CN114002439A - Application of KS in follicular fluid as EM diagnosis and pregnancy outcome assessment marker - Google Patents
Application of KS in follicular fluid as EM diagnosis and pregnancy outcome assessment marker Download PDFInfo
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- 230000035935 pregnancy Effects 0.000 title claims abstract description 61
- 210000001733 follicular fluid Anatomy 0.000 title claims abstract description 46
- 239000003550 marker Substances 0.000 title claims abstract description 11
- 238000003745 diagnosis Methods 0.000 title claims abstract description 8
- 102100023012 Kallistatin Human genes 0.000 claims abstract description 26
- 108010050180 kallistatin Proteins 0.000 claims abstract description 26
- 238000001514 detection method Methods 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 201000009273 Endometriosis Diseases 0.000 abstract description 59
- 230000035945 sensitivity Effects 0.000 abstract description 6
- 238000004458 analytical method Methods 0.000 abstract description 5
- 244000005700 microbiome Species 0.000 abstract 1
- 238000011895 specific detection Methods 0.000 abstract 1
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- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 101000605522 Homo sapiens Kallikrein-1 Proteins 0.000 description 2
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- 208000000509 infertility Diseases 0.000 description 2
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- 210000001161 mammalian embryo Anatomy 0.000 description 2
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- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/36—Gynecology or obstetrics
- G01N2800/364—Endometriosis, i.e. non-malignant disorder in which functioning endometrial tissue is present outside the uterine cavity
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses application of KS in follicular fluid as an EM diagnosis and ART pregnancy outcome assessment marker. According to the invention, by comparatively analyzing the KS concentration in the follicular fluid of the EM patient and the EM-free patient, the fact that the KS concentration in the follicular fluid of the EM patient is obviously lower than that of the EM-free patient of a control group, and the ART laboratory of the EM patient is worse. Further analysis of the presence or absence of pregnancy for KS detection in FF in EM patients revealed that KS expression was significantly higher in the group of EM patients on ART than in the group of FF patients on pregnancy failure. Finally, ROC analysis is carried out on KS and ART pregnancy outcome in FF, and the KS in the follicular fluid can be used as a new index for predicting the pregnancy outcome of the endometriosis female in assisted reproduction and assisted pregnancy, and the optimal prediction point, sensitivity, specificity and AUC value are ideal. The results prove that the Kallistatin can be used as a specific detection marker of EM (effective microorganisms) and used for predicting pregnancy outcome of endometriosis women in assisted reproduction and assisted pregnancy, and has good sensitivity and specificity.
Description
Technical Field
The invention belongs to the technical field of assisted reproduction, and particularly relates to application of human tissue kallikrein binding protein (KS) in follicular fluid as an Endometriosis (EM) diagnosis and pregnancy outcome assessment marker.
Background
At present, the incidence rate of global infertility is higher and higher, and more infertile patients obtain their own offspring by means of the assisted reproduction technology ART (tube baby). In particular, women with Endometriosis (EM) have a higher incidence of infertility. Although ART technology is well established, there is currently no non-invasive indicator of predicting pregnancy outcome in EM patients prior to embryo implantation.
Follicular Fluid (FF) provides an environment for oocyte growth and maturation and plays a key role in ovulation, subsequent fertilization, and early embryo development. Human tissue kallikrein binding protein (KS) is an endogenous protein for regulating differential signaling, and has multiple biological functions of inhibiting inflammation, angiogenesis, oxidative stress, apoptosis, tumor growth, transfer of animal models and cultured cells and the like.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a related product for diagnosing EM and/or evaluating pregnancy fate of an EM patient and application of Kallistatin protein serving as an EM diagnosis and pregnancy fate evaluation marker.
In a first aspect of the invention, there is provided the use of a Kallistatin protein as a detection marker in the manufacture of a product for the diagnosis of EM and/or for the assessment of pregnancy outcome in EM patients.
Further, the product can be used for diagnosing whether a patient suffers from EM and/or evaluating pregnancy outcome of patients suffering from EM by detecting the expression level of the Kallistatin protein in follicular fluid.
In a second aspect of the invention, there is provided the use of an agent for detecting the expression level of Kallistatin protein in the manufacture of a product for diagnosing EM and/or assessing pregnancy outcome of EM patients.
Further, the product can be used for diagnosing whether a patient suffers from EM and/or evaluating pregnancy outcome of patients suffering from EM by detecting the expression level of the Kallistatin protein in follicular fluid.
In a third aspect of the invention, there is provided a product for diagnosing EM and/or assessing pregnancy outcome in EM patients, the product being characterised by: the product can be used for diagnosing EM and/or evaluating pregnancy outcome of EM patients by detecting the expression level of Kallistatin protein in follicular fluid.
Has the advantages that: according to the invention, by analyzing the concentration of KS in the follicular fluid of the endometriosis-infertile women, the fact that the content of KS in the follicular fluid of a patient with EM is obviously lower than that of a patient without EM in a control group is found, and the fact that Kallistatin can be used as an EM detection marker is suggested; and the ART laboratory of the EM patient is worse, which suggests that KS in the follicular fluid may have certain application value in predicting the pregnancy outcome of the endometriosis female in assisted reproduction and assisted pregnancy. Further analysis of the presence or absence of pregnancy for the detection of KS in FF in EM patients revealed that KS expression was significantly higher in the group of EM patients subjected to ART than in the group of patients subjected to pregnancy failure. Finally, ROC analysis is carried out on KS and ART pregnancy outcome in FF, the KS in the follicular fluid can be used as a new index for predicting the pregnancy outcome of the endometriosis female in assisted reproduction assisted pregnancy, the optimal prediction point, sensitivity, specificity and AUC value are ideal, and compared with a control group for assisted reproduction, the expression of Kallistatin protein in the follicular fluid of an EM high-risk group is obviously reduced, so that Kallistatin can be used as a detection marker of EM; in addition, in the follicular fluid of the eventually EM patients, there was a significant reduction in Kallistatin protein compared to normal pregnant women. The results prove that the Kallistatin can be used as a specificity detection marker of EM, is used for predicting pregnancy outcome screening and preparing EM detection reagent when the endometriosis female carries out assisted reproduction and assisted pregnancy, and has good sensitivity and specificity.
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FIG. 1 shows the expression verification of Kallistatin protein in follicular fluid of successful Pregnancy group and unsuccessful Pregnancy group, wherein Pregnancy represents the successful Pregnancy group; non-pregnancy represents the group of pregnancy failures; (A) the concentration of KS in follicular fluid of the successful pregnancy group and the failed pregnancy group in the control group of patients, (B) the concentration of KS in follicular fluid of the successful pregnancy group and the failed pregnancy group in the EM patient, (C) the concentration of KS in follicular fluid of the successful pregnancy group and the failed pregnancy group in all patients (p < 0.05).
FIG. 2 is a graph of the operating characteristics (ROC curve) of subjects in Kallistatin protein diagnosis EM.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Example 1 expression of Kallistatin protein in follicular fluid of EM patients undergoing assisted reproduction and non-EM patients
Under the knowledge of the patient, female infertility patients who are subjected to in-vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) assisted pregnancy at the reproductive center of the third hospital affiliated to Guangzhou medical university from 7 months to 8 months in 2017 are selected, and follicular fluid of the patients on the day of taking eggs is collected for experiment. All patient inclusion criteria: (1) the age is less than 33 years; (2) hormone therapy is not received at least 6 months prior to surgery; (3) women with polycystic ovary syndrome, diabetes, hypertension, dyslipidemia, HIV infection or any active infection and autoimmune disease were excluded. Among them, 40 EM patients were selected as an experimental group, and 40 non-EM patients who underwent assisted reproduction were selected as a control group. Collecting follicular fluid obtained by two groups of patients, detecting the expression level of Kallistatin in follicular fluid by ELISA method, comparing between groups, and making ROC curve.
1. Collecting and extracting follicular fluid
And FF is preserved when the oocyte is taken, so that blood pollution is avoided. FF samples from each patient were collected from the follicles and KS concentration measurements were performed. Pooled FFs were centrifuged at 1500g for 10 min to eliminate red blood cells and cell debris. Collecting supernatant, storing at-20 deg.C, and detecting.
2. ELISA method for detecting expression of Kallistatin in follicular fluid
KS levels in follicular fluid of EM patients and those without EM were determined by enzyme-linked immunosorbent assay (ELISA), and the kit was purchased from R & D (cat # DY 1669). The procedure was performed using 96-well plates, following the exact procedure as described. OD values of the standard and each well of the specimen were read at a wavelength of 450nm by an enzyme-linked immunosorbent assay (Finland Leber), and the concentration of each specimen KS was obtained by referring to the standard curve.
3. Prediction model-ROC curve making
And drawing a receiver working characteristic curve ROC, wherein the receiver working characteristic curve is a coordinate graph formed by taking the probability of false positive as a horizontal axis and the probability of true positive as a vertical axis, and is drawn by different results obtained by the receiver under a specific stimulation condition by adopting different judgment standards. The ROC curves were generated using the SPSS software.
4. The result of the detection
4.1 expression of Kallistatin protein in follicular fluid of EM patients
TABLE 1 comparison of sex hormone and KS concentrations in EM patients versus controls
As shown in Table 1, the concentrations of LH, FSH, P, T, E2 and AMH in EM patients were not significantly different from those in the control group. However, the KS concentration in the follicular fluid of EM patients in the experimental group was 281.67 + -104.60 pg/ml, which is significantly lower than that in the control group (490.70 + -216.33 pg/ml) (p < 0.05). That is, the expression level of Kallistatin protein in follicular fluid of EM patients is significantly reduced compared to non-EM patients.
4.2 ART outcome characteristics of EM patients versus controls
TABLE 2 comparison of ART outcome characteristics of EM patients with controls
As can be seen from Table 1, the AFC, Gn doses, endometrial thickness, number of eggs obtained, cleavage rate and number of embryos transferred were similar for both groups. However, the fertilization rate, the usable embryo rate and the good embryo rate of EM patients are all significantly lower than those of the control group. I.e., the ART laboratory outcome of EM patients is even worse. It is predicted that KS may play an important role in the assisted reproductive and pregnancy.
4.3 success rate of pregnancy
The clinical pregnancy rate of the EM group is 61.54%, which is significantly lower than 67.57% of the control group.
Example 2 expression of Kallistatin protein in follicular fluid of subjects with different pregnancy fates
On the basis of example 1, the expression of Kallistatin protein in follicular fluid of the pregnancy success group and the pregnancy failure group was further analyzed by comparison, and as a result, as shown in fig. 1, it was found that the concentration of KS in follicular fluid of the pregnancy success group was significantly higher than that of follicular fluid of the pregnancy failure group, as shown in both the EM group (see fig. 1 (B)) and the control group (see fig. 1 (a)). Taken together, the KS concentration in follicular fluid from the group with successful pregnancy was also significantly higher than that from the group with failed pregnancy (p < 0.05; see FIG. 1 (C)).
Example 3 expression of Kallistatin protein in follicular fluid and ART pregnancy outcome of ROC analysis
To assess the potential of KS concentration in follicular fluid to predict clinical pregnancy, Receiver Operating Characteristic (ROC) curves were plotted as shown in fig. 2, and the area under the curve (AUC) values were determined with the highest specificity and sensitivity as the best prediction point. It is known that the optimal predicted point, sensitivity, specificity and AUC values are 292.78 pg/ml, 71.7%, 65% and 0.7279, respectively, with p value = 0.0024. The result shows that the KS concentration in the follicular fluid can be used as a new index for predicting the pregnancy outcome of the endometriosis female in assisted reproduction and assisted pregnancy.
Claims (4)
- Use of a Kallistatin protein as a detection marker for the preparation of a product for the diagnosis of EM and/or for the assessment of pregnancy outcome of EM patients.
- 2. Application of a reagent for detecting Kallistatin protein expression level in preparation of products for diagnosing EM and/or evaluating pregnancy outcome of EM patients.
- 3. Use according to claim 1 or 2, characterized in that: the product can diagnose whether a patient has EM and/or evaluate pregnancy outcome of patients with EM by detecting the expression level of Kallistatin protein in follicular fluid.
- 4. A product for diagnosing EM and/or assessing pregnancy outcome in EM patients, characterized by: the product can be used for diagnosing EM and/or evaluating pregnancy outcome of EM patients by detecting the expression level of Kallistatin protein in follicular fluid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108061804A (en) * | 2016-11-09 | 2018-05-22 | 北京大学人民医院 | For the biomarker of diagnosis of endometriosis |
| RU2730952C1 (en) * | 2020-05-22 | 2020-08-26 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт морфологии человека" (ФГБНУ НИИМЧ) | Method for early diagnosis of neoplastic transformation of endometrioid ovarian cysts |
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- 2021-12-21 CN CN202111577784.0A patent/CN114002439A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108061804A (en) * | 2016-11-09 | 2018-05-22 | 北京大学人民医院 | For the biomarker of diagnosis of endometriosis |
| RU2730952C1 (en) * | 2020-05-22 | 2020-08-26 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт морфологии человека" (ФГБНУ НИИМЧ) | Method for early diagnosis of neoplastic transformation of endometrioid ovarian cysts |
Non-Patent Citations (1)
| Title |
|---|
| YULING MAO ET AL: ""Kallistatin in follicular fluid of women with endometriosis and its correlation with IVF outcome"", 《GYNECOLOGICAL ENDOCRINOLOGY》, vol. 37, no. 12, 6 July 2021 (2021-07-06), pages 1102 - 1106 * |
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