CN115198010A - New application of PDK4, NRG1 and EPHB2 detection agent and depression detection reagent - Google Patents

New application of PDK4, NRG1 and EPHB2 detection agent and depression detection reagent Download PDF

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CN115198010A
CN115198010A CN202210639638.4A CN202210639638A CN115198010A CN 115198010 A CN115198010 A CN 115198010A CN 202210639638 A CN202210639638 A CN 202210639638A CN 115198010 A CN115198010 A CN 115198010A
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高雯琪
邓志芳
肖晗
袁程
倪利华
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Abstract

The invention belongs to the field of biochemical detection, and particularly discloses a new application of a PDK4, NRG1 and EPHB2 detection agent and a depression detection reagent. Use of a combination of expression level detectors for at least one of PDK4, NRG1, EPHB2 in the preparation of a major depressive disorder detection product. The application of the combination of the expression level detection agents of at least two of PDK4, NRG1 and EPHB2 in the preparation of major depression detection products. The application of the combination of PDK4, NRG1 and EPHB2 expression level detection agents in the preparation of major depression detection products. A major depression detection reagent comprising an expression level detection agent for at least two of PDK4, NRG1, and EPHB 2. The detection of the expression levels of PDK4, NRG1 and EPHB2 has higher diagnosis efficiency and can be used as an independent candidate diagnosis biomarker. The accuracy of the combined expression index as a screening index reaches 0.6-0.8, the accuracy of the combined expression index as a screening index is obviously improved, and the combined expression index meets the clinical detection standard.

Description

New application of PDK4, NRG1 and EPHB2 detection agent and depression detection reagent
The application is a divisional application of an invention patent with the application number of 202110451314.3 and the application date of 2021, 4 and 26, entitled major depression detection reagent, system and application.
Technical Field
The invention belongs to the technical field of biochemical detection, and particularly relates to a new application of a PDK4, NRG1 and EPHB2 detection agent and a depression detection reagent.
Background
Major depression is one of the most common neuropsychiatric diseases. With the development of social economy and the increase of working pressure of people, the incidence rate of depression in the world rises year by year, and the incidence rate of depression accounts for 1.4 percent of the world. Depression can cause serious injury to individuals, families, and society. Currently, the current clinical criteria for diagnosis and treatment of major depression are based on the affective disorder profile of the patient. The objective criteria for early diagnosis of patients with major depression are not yet clear, and the existing biomarkers are questioned because of poor specificity and sensitivity.
In addition, depression is a chronic disease caused by various factors, and is affected by epigenetic, endocrine, physiological changes, environmental factors, and the like. There is increasing evidence that environmental factors interact with genetic factors to induce epigenetic changes through long-term changes in neural circuits, endocrine and synaptic structures, leading to the risk of depressive symptoms and other neuropsychiatric diseases. This evidence suggests that genetic factors play a role in the development and progression of major depression in an extremely complex pattern.
Autophagy is a highly conserved biolytic process in eukaryotes that transports intracellular compartments (including proteins and organelles) to lysosomes. When autophagy genes are involved in metabolic regulation, significant changes in expression occur, for example, amino acids are supplied to the energy supply under starvation, and the expression level is significantly increased, particularly in the liver. In neurons, autophagy maintains neuronal balance and function by clearing misfolded proteins and organelles, which play the role of housekeeping genes, with expression levels maintained steady.
Over 30 autophagy-related genes (ARGs) are thought to be critically involved in disease, metabolic disorders, and are thought to be involved in a variety of pathological processes, however, the role of autophagy-related genes in severe depression is not clear. Through data mining, the autophagy-related genes are found to be possibly involved in immune dysregulation accompanied by major depression, particularly depression metabolic pathways involved in prostate cytokines. The data demonstrate that autophagy-related genes can be used as biomarkers for major depression as biochemical detection indicators.
Disclosure of Invention
Aiming at the defects or the improvement requirements of the prior art, the invention provides a new application of the PDK4, NRG1 and EPHB2 detection agent and a depression detection reagent, and mainly solves some research blanks of PDK4, NRG1 and EPHB2 and the defects of depression detection.
Use of a combination of detection agents for the expression level of at least one of PDK4, NRG1, EPHB2 for the preparation of a major depression detection product.
The application of the combination of the expression level detection agents of at least two of PDK4, NRG1 and EPHB2 in preparing a major depression detection product.
In some forms, the use of a combination of expression level detectors for PDK4, NRG1, EPHB2 in the preparation of a major depression detection product.
In some forms, the major depression detection product is an early major depression non-invasive quantitative detection reagent.
In some embodiments, the expression level detection agent comprises a GSE98793 chip.
A major depressive disorder detection reagent comprising an expression level detection agent for at least two of PDK4, NRG1, and EPHB 2.
In some embodiments, the major depressive disorder detection reagent is an early major depressive disorder noninvasive quantitative detection reagent.
The invention has the beneficial effects that:
the detection of the expression levels of GPR18, PDK4, NRG1 and EPHB2 has higher diagnosis efficiency, can be used as an independent candidate diagnosis biomarker to play a role, and a blood sample can be subjected to noninvasive high-flux detection of the expression levels by using a GSE98793 chip. The accuracy of the combined expression index of the two genes respectively serving as the screening indexes reaches 0.6-0.8, the standard of the medium-intensity screening index is reached, the accuracy of the combined expression index serving as the screening index is obviously improved, and the clinical detection standard is met.
Drawings
FIG. 1 is a graph of the difference in expression of different genes between a normal healthy control population and a depressed patient, as analyzed in example 1 for the GSE98793 dataset (tissue source is whole blood);
figure 2 is an analysis of the GSE53987 dataset of example 3 with a significant decrease in GPR18 expression in prefrontal cortex tissue relative to normal controls in depressed patients,. P <0.05;
FIG. 3 is a diagnostic efficacy assessment of GPR18, PDK4, NRG1 and EPHB2 genes in example 4;
FIG. 4 is a graph of the results of the animal model modeling test for depression in example 5;
FIG. 5 shows the result of the test of GPR18 expression level in the tissue of the prefrontal cortex of a mouse model of depression in example 5;
figure 6 is a graph of results obtained following AUC multiple combination analysis with the GSE53987 dataset.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention. In addition, the technical features involved in the respective embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The major depression detection reagent provided by the invention comprises one or more combinations of CAPNS2, WDR41, GPR18, PDK4, NRG1 and EPHB2 gene expression level detection reagents; preferably includes one or more of GPR18, PDK4, NRG1 and EPHB2 gene expression level detection reagent; more preferably, GPR18, PDK4, NRG1 and EPHB2 gene expression level detection reagents are included.
It is a gene expression level detection reagent, preferably a gene mRNA expression level detection reagent, such as GSE98793 chip.
The depression detection system provided by the invention comprises a gene expression level acquisition module and a judgment module;
the gene expression level acquisition module is used for acquiring the expression levels of one or more genes in CAPNS2, WDR41, GPR18, PDK4, NRG1 and EPHB2 genes and providing the expression levels to the judgment module; preferably, the expression level of one or more of the GPR18, PDK4, NRG1 and EPHB2 genes is obtained; more preferably, the expression levels of GPR18, PDK4, NRG1 and EPHB2 genes are obtained.
The judging module takes the expression level of one or more genes in CAPNS2, WDR41, GPR18, PDK4, NRG1 and EPHB2 genes as the input of the classifier, and judges whether the sample is from a severe depression patient.
The expression levels of GPR18, PDK4, NRG1 and EPHB2 genes are used as classification bases, AUC reaches above 0.7, and the classification bases can be used as reference bases for clinical screening of severe depression.
The following are examples:
example 1 statistical analysis of expression level difference analysis in Normal controls and in patients with Severe Depression
The data source is as follows: validation of Gene differential Expression data for Depression patients and normal controls from the GEO database (Gene Expression Omnibus) GSE98793 dataset, blood samples were analyzed using the GPL570 platform ([ HG-U133_ Plus _2], affymetrix Human Genome U133 Plus 2.0 array.). Among them, 128 patients with major depression, 64 normal controls, contained two batches of data, and the use of limma package tool, "removeBatchEffect" eliminated the batch effect.
Counting: expression differential analysis was performed on CAPNS2, WDR41, GPR18, PDK4, NRG1 and EPHB2 genes using limma toolkit in R language. The results show that the expression amount of the genes in the patients with severe depression is obviously different (the P value is less than 0.05 and (| log FC |) > 0.2), and partial differentially expressed genes are shown in figure 1.
Figure BDA0003683285780000051
Example 2 logistic regression analysis data sources for the difference in expression levels between normal controls and major depressive patients: same as example 1
Multivariate logistic regression analysis: the results of multivariate logistic regression analysis by stepwise backward method are shown in the following table, which shows that the influence among GPR18, PDK4, NRG1 and EPHB2 genes is mutually independent, and the genes are suitable for being used as biochemical detection indexes of depression and provide screening basis together.
Figure BDA0003683285780000052
Example 3GSE53987 cadaver brain tissue validation
To further validate the biological function of GPR18 and depression, we analyzed the quantitative changes in expression of these diagnostic marker genes in cadaveric tissues of depression patients. The results of the GSE53987 assay showed that GPR18 expression was significantly down-regulated in the prefrontal cortex of cadaver brain tissue in depressed patients, consistent with our peripheral results. We then established a chronic social frustration stress mouse model of depression (CSDS model) with significantly reduced GPR18 mRNA levels in the prefrontal cortex tissues of the CSDS model compared to normal mice. The results of the experimental animal model are consistent with the results of the human peripheral blood and cadaver brain tissues.
Example 4 Depression detection System
The expression levels of GPR18, PDK4, NRG1 and EPHB2 genes in blood were used as detection indexes, and the efficacy thereof as a diagnostic marker for major depressive disorder was calculated.
And (3) verifying data: validation Depression and normal Human Gene differential Expression data were obtained from the GEO database (Gene Expression Omnibus) GSE98793 dataset, and blood samples were analyzed using the GPL570 platform ([ HG-U133_ Plus _2], affymetrix Human Genome U133 Plus 2.0 array.). Among them 128 major depression patients, 64 normal controls, contained two batches of data, with the limma package tool "removeBatchEffect" to eliminate batch effects.
The results showed that the accuracy of the detection result of the expression level of GPR18 gene reached 0.702 (95% CI 0.628-0.777), the accuracy of the detection result of the expression level of PDK4 gene reached 0.620 (95% CI 0.536-0.705), the accuracy of the detection result of the expression level of NRG1 gene reached 0.660 (95% CI 0.581-0.741), and the accuracy of the detection result of the expression level of EPHB2 gene reached 0.631 (95% CI 0.550-0.710). All meet the accuracy requirement of medium-intensity screening index (AUC is between 0.5 and 0.8).
It should be noted that: the accuracy of the results of the other gene expression level measurements can also be calculated by the method described above. The calculation of the combined model adopts a common AUC analysis model.
The best diagnostic index is shown by multivariate logistic regression as: (-0.651 pdk4 expression) + (-1.958 gpr18 expression) + (0.638 nrg1 expression) + (0.899 ephb2 expression). The accuracy AUC value of the gene combination index is as high as 0.779 (95% CI = 0.709-0.848), which is higher than the detection accuracy of the expression quantity of a single gene. As shown in the following table:
Figure BDA0003683285780000061
although NRG1, PDK4 and EPHB2 can play a role in the pathophysiological process of depression, no evidence indicates that the expression level of the NRG1, PDK4 and EPHB2 is different from that of the healthy state in the pathological state of severe depression, for example, the polymorphism of the NRG1 gene may be related to depression, but whether the expression level of the NRG1 gene can be used as an early screening index for depression diagnosis depends on whether the index suitable for detection, such as the expression level, of the NRG1 gene under different influencing factors (age and sex) is relatively stable, and whether the NRG1, PDK4 and EPHB2 as a depression screening marker has enough depression sample distinguishing capability (reaches a medium accurate level). The invention firstly confirms the association relationship between the GPR18 gene and the major depression which is not reported in association with depression before, and then provides data demonstration and experimental evidence that the expression levels of 6 genes (CAPNS 2, WDR41, GPR18, PDK4, NRG1 and EPHB 2) can be used as biochemical indexes for detecting the major depression, wherein the data demonstration and the experimental evidence comprise effectiveness and stability. The preferred scheme analyzes the influence independence among the genes and confirms that the optimal major depressive disorder gene expression level detection marker combination is as follows: the expression levels of GPR18, PDK4, NRG1 and EPHB2 genes.
Example 5 animal model validation
An animal model of depression was established and evaluated by behavioral tests (sweet water preference, tail suspension, forced swimming), the results are shown in fig. 4. The results show that: the depression model was successfully established, and compared to normal controls P <0.05.
Designing and synthesizing GPR18 primer sequences, taking forehead cortex tissues of depression mice and normal animals, and detecting the relative expression quantity of GPR-18 mRNA by adopting RT-PCR, wherein the GPR18 primer sequences are as follows:
Forward sequence：5’-GAAGCCCAAGGTCAAGGAGAAGTC-3’
Reverse sequence：5’-GCGAACACTGCGAAGGTAATTGC-3’
the results show that GPR18 expression was significantly reduced by P <0.01 in the prefrontal cortex tissue of depression model mice compared to normal mice as shown in figure 5.
It will be apparent to those skilled in the art that various modifications may be made to the above embodiments without departing from the general spirit and concept of the invention. All falling within the scope of the present invention. The protection scheme of the invention is subject to the appended claims.

Claims (7)

  1. Use of a combination of expression level detection agents for at least one of pdk4, NRG1, EPHB2 in the preparation of a major depression detection product.
  2. 2. Use according to claim 1, characterized by the use of a combination of expression level detectors for at least two of PDK4, NRG1, EPHB2 for the preparation of a major depressive disorder detection product.
  3. 3. Use according to claim 2, characterized in that the combination of the expression level detectors for PDK4, NRG1, EPHB2 is used in the preparation of a major depression detection product.
  4. 4. The use according to any one of claims 1 to 3, wherein the major depression detection product is a non-invasive quantitative detection reagent for early major depression.
  5. 5. The use of any one of claims 1 to 3, wherein the agent for detecting expression levels comprises a GSE98793 chip.
  6. 6. A major depression detection reagent characterized by comprising an expression level detection agent for at least two of PDK4, NRG1 and EPHB 2.
  7. 7. The major depression detection reagent according to claim 6, wherein the major depression detection reagent is a noninvasive quantitative detection reagent for early major depression.
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