CN117607462B - Application of biomarker in preparation of products for diagnosing scleritis - Google Patents
Application of biomarker in preparation of products for diagnosing scleritis Download PDFInfo
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- G—PHYSICS
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G01—MEASURING; TESTING
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
- G01N2800/328—Vasculitis, i.e. inflammation of blood vessels
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- 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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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of a biomarker in preparation of a product for diagnosing scleritis. The biomarker at least comprises PGLYRP1 and/or GSTP1. Experiments prove that the biomarker for diagnosing posterior scleritis has obvious sensitivity and specificity and has very good application and research values in the field of biological medicines.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of a biomarker in preparation of a product for diagnosing scleritis.
Background
Posterior scleritis is an inflammation that jeopardizes vision of the eye, and improper treatment can lead to blindness. The pathogenesis of the disease may be related to genetic, environmental and systemic diseases (such as rheumatoid arthritis and ankylosing spondylitis), but the exact pathogenesis is not completely clear at present. Currently, diseases can be diagnosed and treatments administered by clinical characterization and eye-related examinations. However, there are still cases where the etiology of some cases is unknown or the clinical manifestations are atypical, resulting in missing the best opportunity for treatment.
Proteins are the basis for performing vital activities of an organism, and the severity of different diseases varies, which can lead to changes in the composition and expression of proteins in the body. Proteomics is the application of technology that involves the identification and quantification of the total protein content present in cells, tissues or organisms, and is widely used in a variety of fields including detection of diagnostic markers, disease mechanism studies, and drug development and personalized therapies. Clinically, the blood plasma has the advantages of convenient material taking, non-invasiveness and small trauma, and can be applied to real-time dynamic personalized diagnosis and treatment. Many research results show that the plasma contains abundant proteins and can be used for proteomics research. However, in practical applications, the detection results are often unsatisfactory due to the presence of high abundance proteins and the large dynamic fluctuation range of protein abundance. With the development of Mass Spectrometry (MS) based proteomic techniques and bioinformatics, more and more biomarkers have been found, and current techniques have been able to recognize more than 1,000 proteins, and even more than 5000 proteins, in plasma. Therefore, the method is helpful for finding the markers which change along with the change of eyes in the plasma of patients, assisting the diagnosis of diseases and exploring the pathogenesis of the diseases.
Disclosure of Invention
The present application identifies proteins in plasma of patients including healthy controls, behcet's disease uveitis, posterior scleritis, and Vogt-small Liu Yuantian syndrome (VKH) by SWATH-MS technology. Screening out potential disease markers by a bioinformatics method, further selecting another group of sample queues, verifying two markers by using an ELISA kit, and constructing a diagnosis model by SPSS. The results show that PGLYRP1 and/or GSTP1 has higher sensitivity and specificity as biomarkers for diagnosing the posterior scleritis.
In a first aspect of the invention, there is provided the use of a biomarker or a reagent for detecting a biomarker in the manufacture of a product for diagnosis or prognostic evaluation of scleritis.
The biomarker comprises PGLYRP1 and/or GSTP1.
Preferably, the biomarker further comprises one or more than two of HSD17B11, KARS1, LMAN2 or YWHAG.
In one embodiment of the invention, the application is: use of PGLYRP1 and/or GSTP1 as biomarkers in the preparation of a product for diagnosis or prognosis evaluation of posterior scleritis.
The biomarker is a biomarker in blood plasma.
The biomarker is protein.
In one embodiment of the invention, the application is: use of PGLYRP1 and/or GSTP1 in plasma as biomarkers in the preparation of a product for diagnosis or prognosis evaluation of scleritis.
Reagents for detecting a biomarker include reagents for detecting the presence or amount of a biomarker.
The product comprises a protein chip, a kit, test paper, a membrane strip or equipment. The apparatus may be selected from liquid phase or mass spectrometry.
Preferably, the product comprises reagents for detecting a biomarker. Further preferred are reagents comprising detecting the presence or absence or the level of expression of a biomarker in a sample.
Preferably, the sample is a plasma sample.
The diagnosis or prognosis evaluation of scleritis includes detecting the presence or amount of a biomarker. And then compares it to a threshold. The threshold is obtained by early experiments, namely, the threshold is determined by the degree of difference of the biomarker between the posterior scleritis and healthy people or the posterior scleritis and other eye diseases through experiments and data analysis.
A biomarker described herein is determined to be a disease when it differs or significantly differs from a threshold (differences are statistically significant, e.g., p <0.05, p <0.01, p <0.001, p < 0.0001). For example:
a) PGLYRP1 above a threshold or significantly above a threshold is indicative of the onset of posterior scleritis; and/or the number of the groups of groups,
b) GSTP1 above or significantly above the threshold is indicative of the occurrence of posterior scleritis; and/or the number of the groups of groups,
c) KARS1 above or significantly above the threshold value indicates the occurrence of posterior scleritis; and/or the number of the groups of groups,
d) LMAN2 above or significantly above the threshold is indicative of the occurrence of posterior scleritis; and/or the number of the groups of groups,
e) A YWHAG above or significantly above the threshold indicates the occurrence of posterior scleritis; and/or the number of the groups of groups,
f) HSD17B11 below or significantly below the threshold is indicative of the onset of posterior scleritis.
In a second aspect of the invention, there is provided the use of a biomarker in the construction of a diagnostic model for posterior scleritis.
The biomarker comprises PGLYRP1 and/or GSTP1. Preferably, the biomarker further comprises one or more than two of HSD17B11, KARS1, LMAN2 or YWHAG.
The diagnostic model includes reagents for detecting biomarkers.
In a third aspect of the invention, a diagnostic model of posterior scleritis is provided, the diagnostic model comprising reagents for detecting a biomarker.
In a fourth aspect of the invention, there is provided a method of diagnosing or prognosticating posterior scleritis, said method comprising detecting a biomarker in a sample from a subject.
Preferably, the presence or amount of a biomarker, e.g., the amount of protein expressed, is detected.
The sample is a plasma sample.
The method further comprises comparing the detected expression level of the biomarker to a threshold value.
A biomarker described herein is determined to be a disease when it differs or significantly differs from a threshold (differences are statistically significant, e.g., p <0.05, p <0.01, p <0.001, p < 0.0001). For example:
a) PGLYRP1 above a threshold or significantly above a threshold is indicative of the onset of posterior scleritis; and/or the number of the groups of groups,
b) GSTP1 above or significantly above the threshold is indicative of the occurrence of posterior scleritis; and/or the number of the groups of groups,
c) KARS1 above or significantly above the threshold value indicates the occurrence of posterior scleritis; and/or the number of the groups of groups,
d) LMAN2 above or significantly above the threshold is indicative of the occurrence of posterior scleritis; and/or the number of the groups of groups,
e) A YWHAG above or significantly above the threshold indicates the occurrence of posterior scleritis; and/or the number of the groups of groups,
f) HSD17B11 below or significantly below the threshold is indicative of the onset of posterior scleritis.
Preferably, the method of detection may be selected from mass spectrometry, liquid phase, ELISA.
In a fifth aspect of the invention, a diagnostic kit is provided, comprising a detection biomarker reagent.
In a sixth aspect of the invention, there is provided the use of a biomarker in the manufacture of a product for distinguishing posterior scleritis from uveitis.
The biomarker comprises PGLYRP1 and/or GSTP1. Preferably, the biomarker further comprises one or more than two of HSD17B11, KARS1, LMAN2 or YWHAG.
The expression level of the biomarker in posterior scleritis is significantly different from the expression level in uveitis (the difference is statistically significant, e.g., p <0.05, p <0.01, p <0.001, p < 0.0001). For example:
a) The expression level of PGLYRP1 in posterior scleritis is significantly higher than in uveitis, indicating the occurrence of posterior scleritis; conversely, it may have uveitis or health, and need to be further determined. And/or the number of the groups of groups,
b) The expression level of GSTP1 in posterior scleritis is significantly higher than in uveitis, indicating the occurrence of posterior scleritis; conversely, it may have uveitis or health, and need to be further determined.
The uveitis comprises one or more than two of Behcet's disease uveitis, vogt-small Liu Yuantian syndrome, uveitis caused by ankylosing spondylitis, fuchs syndrome, sympathogenic ophthalmitis or idiopathic uveitis.
In a seventh aspect of the invention, there is provided a method of distinguishing posterior scleritis from uveitis, the method comprising detecting the expression level of a biomarker in a sample from a subject.
The uveitis comprises one or more than two of Behcet's disease uveitis, vogt-small Liu Yuantian syndrome, uveitis caused by ankylosing spondylitis, fuchs syndrome, sympathogenic ophthalmitis or idiopathic uveitis.
The sample is a plasma sample.
The term "diagnosis" as used herein refers to ascertaining whether a patient has a disease or disorder.
As used herein, "prognostic evaluation" refers to assessing a patient's response to treatment.
The "subject" of the present invention is a human.
The shorthand and full scale comparison of this application is shown in Table 1.
TABLE 1
The invention has the beneficial effects that: (1) The invention identifies the proteins in the plasma of healthy control patients, the patients with Behcet's disease uveitis, posterior scleritis and Vogt-small Liu Yuantian syndrome by SWATH-MS technology, and screens 6 biomarkers of posterior scleritis by combining with a bioinformatics method. (2) ELISA further verifies that the expression level of PGLYRP1 and GSTP1 in posterior scleritis and Behcet's uveitis or Vogt-small Liu Yuantian syndrome or non-diseased is significantly different, and can be used as a biomarker for distinguishing posterior scleritis and Behcet's uveitis or Vogt-small Liu Yuantian syndrome or non-diseased. (3) The PGLYRP1 and/or GSTP1 obtained by screening of the invention has higher sensitivity and specificity as biomarkers for diagnosing the posterior scleritis, and has excellent clinical diagnosis significance.
Drawings
Fig. 1A: SWATH-MS quantitative analysis results.
Fig. 1B: PLS-DA analysis results.
Fig. 1C: GSEA enrichment analysis result graph.
Fig. 2A: differential protein volcanic profile of posterior scleritis patients compared to healthy controls.
Fig. 2B: velutina, vogt-small Liu Yuantian syndrome and Venn plot of posterior scleritis protein differential protein, wherein C-S represents the number of differential proteins of control group and posterior scleritis, B-S represents the number of differential proteins of velutina and posterior scleritis, and V-S represents the number of differential proteins of Vogt-small Liu Yuantian syndrome and posterior scleritis.
Fig. 3A: mass spectrum results of PGLYRP1 protein expression levels in plasma.
Fig. 3B: mass spectrum results of GSTP1 protein expression levels in plasma.
Fig. 3C: ELISA results for PGLYRP1 protein in blood plasma.
Fig. 3D: ELISA results for GSTP1 protein in plasma.
Fig. 4: posterior scleritis patients and three other groups of ROC curves for PGLYRP1 and GSTP1.
Fig. 5: ROC curves for PGLYRP1 in posterior scleritis patients and in three other groups.
Fig. 6: posterior scleritis patients and three other groups of ROC curves for GSTP1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The subjects and experimental methods involved in the examples are as follows:
1. experimental objects
The study was approved by the ethical committee of ophthalmic hospitals at the university of Tianjin medical science. Patients who were enrolled in the ophthalmic hospital at the university of Tianjin medical science all signed informed consent. Patients with uveitis, VKH and posterior scleritis of behcet's disease, treated in an ophthalmic hospital from 1 st 2018 to 10 nd 2022, were selected as experimental groups, while another healthy cohort was recruited as control group.
1.1 experimental group inclusion criteria:
1) Patients with autoimmune uveitis (including Behcet's disease uveitis, vogt-small Liu Yuantian syndrome), posterior scleritis with/without bulbar wall lesions; 2) Age between 16-70 years old; 3) No diabetes, hypertension, hyperlipidemia, cardiovascular diseases, mental diseases, etc., and no systemic organic lesions; 4) No history of eyeball punch-through injury and intraocular surgery; both eyes have no other ocular lesions except cataract.
1.2 exclusion criteria:
1) Serious infectious diseases exist; 2) Other ocular lesions that affect vision in addition to cataracts; 3) There are other systemic diseases.
1.3 disease diagnostic criteria:
1) The diagnosis was Vogt-small Liu Yuantian syndrome. Initial activity period: the first onset of the eye, elevated ocular inflammation (anterior chamber cell, vitreous opacity), OCT shows abnormal changes in the retina; initial inactivity period: after treatment, the anterior chamber inflammation subsides and the retinal structure returns to normal; recurrence: the onset was again continued more than 3 months after the primary treatment was stopped.
2) The diagnosis is Behcet's disease uveitis. Highly active period: the first onset or recurrence of the eye, elevated levels of anterior chamber inflammation, and most cases may be accompanied by varying degrees of posterior ocular lesions and systemic changes; low active period: the treatment of posterior ocular inflammation and systemic changes is controlled, anterior chamber inflammation grades less than 1 order of magnitude, posterior ocular segment inflammation tending to stabilize.
3) The diagnosis was posterior scleritis. Scleral thickening: the first onset or recurrence of the eye, elevated levels of anterior chamber inflammation, and increased bulbar wall thickness as demonstrated by B-ultrasound; sclera non-thickening: the ultrasonic B-mode shows that the ball wall has no obvious thickening of posterior scleritis or the thickness of the sclera returns to be normal after treatment.
2. Protein library establishment and discovery queue screening experiment method
2.1 construction of protein libraries
Establishing a library queue: the method comprises the steps of selecting 26 frozen samples of healthy adults, beckman uveitis, posterior scleritis and VKH, extracting exosomes and microvesicles in the frozen samples by using a super-high-speed centrifuge (Beckman Coulter Co.), and mixing the frozen samples with a plasma sample to construct a protein library.
2.2 extraction and preservation of plasma
Sample collection: screening a discovery queue consisting of 48, 46, 48 and 48 samples of healthy control, behcet's disease uveitis, posterior scleritis and VKH respectively, and collecting 5ml of peripheral venous blood of 190 samples in the discovery queue in EDTA anticoagulation tubes. After centrifugation at 1800g for 15min at 4℃2ml of plasma were extracted and stored in a-80℃freezer for subsequent use.
2.3 in-solution cleavage of protein and measurement of protein concentration
1) Frozen plasma samples were removed, 2. Mu.l were withdrawn, and 100. Mu.l urea lysate (Sigma-Aldrich Co.) was added.
2) And (3) reduction: dithiothreitol DTT (Sigma-Aldrich) was added at a final concentration of 10mM and incubated at 37℃for 1h.
3) Alkylation: iodoacetamide IAA (Sigma-Aldrich Co.) was added at a final concentration of 40mM and incubated at room temperature for 1h in the absence of light.
4) Balanced ultrafiltration tube and sample filtration: add 300 μl 50mM ammonium bicarbonate and centrifuge twice (14000 g×5min, room temperature); adding the sample after reductive alkylation into a balanced ultrafiltration tube, and centrifuging (14000 g×20min, room temperature); after the sample was completely filtered, 300. Mu.l of 50mM ammonium bicarbonate (Sigma-Aldrich Co.) was added and washed three times (14000 g. Times.5 min, room temperature); the collection tube was replaced and 75. Mu.l of 50mM ammonium bicarbonate was added to the ultrafiltration tube.
5) Protease cleavage: adding pancreatin (Roche biosystems) to the mixture for digestion at 37℃overnight; after incubation was completed, centrifugation (14000 g×5min,20 min); cleavage was stopped by adding 1% formic acid (Sigma-Aldrich Co.) and evaporated to dryness in vacuo at 60 ℃.
6) A0.1% formic acid resuspension sample was added and the protein concentration was measured by Nanodrop (Thermo Fisher Scientific).
2.4 Mass Spectrometry detection and identification
And (3) selecting a part of peptide fragments obtained after protease cleavage in 2.3, and carrying out protein detection by means of information dependency acquisition.
2.5 processing of quantitative data values
The obtained quantitative value of the protein is treated by using R language, and the difference protein is defined as p less than 0.05 and the absolute value of Fold Change (FC) is more than 1.2 times.
2.6 screening of candidate biomarkers
Proteins with differences between single diseases and other 3 groups are screened as disease protein markers, and Hiplot is used for drawing Wen character screening results.
3. Alternative validation queue ELISA validation of candidate biomarkers
Screening a verification queue consisting of 67, 65 and 65 samples of healthy control, behcet's disease uveitis, posterior scleritis and VKH based on the same standard as the discovery queue, and performing ELISA verification on biomarkers of the mass spectrum screening, wherein the extraction and preservation of plasma samples are the same as the extraction and preservation of 2.2 plasma, and the used kits are all from FineTest company. The method comprises the following steps:
1) All reagents and samples in the kit are taken out in advance and are put to room temperature. To a standard tube provided with the kit, 1ml of a standard diluent was added, and 7 ep tubes numbered 1 to 7 were taken as a 0-th tube, and 300. Mu.l of a standard diluent was added, respectively. And adding 300 mu l of the uniformly mixed liquid into a No. 1 tube, adding 300 mu l of the uniformly mixed liquid into a No. 2 tube from the No. 1 tube, and the like, wherein 300 mu l of the standard substance diluent is kept unchanged in a No. 7 tube.
2) 100 μl of standard dilutions and plasma dilutions were added to the well plate and incubated for 90 min at 37 ℃. 48ml of ultrapure water was prepared, and 2ml of concentrated washing solution was added to prepare a washing solution diluted 25-fold, and the plate was washed twice.
3) A biotin antibody working solution was prepared, and 100. Mu.l of the antibody working solution was added to each well to incubate for 60 minutes. The plate was washed 3 times.
4) HRP-streptavidin was formulated and 100 μl was added to each well for 30 min incubation. The plate was washed 5 times.
5) 90. Mu.l of TMB chromogenic substrate is added and incubated for 10-20 minutes in the dark.
6) Mu.l of the reaction termination solution was added, and the absorbance at 450nm was read by an enzyme-labeled instrument (TECAN Co.) and calculated.
7) One-way ANOVA analysis of variance using SPSS software for statistical analysis of differences between the four groups, p<A difference of 0.05 was considered statistically significant.Represents p<0.05，/>Represents p<0.01，/>Represents p<0.001，Represents p<0.0001。
4. Diagnostic effect verification
A validation queue consisting of 67, 65 samples of healthy control, behcet's uveitis, posterior scleritis, and VKH, respectively, was screened for evaluation of diagnostic effects. And performing ROC curve analysis on the PGLYRP1 and the GSTP1 by adopting SPSS software, and performing joint ROC curve analysis on the PGLYRP1 and the GSTP1 by adopting SPSS software through binary logistic regression to obtain a predicted value.
Example 1: protein spectrogram
To expand the number of protein identifications, a database of 2432 proteins was constructed using a mix of small extracellular vesicles, large extracellular vesicles, and plasma samples in 26 cryopreserved samples. Mass spectrometry found that the queue showed: 2028 proteins were quantified by SWATH-MS (FIG. 1A). PLS-DA (partial least squares discriminant analysis) analysis (fig. 1B) was performed on four groups within a 95% confidence interval, and it was found that there was some difference between the four groups that could be distinguished. To fully understand posterior scleritis, GSEA enrichment analysis was performed with all quantifiable proteins (fig. 1C), and the results show that the biological processes and pathways affected by the disease are mainly focused on signal pathways such as MAPK, NF-kB and C-type lectin receptors.
Volcanic images show up-down regulated differential protein of posterior scleritis compared to healthy controls (fig. 2A). To further screen for independently expressed proteins in the disease as disease markers, posterior scleritis was compared to the other 3 groups, respectively, to finally obtain 6 potential protein markers, namely PGLYRP1, GSTP1, HSD17B11, KARS1, LMAN2 and ywhagg, which were shown by Venn plot (fig. 2B) and could be used as markers for diagnosis of posterior scleritis.
Example 2: further validation of protein markers using ELISA
Another group of queues was selected as validation queues, and PGLYRP1 and GSTP1 were used as examples for validation according to the functions of proteins and the expression conditions between groups, and the two proteins were found to be in an ascending trend in the plasma of patients with posterior scleritis according to the quantitative values obtained by mass spectrometry of the discovery queues (fig. 3A and 3B). The results of ELISA validation (FIGS. 3C and 3D) also confirmed the correctness of the early findings.
Example 3: diagnostic effect assessment
Taking PGLYRP1 and GSTP1 as examples, the ELISA results were subjected to subject working characteristics (Receiver Operation Characteristic, ROC) curve analysis, wherein the ROC curve of PGLYRP1 as biomarker for diagnosing post scleritis is shown in fig. 5, auc=0.718; ROC curve of GSTP1 as biomarker diagnostic for postscleritis is shown in fig. 6, auc=0.707.
After combined values of PGLYRP1 and GSTP1 markers were obtained by binary logistic regression, ROC analysis was performed and the area under the curve was calculated (auc=0.826) to obtain the final diagnostic model (fig. 4).
Claims (9)
1. Use of a biomarker in the manufacture of a product for diagnosing posterior scleritis, wherein the biomarker comprises PGLYRP1 and/or GSTP1; the biomarker is a biomarker in blood plasma.
2. The use of claim 1, wherein the biomarker further comprises one or more of HSD17B11, KARS1, LMAN2, or YWHAG.
3. The use according to claim 1, wherein the product comprises a kit, a test strip or a membrane strip.
4. The use of claim 1, wherein the product comprises a protein chip.
5. The use of claim 1, wherein the product comprises an agent for detecting the presence or level of expression of a biomarker in a sample.
6. The use of claim 5, wherein the sample is a plasma sample.
7. Use of a biomarker in the manufacture of a product for distinguishing posterior scleritis from uveitis, wherein the biomarker comprises PGLYRP1 and/or GSTP1; the biomarker is a biomarker in blood plasma.
8. The use of claim 7, wherein the biomarker further comprises one or more of HSD17B11, KARS1, LMAN2, or YWHAG.
9. The use according to claim 7, wherein said uveitis comprises one or more of behcet's disease uveitis, vogt-small Liu Yuantian syndrome, uveitis caused by ankylosing spondylitis, fuchs syndrome, sympathogenic ophthalmitis or idiopathic uveitis.
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