CN111876478A - Pulmonary nodule diagnostic marker and application - Google Patents
Pulmonary nodule diagnostic marker and application Download PDFInfo
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6884—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from lung
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/12—Pulmonary diseases
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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
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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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
- G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis
Abstract
The invention discloses a pulmonary nodule diagnostic marker and application thereof, belonging to the technical field of biotechnology detection. The invention provides application of one or more of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 genes as biomarker molecules for diagnosing pulmonary sarcoidosis, wherein the markers can be used for assisting in biopsy and helping to diagnose related pulmonary diseases, and the genes for identifying sarcoidosis provided by the invention have the accuracy (area under ROC curve) of distinguishing healthy people, patients with lung adenocarcinoma and patients with pulmonary tuberculosis of 96.5%, 90.9%, 89.1%, 87.5%, 87.2% and 85.8% in sequence, and the comprehensive accuracy is 90.9%. The invention collects a certain amount of clinical samples for research and verification, the research result accords with the clinical practice, and the invention has good clinical application prospect.
Description
Technical Field
The invention relates to a pulmonary nodule diagnostic marker and application thereof, in particular to development of products such as a kit for diagnosing pulmonary nodule disease by utilizing a lung tissue sample of a patient, and belongs to the technical field of biotechnology detection.
Background
Pulmonary nodules (sarcodosis) are granulomatous diseases with unknown causes, multiple systems and multiple organs, often invade organs such as lung, bilateral pulmonary lymph nodes, eyes and skin, and have a breast invasion rate as high as 80-90%. Clinically, pulmonary nodules have very similar symptoms, pathological features, and imaging results to many other chronic lung diseases, such as lung cancer and tuberculosis, which pose a significant challenge to differential diagnosis. Lung cancer is the most lethal cancer of human, and the number of deaths caused by lung cancer in 2018 is more than 170 thousands. Among them, lung adenocarcinoma (lung adenocarinoma) is one of the most common lung cancer subtypes. Sarcoidosis is an autoimmune disease with unclear etiology, often occurring in the lungs, forming granulomatous (granuloma) structures similar to the characteristics of tuberculosis, causing misdiagnosis. Tuberculosis, adenocarcinoma of lung and pulmonary sarcoidosis are common chronic inflammatory lung diseases widely distributed at home and abroad, so that specific biomarker molecules of the diseases are screened and applied to the development of related differential diagnosis kits, and the method has important significance for timely diagnosis and treatment of the diseases.
Clinically, the differential diagnosis of the above diseases is usually performed by biopsy, and the diagnosis is determined by the characteristics of histopathology. However, as mentioned above, tuberculosis, adenocarcinoma of the lung and sarcoidosis are in many cases not easily distinguishable and effective disease-specific lung tissue biomarkers are needed for the auxiliary detection and diagnosis.
Disclosure of Invention
The invention provides a specific lung tissue biomarker molecule aiming at the pulmonary sarcoidosis, can distinguish the diseases by simple immunohistochemical staining or real-time fluorescence quantification and other methods, and is very suitable for the development of detection, diagnosis and identification kits for related diseases.
The first purpose of the invention is to provide application of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 and AKR1C3 as diagnostic markers of the pulmonary sarcoidosis, alone or in combination.
In one embodiment, the use is of a gene fragment specifically amplifying PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 or AKR1C3 for the preparation of a kit for aiding in the diagnosis of pulmonary sarcoidosis, or for detecting the presence of pulmonary sarcoidosis, or for selecting an agent for reducing the risk of a patient developing pulmonary sarcoidosis, or for identifying in vitro a candidate agent for treating pulmonary sarcoidosis, or for evaluating the likelihood of a patient benefiting from treatment with an agent for reducing the risk of pulmonary sarcoidosis, or for evaluating the likelihood of a patient benefiting from treatment with an antibody or antigen-binding fragment that reduces the risk of pulmonary sarcoidosis.
In one embodiment, the PTGER4 has the nucleotide sequence shown in SEQ ID No. 1; the nucleotide sequence of the AKR1C1 is shown as SEQ ID NO. 2; the nucleotide sequence of the PLA2G6 is shown as SEQ ID NO. 3; the LTA4H has a nucleotide sequence shown in SEQ ID NO. 4; the nucleotide sequence of the PLA2G7 is shown as SEQ ID NO. 5; the nucleotide sequence of the AKR1C3 is shown in SEQ ID NO. 6.
In one embodiment, the detection product comprises primers and/or probes capable of specifically amplifying the PTGER4 gene; the primer sequences are AGGGCTATCATCATCCTACAACTCA and TAGGTCTTCGCAGCCATCAAG.
In one embodiment, the test product comprises primers and/or probes capable of specifically amplifying the AKR1C1 gene; the primer sequences are TTCATGCCTGTCCTGGGATTT and CTGGCTTTACAGACACTGGAAAA.
In one embodiment, the test product comprises primers and/or probes capable of specifically amplifying the PLA2G6 gene; the primer sequences are TTTGGCCGCCTGGTCAATAC and CTCCCGAACTCGGTCACTC.
In one embodiment, the assay product comprises primers and/or probes capable of specifically amplifying the LTA4H gene; the primer sequences are AGACAAAGTTACAAGGGATCGC and AGATATGGGTGTTCCTTCCCAG.
In one embodiment, the test product comprises primers and/or probes capable of specifically amplifying the PLA2G7 gene; the primer sequences are TCATCAGCATGGGTCAACAAAA and CCAAAGGGTGTCAAGGCGAT.
In one embodiment, the test product comprises primers and/or probes capable of specifically amplifying the AKR1C3 gene; the primer sequences are GTCATCCGTATTTCAACCGGAG and CCACCCATCGTTTGTCTCGTT.
In one embodiment, levels of mRNA of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H, PTGER4 are evaluated using ACTB and 18S rRNA as reference genes.
In one embodiment, the primers specific for ACTB are CATGTACGTTGCTATCCAGGC and CTCCTTAATGTCACGCACGAT.
In one embodiment, the 18S rRNA specific primers are CGAACGTCTGCCCTATCAACT and ACCCGTGGTCACCATGGTAG.
The second purpose of the invention is to provide the application of the reagent for detecting the marker in preparing a pulmonary sarcoidosis detection product.
In one embodiment, the reagent comprises a PCR amplification primer used in detecting the expression level of the marker using SYBR Green, TaqMan probes, molecular beacons, two-hybrid probes, or multiplex probes.
In one embodiment, the assay product detects expression of at least one gene selected from PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7, and AKR1C3 in a sample by quantitative fluorescence PCR, Southern hybridization, Northern hybridization, fluorescent in situ hybridization, DNA microarray, high throughput sequencing, and immunoassay.
In one embodiment, the immunological method comprises ELISA, radioimmunoassay, immunohistochemistry, Western blot.
In one embodiment, the test product comprises primers and/or probes capable of specifically amplifying at least one gene of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7, or AKR1C 3; or an antibody capable of specifically binding to the corresponding protein.
In one embodiment, the sample is tissue or peripheral blood.
In one embodiment, the test product comprises a diagnostic reagent, a kit, a chip, a strip or a high throughput sequencing platform.
In one embodiment, the chip comprises a nucleic acid or antibody that binds to the marker or its DNA sequence.
In one embodiment, the strip comprises a nucleic acid or antibody that binds to the marker or its DNA sequence.
In one embodiment, the high throughput sequencing platform comprises a nucleic acid or antibody that binds to the marker or its DNA sequence.
In one embodiment, the kit comprises a nucleic acid or antibody that binds to the marker or its DNA sequence.
In some embodiments, the kit can include a DNA extraction reagent and a bisulfite reagent.
In some embodiments, DNA extraction reagents may include a lysis buffer, a binding buffer, a wash buffer, and an elution buffer; the lysis buffer typically consists of protein denaturants, detergents, pH buffers and nuclease inhibitors; the binding buffer typically consists of a protein denaturant and a pH buffer. The washing buffer solution is divided into a washing buffer solution A and a washing buffer solution B: the washing buffer solution A consists of a protein denaturant, a nuclease inhibitor, a detergent, a pH buffer and ethanol; the washing buffer solution B consists of a nuclease inhibitor, a pH buffer and ethanol; the elution buffer typically consists of a nuclease inhibitor and a pH buffer.
In one embodiment, the protein denaturant is selected from one or more of guanidinium isothiocyanate, guanidinium hydrochloride, and urea; the detergent is selected from one or more of Tween20, IGEPAL CA-630, Triton X-100, NP-40 and SDS; the pH buffering agent is selected from one or more of Tris, boric acid, phosphate, MES and HEPES; the nuclease inhibitor is selected from one or more of EDTA, EGTA and DEPC.
In one embodiment, the bisulfite reagent includes a bisulfite buffer and a protection buffer; wherein the bisulfite is selected from one or more of sodium bisulfite, sodium sulfite, sodium bisulfite, ammonium bisulfite and ammonium sulfite; the protective buffer solution consists of an oxygen radical scavenger, and the oxygen radical scavenger is one or more selected from hydroquinone, vitamin E derivatives, gallic acid, Trolox, trihydroxybenzoic acid and trihydroxybenzoic acid derivatives.
The invention also provides a method for detecting the pulmonary sarcoidosis, which comprises the following steps:
(1) obtaining a lung tissue sample to be detected of a subject;
(2) detecting the expression level of the aforementioned marker in the ex vivo sample obtained in step (1);
(3) comparing the expression level of the marker measured in step (2) with a control.
In one embodiment, an expression level of PLA2G6 that is more than 2.851 times that of the control, or an expression level of PLA2G7 that is more than 3.347 times that of the control, or an expression level of AKR1C1 that is more than 9.366 times that of the control, or an expression level of AKR1C3 that is more than 5.588 times that of the control, or an expression level of LTA4H that is more than 3.132-7.494 times that of the control, or an expression level of PTGER4 that is more than 4.699 times that of the control, or an expression level of the above genes in total that is more than 7.677 times that of the control is considered as having lung nodules.
The invention also claims the use of the diagnostic marker for screening a medicament for reducing the risk of pulmonary sarcoidosis, or for screening an agent for reducing the risk of pulmonary sarcoidosis.
In one embodiment, the screening is performed by an ex vivo assay.
Has the advantages that: the genes PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 for identifying the sarcoidosis have the accuracy (area under the ROC curve) of 0.965, 0.909, 0.891, 0.875, 0.872 and 0.858 in sequence and the comprehensive accuracy of 0.909. The invention collects a certain amount of clinical samples for research and verification, the research result accords with the clinical practice, and the invention has good clinical application prospect.
Drawings
FIG. 1 shows the results of qPCR analysis of the difference in marker expression levels in different samples; (A) PLA2G6mRNA, (B) PLA2G7mRNA, (C) AKR1C1mRNA, (D) AKR1C3mRNA, (E) LTA4H mRNA, and (F) PTGER4 mRNA; NC, normal lung tissue sample set; TB, pulmonary tissue sample group of tuberculosis patients; AD, lung tissue sample group of lung adenocarcinoma patients; SA, lung tissue sample group of patients with pulmonary sarcoidosis.
FIG. 2(A) is a redundant analysis (RDA) of the expression levels of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 in various samples; (B) the method is characterized in that the method is characterized by comprising the following steps of (1) analyzing an operation characteristic curve (ROC) of the expression quantity of genes PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 in various samples; NC, normal lung tissue sample set; TB, pulmonary tissue sample group of tuberculosis patients; AD, lung tissue sample group of lung adenocarcinoma patients; SA, lung tissue sample group of patients with pulmonary sarcoidosis.
FIG. 3 shows the expression of different genes in lung tissues of patients with pulmonary sarcoidosis, patients with pulmonary tuberculosis and patients with lung adenocarcinoma; (A) PLA2G4A mRNA; (B) PLA2G4B mRNA; (C) PLA2G4C mRNA; (D) PLA2G4 DmRNA; (E) PLA2G4E mRNA; (F) PLA2G4F mRNA; (G) PTGS1 mRNA; (H) PTGS2 mRNA; (I) ALOX5 mRNA; (J) ALOX12B mRNA; (K) ALOX15B mRNA; (L), AKR1B1 mRNA; (M), AKR1C2 mRNA; (N), CBR1 mRNA; (O), PTGES mRNA; (P), PTGES2 mRNA; (Q), PTGES3 mRNA; (R), LTC4S mRNA; (S), GGT1 mRNA; (T), DPEP1 mRNA; (U), PTGDR mRNA; (V), PTGDR2 mRNA; (W), GLRA3 mRNA; (X), PTGER1 mRNA; (Y), PTGER2 mRNA; (Z), PTGER3 mRNA; (AA), PTGFR mRNA; (AB), FPR2 mRNA; (AC), GPR32 mRNA; (AD) LTB4R mRNA; (AE), LTB4R2 mRNA; (AF), CYSLTR1 mRNA; (AG), CYSLTR2 mRNA; NC, normal lung tissue sample set; TB, pulmonary tissue sample group of tuberculosis patients; AD, lung tissue sample group of lung adenocarcinoma patients; SA, lung tissue sample group of patients with pulmonary sarcoidosis.
Detailed Description
In the context of the present invention, "diagnosing" includes determining whether a subject has suffered a disease, determining whether a subject is at risk of suffering a disease, determining whether a patient has relapsed, determining the responsiveness of a patient to a drug treatment, or determining the prognosis of a patient.
In the context of the present invention, the term "marker" as used herein means a label that allows to distinguish between normal and disease states, or enables the treatment outcome to be predicted or objectively measured. In particular, in the context associated with the disease, a marker means an organic biomolecule, such as a polypeptide or nucleic acid (e.g., mRNA, etc.), a lipid, glycolipid, glycoprotein, sugar (mono-, di-, oligo-, etc.), that has a significantly increased or decreased level of protein or gene expression in a subject with, or at risk of developing, pulmonary sarcoidosis compared to a normal control (a subject not suffering from the corresponding disease).
Example 1mRNA levels of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 and AKR1C3 were significantly elevated in diseased lung tissue from patients with pulmonary sarcoidosis
1) Lung tissue samples (n ═ 35,48, and 21) from tuberculosis patients (TB), adenocarcinoma lung patients (AD), and Sarcoidosis (SA) patients to be tested were obtained, and paracancerous normal tissues from adenocarcinoma lung patients were used as normal lung tissue controls (NC; n-40).
2) Lung tissue samples were milled, mRNA extracted and purified using RNeasy Plus Mini Kit (Qiagen), and subsequently used
III 1st Strand cDNASynthesis SuperMix (Yeasen) kit was reverse transcribed to generate cDNA.
3) The cDNA samples were subjected to qPCR analysis using an Applied Biosystems 7500Real-Time PCR system to detect mRNA levels of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER 4. ACTB and 18S rRNA were used as reference genes. The primers used were as follows:
TABLE 1 primers for amplifying marker genes
4) The correlation of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 with each group of samples was determined by performing Redundancy Analysis (RA) using two R language packages, R package of randomForest 4.6.14 and The R package of vegan 2.5.6.
5) PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 and AKR1C3 were analyzed using IBM SPSS statics 22.0 software as differential diagnostic markers for pulmonary sarcoidosis to distinguish the areas under the ROC curve for healthy, adenocarcinoma and tuberculosis patients.
As shown in fig. 1, it can be seen from the box plot that the mRNA levels of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 were significantly increased in the SA group, but not significantly changed in the TB and AD groups, compared to the NC group. PLA2G6 expression level was 8.981. + -. 2.939 (mean. + -. standard error), 2.851-15.11 (95% confidence interval); PLA2G7 expression level was 7.937 ± 2.201 (mean ± sem), 3.347-12.53 (95% confidence interval); AKR1C1 expression level of 17.02 + -3.671 (mean deviation + -SE), 9.366-24.68 (95% confidence interval); AKR1C3 expression level 8.475 + -1.384 (mean deviation + -SE), 5.588-11.36 (95% confidence interval); LTA4H expression was 5.313. + -. 1.046 (mean. + -. standard error), 3.132-7.494 (95% confidence interval); the expression level of PTGER4 was 11.91. + -. 3.459 (mean. + -. standard error), 4.699-19.13 (95% confidence interval); total expression (6 gene expression values added to each sample averaged) 9.941. + -. 1.085 (mean. + -. standard error), 7.677-12.2 (95% confidence interval).
As shown in FIG. 2A, the direction of the arrow indicates that the expression level of each marker is positively correlated with the sample, and the length of the arrow indicates the intensity of the correlation. As can be seen from the figure, PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 are in positive correlation with the samples of the SA group, but in negative correlation or weak correlation with the samples of the other groups.
As shown in fig. 2B, the ability of PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 as differential diagnostic markers for pulmonary sarcoidosis was evaluated using a subject working characteristic curve (ROC curve) and area under line (AUC) for 0.965, 0.909, 0.891, 0.875, 0.872 and 0.858, in order, and a combined AUC of 0.909, to differentiate healthy subjects, patients with lung adenocarcinoma and patients with tuberculosis. The results suggest that PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H and PTGER4 have higher diagnostic ability as biomarkers.
EXAMPLE 2 preparation and use of the detection kit
Nucleotide sequences shown in Table 1 were synthesized as primers for amplifying reference genes and markers.
For ease of use, the kit may further comprise controls: cDNA sequence of normal human lung tissue samples.
The using method of the kit comprises the following steps: taking a lung tissue sample of a subject, extracting RNA from the lung tissue sample by using a conventional method (or using a specific kit), using a reagent in a detection kit, using a cDNA sequence of a normal lung tissue sample in the kit as a control cDNA in Real-Time PCR quantitative detection, and detecting the relative expression change of at least one gene in the lung tissue of the subject such as SEQ ID No. 1-6.
The expression level of PLA2G6 is more than 2.851 times of that of a control, or the expression level of PLA2G7 is more than 3.347 times of that of the control, or the expression level of AKR1C1 is more than 9.366 times of that of the control, or the expression level of AKR1C3 is more than 5.588 times of that of the control, or the expression level of LTA4H is more than 3.132-7.494 times of that of the control, or the expression level of PTGER4 is more than 4.699 times of that of the control, or the total expression level of the genes is more than 7.677 times of that of the control, the lung nodule is considered to be suffered.
Example 3 use of markers in clinical diagnostics
A plurality of subjects were tested according to the method of example 1, and the results of the tests were compared with those of the current diagnostic methods (e.g., blood test, sarcoidosis antigen test, biopsy, pulmonary X-ray, chest computed tomography, etc.). The results show that the diagnosis results obtained by the detection of the diagnosis marker of the application are consistent with the pathological diagnosis results.
Comparative example
Following the same strategy as in example 1, primers were also designed to detect mRNA levels of genes encoding other major enzymes and receptors in the arachidonic acid metabolism (arachidonic acid metabolism) pathway, in addition to PLA2G6, PLA2G7, AKR1C1, AKR1C3, LTA4H, and PTGER4, respectively. The primers used were as follows:
TABLE 2 primers for amplification of different genes
As shown in FIG. 3, the expression levels of these genes were not as specific as those of the 6 genes selected in example 1 in the lung of patients with pulmonary sarcoidosis.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
SEQUENCE LISTING
<110> institute of microbiology of Chinese academy of sciences
<120> pulmonary nodule diagnostic marker and application
<160>18
<170>PatentIn version 3.3
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tacacttcaa agctttggtg caattcccat cgaccagagt tggtccgacc agccttggaa 300
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ctacagcgtg gggttgtggt cctggccaag agctacaatg agcagcgcat cagacagaac 840
gtgcaggtgt ttgaattcca gttgacttca gaggagatga aagccataga tggcctaaac 900
agaaatgtgc gatatttgac ccttgatatt tttgctggcc cccctaatta tccattttct 960
gatgaatatt aa 972
<210>3
<211>2421
<212>DNA
<213>Homo sapiens
<400>3
atgcagttct ttggccgcct ggtcaatacc ttcagtggcg tcaccaactt gttctctaac 60
ccattccggg tgaaggaggt ggctgtggcc gactacacct cgagtgaccg agttcgggag 120
gaagggcagc tgattctgtt ccagaacact cccaaccgca cctgggactg cgtcctggtc 180
aaccccagga actcacagag tggattccga ctcttccagc tggagttgga ggctgacgcc 240
ctagtgaatt tccatcagta ttcttcccag ctgctaccct tctatgagag ctcccctcag 300
gtcctgcaca ctgaggtcct gcagcacctg accgacctca tccgtaacca ccccagctgg 360
tcagtggccc acctggctgt ggagctaggg atccgcgagt gcttccatca cagccgtatc 420
atcagctgtg ccaattgcgc ggagaacgag gagggctgca cacccctgca cctggcctgc 480
cgcaagggtg atggggagat cctggtggag ctggtgcagt actgccacac tcagatggat 540
gtcaccgact acaagggaga gaccgtcttc cattatgctg tccagggtga caattctcag 600
gtgctgcagc tccttggaag gaacgcagtg gctggcctga accaggtgaa taaccaaggg 660
ctgaccccgc tgcacctggc ctgccagctg gggaagcagg agatggtccg cgtgctgctg 720
ctgtgcaatg ctcggtgcaa catcatgggc cccaacggct accccatcca ctcggccatg 780
aagttctctc agaaggggtg tgcggagatg atcatcagca tggacagcag ccagatccac 840
agcaaagacc cccgttacgg agccagcccc ctccactggg ccaagaacgc agagatggcc 900
cgcatgctgc tgaaacgggg ctgcaacgtg aacagcacca gctccgcggg gaacacggcc 960
ctgcacgtgg cggtgatgcg caaccgcttc gactgtgcca tagtgctgct gacccacggg 1020
gccaacgcgg atgcccgcgg agagcacggc aacaccccgc tgcacctggc catgtcgaaa 1080
gacaacgtgg agatgatcaa ggccctcatc gtgttcggag cagaagtgga caccccgaat 1140
gactttgggg agactcctac attcctagcc tccaaaatcg gcagacttgt caccaggaag 1200
gcgatcttga ctctgctgag aaccgtgggg gccgaatact gcttcccacc catccacggg 1260
gtccccgcgg agcagggctc tgcagcgcca catcatccct tctccctgga aagagctcag 1320
cccccaccga tcagcctaaa caacctagaa ctacaggatc tcatgcacat ctcacgggcc 1380
cggaagccag cgttcatcct gggctccatg agggacgaga agcggaccca cgaccacctg 1440
ctgtgcctgg atggaggagg agtgaaaggc ctcatcatca tccagctcct catcgccatc 1500
gagaaggcct cgggtgtggc caccaaggac ctgtttgact gggtggcggg caccagcact 1560
ggaggcatcc tggccctggc cattctgcac agtaagtcca tggcctacat gcgcggcatg 1620
tactttcgca tgaaggatga ggtgttccgg ggctccaggc cctacgagtc ggggcccctg 1680
gaggagttcc tgaagcggga gtttggggag cacaccaaga tgacggacgt caggaaaccc 1740
aaggtgatgc tgacagggac actgtctgac cggcagccgg ctgaactcca cctcttccgg 1800
aactacgatg ctccagaaac tgtccgggag cctcgtttca accagaacgt taacctcagg 1860
cctccagctc agccctcaga ccagctggtg tggcgggcgg cccgaagcag cggggcagct 1920
cctacttact tccgacccaa tgggcgcttc ctggacggtg ggctgctggc caacaacccc 1980
acgctggatg ccatgaccga gatccatgag tacaatcagg acctgatccg caagggtcag 2040
gccaacaagg tgaagaaact ctccatcgtt gtctccctgg ggacagggag gtccccacaa 2100
gtgcctgtga cctgtgtgga tgtcttccgt cccagcaacc cctgggagct ggccaagact 2160
gtttttgggg ccaaggaact gggcaagatg gtggtggact gttgcacgga tccagacggg 2220
cgggctgtgg accgggcacg ggcctggtgc gagatggtcg gcatccagta cttcagattg 2280
aacccccagc tggggacgga catcatgctg gatgaggtca gtgacacagt gctggtcaac 2340
gccctctggg agaccgaggt ctacatctat gagcaccgcg aggagttcca gaagctcatc 2400
cagctgctgc tctcaccctg a 2421
<210>4
<211>1836
<212>DNA
<213>Homo sapiens
<400>4
atgcccgaga tagtggatac ctgttcgttg gcctctccgg cttccgtctg ccggaccaag 60
cacctgcacc tgcgctgcag cgtcgacttt actcgccgga cgctgaccgg gactgctgct 120
ctcacggtcc agtctcagga ggacaatctg cgcagcctgg ttttggatac aaaggacctt 180
acaatagaaa aagtagtgat caatggacaa gaagtcaaat atgctcttgg agaaagacaa 240
agttacaagg gatcgccaat ggaaatctct cttcctatcg ctttgagcaa aaatcaagaa 300
attgttatag aaatttcttt tgagacctct ccaaaatctt ctgctctcca gtggctcact 360
cctgaacaga cttctgggaa ggaacaccca tatctcttta gtcagtgcca ggccatccac 420
tgcagagcaa tccttccttg tcaggacact ccttctgtga aattaaccta tactgcagag 480
gtgtctgtcc ctaaagaact ggtggcactt atgagtgcta ttcgtgatgg agaaacacct 540
gacccagaag acccaagcag gaaaatatac aaattcatcc aaaaagttcc aataccctgc 600
tacctgattg ctttagttgt tggagcttta gaaagcaggc aaattggccc aagaactttg 660
gtgtggtctg agaaagagca ggtggaaaag tctgcttatg agttttctga gactgaatct 720
atgcttaaaa tagcagaaga tctgggagga ccgtatgtat ggggacagta tgacctattg 780
gtcctgccac catccttccc ttatggtggc atggagaatc cttgccttac ttttgtaact 840
cctactctac tggcaggcga caagtcactc tccaatgtca ttgcacatga aatatctcat 900
agctggacag ggaatctagt gaccaacaaa acttgggatc acttttggtt aaatgaggga 960
catactgtgt acttggaacg ccacatttgc ggacgattgt ttggtgaaaa gttcagacat 1020
tttaatgctc tgggaggatg gggagaacta cagaattcgg taaagacatt tggggagaca 1080
catcctttca ccaaacttgt ggttgatctg acagatatag accctgatgt agcttattct 1140
tcagttccct atgagaaggg ctttgcttta cttttttacc ttgaacaact gcttggagga 1200
ccagagattt tcctaggatt cttaaaagct tatgttgaga agttttccta taagagcata 1260
actactgatg actggaagga tttcctgtat tcctatttta aagataaggt tgatgttctc 1320
aatcaagttg attggaatgc ctggctctac tctcctggac tgcctcccat aaagcccaat 1380
tatgatatga ctctgacaaa tgcttgtatt gccttaagtc aaagatggat tactgccaaa 1440
gaagatgatt taaattcatt caatgccaca gacctgaagg atctctcttc tcatcaattg 1500
aatgagtttt tagcacagac gctccagagg gcacctcttc cattggggca cataaagcga 1560
atgcaagagg tgtacaactt caatgccatt aacaattctg aaatacgatt cagatggctg 1620
cggctctgca ttcaatccaa gtgggaggac gcaattcctt tggcgctaaa gatggcaact 1680
gaacaaggaa gaatgaagtt tacccggccc ttattcaagg atcttgctgc ctttgacaaa 1740
tcccatgatc aagctgtccg aacctaccaa gagcacaaag caagcatgca tcccgtgact 1800
gcaatgctgg tggggaaaga cttaaaagtg gattaa 1836
<210>5
<211>1326
<212>DNA
<213>Homo sapiens
<400>5
atggtgccac ccaaattgca tgtgcttttc tgcctctgcg gctgcctggc tgtggtttat 60
ccttttgact ggcaatacat aaatcctgtt gcccatatga aatcatcagc atgggtcaac 120
aaaatacaag tactgatggc tgctgcaagc tttggccaaa ctaaaatccc ccggggaaat 180
gggccttatt ccgttggttg tacagactta atgtttgatc acactaataa gggcaccttc 240
ttgcgtttat attatccatc ccaagataat gatcgccttg acaccctttg gatcccaaat 300
aaagaatatt tttggggtct tagcaaattt cttggaacac actggcttat gggcaacatt 360
ttgaggttac tctttggttc aatgacaact cctgcaaact ggaattcccc tctgaggcct 420
ggtgaaaaat atccacttgt tgttttttct catggtcttg gggcattcag gacactttat 480
tctgctattg gcattgacct ggcatctcat gggtttatag ttgctgctgt agaacacaga 540
gatagatctg catctgcaac ttactatttc aaggaccaat ctgctgcaga aataggggac 600
aagtcttggc tctaccttag aaccctgaaa caagaggagg agacacatat acgaaatgag 660
caggtacggc aaagagcaaa agaatgttcc caagctctca gtctgattct tgacattgat 720
catggaaagc cagtgaagaa tgcattagat ttaaagtttg atatggaaca actgaaggac 780
tctattgata gggaaaaaat agcagtaatt ggacattctt ttggtggagc aacggttatt 840
cagactctta gtgaagatca gagattcaga tgtggtattg ccctggatgc atggatgttt 900
ccactgggtg atgaagtata ttccagaatt cctcagcccc tcttttttat caactctgaa 960
tatttccaat atcctgctaa tatcataaaa atgaaaaaat gctactcacc tgataaagaa 1020
agaaagatga ttacaatcag gggttcagtc caccagaatt ttgctgactt cacttttgca 1080
actggcaaaa taattggaca catgctcaaa ttaaagggag acatagattc aaatgtagct 1140
attgatctta gcaacaaagc ttcattagca ttcttacaaa agcatttagg acttcataaa 1200
gattttgatc agtgggactg cttgattgaa ggagatgatg agaatcttat tccagggacc 1260
aacattaaca caaccaatca acacatcatg ttacagaact cttcaggaat agagaaatac 1320
aattag 1326
<210>6
<211>972
<212>DNA
<213>Homo sapiens
<400>6
atggattcca aacaccagtg tgtaaagcta aatgatggcc acttcatgcc tgtattggga 60
tttggcacct atgcacctcc agaggttccg agaagtaaag ctttggaggt cacaaaatta 120
gcaatagaag ctgggttccg ccatatagat tctgctcatt tatacaataa tgaggagcag 180
gttggactgg ccatccgaag caagattgca gatggcagtg tgaagagaga agacatattc 240
tacacttcaa agctttggtc cacttttcat cgaccagagt tggtccgacc agccttggaa 300
aactcactga agaaagctca attggactat gttgacctct atcttattca ttctccaatg 360
tctctaaagc caggtgagga actttcacca acagatgaaa atggaaaagt aatatttgac 420
atagtggatc tctgtaccac ctgggaggcc atggagaagt gtaaggatgc aggattggcc 480
aagtccattg gggtgtcaaa cttcaaccgc aggcagctgg agatgatcct caacaagcca 540
ggactcaagt acaagcctgt ctgcaaccag gtagaatgtc atccgtattt caaccggagt 600
aaattgctag atttctgcaa gtcgaaagat attgttctgg ttgcctatag tgctctggga 660
tctcaacgag acaaacgatg ggtggacccg aactccccgg tgctcttgga ggacccagtc 720
ctttgtgcct tggcaaaaaa gcacaagcga accccagccc tgattgccct gcgctaccag 780
ctgcagcgtg gggttgtggt cctggccaag agctacaatg agcagcgcat cagacagaac 840
gtgcaggttt ttgagttcca gttgactgca gaggacatga aagccataga tggcctagac 900
agaaatctcc actattttaa cagtgatagt tttgctagcc accctaatta tccatattca 960
gatgaatatt aa 972
<210>7
<211>25
<212>DNA
<213> Artificial sequence
<400>7
agggctatca tcatcctaca actca 25
<210>8
<211>21
<212>DNA
<213> Artificial sequence
<400>8
taggtcttcg cagccatcaa g 21
<210>9
<211>21
<212>DNA
<213> Artificial sequence
<400>9
ttcatgcctg tcctgggatt t 21
<210>10
<211>23
<212>DNA
<213> Artificial sequence
<400>10
ctggctttac agacactgga aaa 23
<210>11
<211>20
<212>DNA
<213> Artificial sequence
<400>11
tttggccgcc tggtcaatac 20
<210>12
<211>19
<212>DNA
<213> Artificial sequence
<400>12
ctcccgaact cggtcactc 19
<210>13
<211>22
<212>DNA
<213> Artificial sequence
<400>13
agacaaagtt acaagggatc gc 22
<210>14
<211>22
<212>DNA
<213> Artificial sequence
<400>14
agatatgggt gttccttccc ag 22
<210>15
<211>22
<212>DNA
<213> Artificial sequence
<400>15
tcatcagcat gggtcaacaa aa 22
<210>16
<211>20
<212>DNA
<213> Artificial sequence
<400>16
ccaaagggtg tcaaggcgat 20
<210>17
<211>22
<212>DNA
<213> Artificial sequence
<400>17
gtcatccgta tttcaaccgg ag 22
<210>18
<211>21
<212>DNA
<213> Artificial sequence
<400>18
ccacccatcg tttgtctcgt t 21
Claims (10)
1. The application of amplifying one or more gene segments of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 and AKR1C3 in preparing a product for detecting and/or diagnosing the pulmonary sarcoidosis.
2. The method according to claim 1, wherein the PTGER4 has the nucleotide sequence shown in SEQ ID No. 1; the nucleotide sequence of the AKR1C1 is shown as SEQ ID NO. 2; the nucleotide sequence of the PLA2G6 is shown as SEQ ID NO. 3; the LTA4H has a nucleotide sequence shown in SEQ ID NO. 4; the nucleotide sequence of the PLA2G7 is shown as SEQ ID NO. 5; the nucleotide sequence of the AKR1C3 is shown in SEQ ID NO. 6.
3. A pulmonary nodule detection product comprising primers and/or probes for specifically amplifying one or more of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7, AKR1C 3.
4. The test product according to claim 3, wherein the test product comprises at least one of (a) to (f):
(a) DNA fragments as shown in SEQ ID NO.7 and SEQ ID NO. 8;
(b) DNA fragments shown as SEQ ID NO.9 and SEQ ID NO. 10;
(c) DNA fragments as shown in SEQ ID NO.11 and SEQ ID NO. 12;
(d) DNA fragments as shown in SEQ ID NO.13 and SEQ ID NO. 14;
(e) DNA fragments as shown in SEQ ID NO.15 and SEQ ID NO. 16;
(f) DNA fragments shown as SEQ ID NO.17 and SEQ ID NO. 18.
5. The assay product of claim 4, further comprising an internal reference gene; the reference genes may be ACTB and 18S rRNA.
6. The assay product of any one of claims 3-5, wherein the assay product detects expression of at least one gene selected from PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7, or AKR1C3 in a sample by quantitative fluorescence PCR, Southern hybridization, Northern hybridization, fluorescence in situ hybridization, DNA microarray, high throughput sequencing, or immunoassay.
7. The assay product of any one of claims 3 to 5, wherein the assay product comprises, but is not limited to, a reagent, a kit, a chip, a strip or a high throughput sequencing platform.
8. Use of a gene fragment specifically amplifying PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 or AKR1C3 for the manufacture of a product for selecting an agent for reducing a patient's risk of developing pulmonary sarcoidosis, or for identifying in vitro a candidate agent for treating pulmonary sarcoidosis.
9. Use of a gene fragment specifically amplifying PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7 or AKR1C3 for assessing a patient's likelihood of benefit from treatment with an agent that reduces the risk of pulmonary sarcoidosis, or for assessing a patient's likelihood of benefit from treatment with an antibody or antigen-binding fragment that reduces the risk of pulmonary sarcoidosis.
Use of PTGER4, AKR1C1, PLA2G6, LTA4H, PLA2G7, AKR1C3, alone or in combination, as a marker in the detection and/or diagnosis of pulmonary sarcoidosis.
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| CN202010350286.1A CN111876478A (en) | 2020-04-28 | 2020-04-28 | Pulmonary nodule diagnostic marker and application |
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| CN112433051A (en) * | 2020-11-23 | 2021-03-02 | 四川大学华西医院 | Application of platelet activating factor acetylhydrolase detection reagent in preparation of lung cancer screening kit |
| CN113278692A (en) * | 2021-05-19 | 2021-08-20 | 北京艾克伦医疗科技有限公司 | Method and kit for identifying pulmonary nodule status |
| CN113552357A (en) * | 2021-07-23 | 2021-10-26 | 燕山大学 | Application of leukotriene A4 hydrolase as early lung cancer marker |
| CN113604576A (en) * | 2021-10-09 | 2021-11-05 | 上海晟燃生物科技有限公司 | Lung adenocarcinoma detection kit, storage medium and electronic equipment |
| CN113881774A (en) * | 2021-10-26 | 2022-01-04 | 上海市第一人民医院 | Detection kit with AKR1C1 as detection target and use method thereof |
| WO2022183483A1 (en) * | 2021-03-05 | 2022-09-09 | 深圳艾欣达伟医药科技有限公司 | Primer-probe composition, kit, and detection method |
| WO2024001668A1 (en) * | 2022-06-28 | 2024-01-04 | 广州市基准医疗有限责任公司 | Methylation molecular marker for detecting benign and malignant pulmonary nodules and use thereof |
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| CN113604576A (en) * | 2021-10-09 | 2021-11-05 | 上海晟燃生物科技有限公司 | Lung adenocarcinoma detection kit, storage medium and electronic equipment |
| CN113881774A (en) * | 2021-10-26 | 2022-01-04 | 上海市第一人民医院 | Detection kit with AKR1C1 as detection target and use method thereof |
| WO2024001668A1 (en) * | 2022-06-28 | 2024-01-04 | 广州市基准医疗有限责任公司 | Methylation molecular marker for detecting benign and malignant pulmonary nodules and use thereof |
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