added to each ml of blood sample to resuspend the cells, a drop of the cell suspension was counted in a blood cell counting plate, and then the cell concentration was adjusted to 2X 10 6 /ml；
(2) Extraction of total RNA from peripheral blood mononuclear cells
Extracting total RNA of peripheral blood mononuclear cells by adopting Trizol reagent, and performing experimental operation according to a product specification, wherein the specific operation is as follows: the isolated peripheral blood mononuclear cells were added with lm1Trizol, vortexed and placed at room temperature for 15min, 0.2ml chloroform was added, and after 15s of shaking, placed at room temperature for 10min. Then centrifuged at 12000rm for 15min. After the supernatant was aspirated, an equal volume of isopropanol was added to precipitate for 10min. Centrifuging at 12000rm for 10min, discarding supernatant, washing precipitate with lm175% ethanol for 10min, centrifuging at 7500rm, discarding supernatant, standing, and adding RNase-free water to thoroughly dissolve RNA.
(3) Mass analysis of RNA samples
The purity of RNA was determined using an ultraviolet spectrophotometer: 1ul of RNA stock solution was added to the centrifuge tube, followed by adding 247 ul of ddH2O thereto, and mixing well. The zero points of A260 and A280 were adjusted sequentially using ddH2O as a control. A260 and A280 were then determined. Calculating the ratio of the two materials to be more than or equal to 1.8 to meet the experimental requirement. RNA concentration (ng/u 1) =a260×40×dilution.
EXAMPLE 3 fluorescent quantitative PCR
The total RNA of the peripheral blood mononuclear cells obtained in example 2 was subjected to reverse transcription, respectively, and the NONHSAT016936.2 gene, the DANCR gene, and the miR-146a-3p gene were subjected to fluorescent quantitative PCR by using primer pairs SQ1 and SQ2, primer pairs SQ3 and SQ4, and primer pairs SQ5 and SQ6, respectively, to detect the gene expression of NONHSAT016936.2, DANCR and miR-146a-3p in osteoarthritis patients and healthy control groups
The gene expression results of NONHSAT016936.2, DANCR and miR-146a-3p in the 36 healthy control groups and the 115 OA patient groups are shown in Table 1, and the expression amounts of NONHSAT016936.2, DANCR and miR-146a-3p in peripheral blood mononuclear cells of the healthy control groups and the OA patients are obviously different.
TABLE 1
Example 4
Further, 115 patients with confirmed knee joint OA were classified into stages I to IV based on X-ray films of the patient, i.e., according to the Kellgren and Lawrence metrics, with OA severity levels,
(1) Class I patients 28 cases (joint cavity gap not less than 6mm and bone formation on joint surface);
(2) 36 patients with class II (with osteophytes and joint cavity gap between 3 and 6 mm);
(3) Class III patients 27 (with osteophytes and joint space less than or equal to 3 mm);
(4) Class IV patients had bone tag and the joint space disappeared in 24 cases.
In 115 cases of patients with OA, the expression level of NONHSAT016936.2 gene was gradually increased and the expression levels of DANCR and miR-146a-3p genes were decreased as shown in Table 2.
TABLE 2
EXAMPLE 5 change of expression levels of NONHSAT016936.2, DANCR and miR-146a-3p in high-risk group of OA before and after follow-up
The patient is told to take more than 3 months of knee pain without obvious imaging change and eliminating OA high risk group of other related diseases such as rheumatism and rheumatoid, only 42 patients successfully obtain follow-up data after 24-38 months (average 33.4 months), and take X-ray film again to carry out OA diagnosis. Follow-up tests demonstrated that 18 were diagnosed with OA grade I by re-diagnosis, OAII grade by 2, P20 by 20 and N22 by the remaining undiagnosed OA. The method for collecting peripheral blood mononuclear cells of 42 patients, extracting and separating total RNA of peripheral blood mononuclear cells and performing fluorescence quantitative PCR are the same as the method for collecting peripheral blood mononuclear cells, obtaining the change of the expression levels of NONHSAT016936.2, DANCR and miR-146a-3p of 42 OA high-risk group before and after follow-up, and the results are shown in Table 3.
TABLE 3 Table 3
Wherein the average expression level of NONHSAT016936.2, DANCR and miR-146a-3p in 42 cases of OA high-risk groups is 12.36, 14.73 and 15.09 respectively. NONHSAT016936.2 and miR-146a-3p indexes, except that the average expression level of DANCR was 14.73 and OA I grade J, were between those of the healthy group and the OA group in example 2.
As shown in Table 3, the NONHSAT016936.2 content of the P20 group was higher than that of the N22 group before the follow-up, and the NONHSAT016936.2 expression level of the P20 group was gradually increased with the progress of time, but the NONHSAT016936.2 expression level of the N22 group was not significantly changed. The NONHSAT016936.2 expression level of the P20 group is significantly higher than that of the N22 group after follow-up. In contrast, before the follow-up, the expression levels of DANCR and miR-146a-3P in the P20 group were lower than those in the N22 group, and as time progressed, the expression levels of DANCR and miR-146a-3P in the P20 group were gradually decreased, but the expression levels of DANCR and miR-146a-3P in the N22 group were not significantly changed. All 3 indices have diagnostic value in early warning of OA sub-clinical patients.
ROC analysis
Setting the group P20 sample as 1 and the group N22 sample as 0, and obtaining a logistic regression equation through a logistic regression analysis method: logit (P) =85.157+7.820 (NONHSAT 016936.2) -11.140 (DANCR) -10.603 (miR-146 a-3P). The left constant term of the equation was truncated and divided by the coefficient 7.820 of NONHSAT016936.2 to give the joint predictor = NONHSAT016936.2-1.425 (DANCR) -1.356 (miR-146 a-3 p). ROC curve analysis was performed with NONHSAT016936.2, DANCR, miR-146a-3p and joint predictor (combination), respectively. The results are shown in Table 4.
TABLE 4 ROC Curve analysis
The analysis result shows that the COMP combined non-coding RNA multi-index combined detection can improve the sensitivity and specificity of single index for early screening of OA sub-clinical crowd, and has better clinical application value.
The present invention is not limited to the above-mentioned embodiments, but is intended to be limited to the following embodiments, and any modifications, equivalents and modifications can be made to the above-mentioned embodiments without departing from the scope of the invention.

Claims (8)

1. Use of a reagent for detecting expression of non-coding RNAs in the preparation of an early diagnosis detection product for osteoarthritis, wherein the non-coding RNAs are the NONHSAT016936.2, DANCR and miR-146a-3p genes.
2. The use according to claim 1, wherein the detection product is for detecting the expression level of the NONHSAT016936.2, DANCR and miR-146a-3p genes in the sample by reverse transcription PCR, fluorescent quantitative PCR, in situ hybridization, chip or high throughput sequencing platform.
3. The use according to claim 2, characterized in that the detection product comprises primers and/or probes capable of specifically amplifying the NONHSAT016936.2, DANCR and miR-146a-3p genes.
4. The use according to claim 3, wherein the primer pair sequences for specifically amplifying the NONHSAT016936.2 gene are: SQ1:5'-CGCCCAGGAACATGGTAACAC-3', SQ2:5'-GCCAAGGCTGTGACACAAGAG-3'.
5. The use according to claim 3, wherein the primer pair sequence for specifically amplifying the DANCR gene is SQ3:5'-AGCGCAGGTTGACAACTACAG-3' or 5'-AGCGCAGAGTTTCATCACCTC-3', SQ4:5'-CTGCAGCTTGGGTGTGTATTC-3'.
6. The use according to claim 3, wherein the primer pair sequence for specifically amplifying miR-146a-3p gene is: SQ5:5'-GACGGGCCTCTGAAATTCAG-3', SQ6:5'-CAGTGCAGGGTCCGAGGTAT-3'.
7. The use according to claim 2, wherein the sample is peripheral blood.
8. The use of claim 1, wherein the test product comprises a chip, a kit, a test strip or a high throughput sequencing platform.
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WO2019229489A1 (en) * 2018-05-31 2019-12-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of mir-146a-5p and mir-186 as biomarkers of osteoarthritis
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Lei Zhang等.Long non-coding RNA DANCR regulates proliferation and apoptosis of chondrocytes in osteoarthritis via miR-216a-5p-JAK2-STAT3 axis.《Bioscience Reports》.2018,第38卷(第6期),第1-11页. *
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