CN112180098B - Screening method of placenta-related disease marker and marker - Google Patents
Screening method of placenta-related disease marker and marker Download PDFInfo
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- G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
Abstract
The invention discloses a screening method of placenta-related disease markers and the markers. The invention screens secreted proteins with cell specificity derived from extravillous trophoblast cells and syncytium trophoblast cells as potential serum markers of placenta-related diseases by the combined use of differential expression profiles of placenta from different diseases and single cell sequencing technology. The serum markers obtained by the method are specifically derived from cell types playing a core role in the occurrence and development of placenta-related diseases, have high specificity and great significance for early diagnosis of the diseases, and meanwhile, the further research on the serum markers is expected to provide therapeutic targets for early intervention of the placenta-related diseases.
Description
Technical Field
The invention relates to a method for screening a marker, in particular to a method for screening a placenta-related disease marker. The invention also relates to corresponding markers.
Background
Pregnancy can be complicated in different ways, related on the one hand to the mortality of pregnant women due to different gestational diseases and on the other hand to the mortality and illness of the fetus. The placenta, which is the largest organ of the fetus, is located at the maternal-fetal interface and develops first during the initial stages of pregnancy and plays a central role in the health of the fetus and mother during pregnancy. At the same time, diseases caused by defects in placental development are also the greatest threat to mothers and fetuses during gestation.
Placenta-related diseases include: preeclampsia, eclampsia, spontaneous abortion, premature placental denudation, fetal growth restriction, and the like [1] . Preeclampsia is a major complication of pregnancy, and about 4-5% of pregnant women are affected by it all over the world [2] . Typical symptoms are new hypertension and proteinuria or other end organ damage in the pregnant woman after 20 weeks of pregnancy. Eclampsia, however, refers to the occurrence of unexplained convulsions on the basis of preeclampsia, and the clinical manifestations and the specificity of the test examination are not strong, but the most common convulsion causes related to hypertension in pregnancy and short postpartum period.
Spontaneous abortion refers to spontaneous abortion which is a common gynecological disease and stops before 28 weeks, and if the spontaneous abortion is not treated in time, inflammation is caused, and heavy bleeding endangers the health of pregnant women and even threatens life.
The premature placental peeling refers to that after 20 weeks of gestation or during childbirth, the placenta in a normal position is partially or completely peeled off from the uterine wall before the fetus is delivered, and is an important reason for vaginal bleeding in the later stage of pregnancy of pregnant women.
The limitation of fetal growth means that the fetus cannot reach the potential of growth and development in the uterus, and is the second leading cause of perinatal fetal death.
Current diagnosis of these placenta-associated diseases still relies on consulting medical history, family genetic history, clinical manifestations of pregnant women, and some routine auxiliary examinations such as B-mode ultrasound, doppler ultrasound, etc. However, due to the complexity of the disease, differential diagnosis of diseases similar to other clinical manifestations is often required. This also makes the diagnosis of placenta-related diseases often have a certain hysteresis, which has a great impact on the health care of pregnant women and fetuses. In recent years, the detection of serum markers has become more and more widely applied to early diagnosis of various diseases,for placenta-related diseases, PAPPA2 [3] Endothelin (ENG) [4] Placenta Growth Factor (PGF) [5] Fms-related tyrosine kinase 1 (FLT 1) [5,6] Is a serum marker which has a certain application value for early diagnosis of preeclampsia reported at home and abroad at present. The detection of PAPPA, ENG, FLT1 and beta HCG has certain predictive value for the limitation of fetal growth [7,8] . The continuous monitoring of the beta HCG also has certain assistance to the prediction of spontaneous abortion [9] . However, the clinical practical use of these serum markers is not sufficient at present. On one hand, the application accuracy and specificity of the serum markers in actual clinical diagnosis are verified by lacking a clinical multi-center random control test; on the other hand, the detection accuracy of the serum marker also limits the wide application of the serum marker to a certain extent [10] 。
The serum markers are mainly screened by differential expression profiles, and secreted proteins in the serum markers are further screened as candidate serum markers for clinical tests. The screening method can screen out genes which change in the process of disease occurrence and development to the maximum extent, but because the genes contain all cell types of diseased tissues, secretory proteins of some cell types may not be secreted into the maternal circulation system, and on the other hand, some cell types may not be core cell types which promote disease occurrence and development, and may cause secondary changes after disease occurrence, the screening efficiency of serum markers and the specificity of the screened serum markers can be greatly reduced. Therefore, the screening of serum markers for placenta-related diseases is blank at present, and the screened markers have certain limitations. The search of a new screening method of serum markers has great significance for early diagnosis of placenta-related diseases.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and relates to a screening method of placenta-related disease markers and application of the markers.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a method of screening for markers for placenta-associated disease in a female subject, comprising:
screening a differential expression profile of a female subject with placenta-related disease and a normal female subject without placenta-related disease;
screening differential expression profiles with placenta cell specific sources by using a single cell transcriptome sequencing technology;
screening secreted proteins of extravillous trophoblast cells or syncytiotroplast cells derived from placenta;
and taking the intersection of the two as a candidate potential marker.
In some examples, the placenta-related disease is selected from one of preeclampsia, eclampsia, premature placental denudation, restricted fetal growth in the uterus, spontaneous abortion.
In some examples, the differential expression profiling is performed using at least one of a protein chip, a gene chip, mass spectrometry, and single cell transcriptome sequencing techniques.
In some examples, the sample for differential expression profiling is selected from placental tissue, blood, serum or plasma, urine of a female subject.
In some examples, potential markers that have significant differences across multiple samples are determined to be risk prediction markers.
In a second aspect of the present invention, there is provided:
a set of markers for use in early-onset preeclampsia diagnosis and potential targets for therapy, at least 1, 2, 3 of said set of up-regulated markers and said set of down-regulated markers, to the total number of said markers; preferably, the markers comprise at least one up-regulating marker and at least one down-regulating marker, wherein:
the group of up-regulating markers is ADAM12, AMD1, CGB, EBI3, FLT4, FSTL3, GFOD2, GREM2, HIPDA, HTRA1, HTRA4, INHBA, MIF, NPB, PAM, PLIN2, PRSS8, PSG9, SEMA7A and TFPI; and
the set of down-regulation markers is ADAMTS1, ADAM28, COL4A1, GADD45A, GPC, GPC4, IGF2, LOXL1, MAPT, PTN, and PCSK5.
In a third aspect of the present invention, there is provided:
use of a detection kit for the preparation of an early onset preeclampsia diagnostic kit, said detection kit being capable of quantifying a marker according to the second aspect of the invention.
The quantification may be direct or indirect.
In some examples, the detection kit is an ELISA detection reagent, a protein chip, a gene chip, mass spectrometry, or single cell transcriptome sequencing.
In some examples, the sample detected by the detection kit is selected from the group consisting of placental tissue, blood, serum or plasma, urine of a female subject.
In a fourth aspect of the present invention, there is provided:
a system for early onset preeclampsia diagnosis, comprising:
a data storage device: for storing information on the expression level of an early-onset preeclampsia diagnostic marker, wherein the early-onset preeclampsia diagnostic marker is the marker according to the second aspect of the present invention;
the data analysis device: calculating the risk of early eclampsia based on the expression amount information of the early eclampsia pre-diagnosis marker;
a result output device: and outputting the result of the data analysis device.
In some examples, a significant up-regulation marker or a significant down-regulation marker is determined as a high risk of early-onset eclampsia.
In a fifth aspect of the present invention, there is provided:
a screening method of a medicine for treating early eclampsia comprises the steps of enabling a compound to be screened to act on cells, detecting the influence of the compound on the expression level of a diagnostic marker for early eclampsia, and determining whether the compound to be screened is selected according to the change condition of the expression level of the marker, wherein the diagnostic marker for early eclampsia is the marker in the second aspect of the invention.
In a sixth aspect of the present invention, there is provided:
a method of diagnosing early onset preeclampsia, comprising:
obtaining a sample to be detected;
detecting the expression level of an early-onset preeclampsia diagnostic marker in a sample to be detected, wherein the early-onset preeclampsia diagnostic marker is as defined in the second aspect of the invention;
and determining the risk of early eclampsia according to the expression quantity of the marker.
In some examples, a significant up-regulation marker or a significant down-regulation marker is determined to be at high risk for early-onset eclampsia.
In some examples, the test sample is selected from the group consisting of placental tissue, blood, serum or plasma, urine of a female subject.
In some examples, ELISA, protein chips, gene chips, mass spectrometry, and single cell transcriptome sequencing techniques are used to detect the amount of expression of a marker in a sample to be tested.
The invention has the beneficial effects that:
the invention screens secreted proteins with cell specificity derived from extravillous trophoblast cells and syncytium trophoblast cells as potential serum markers of placenta-related diseases by the combined use of differential expression profiles of placenta from different diseases and single cell sequencing technology. The serum markers obtained by the method are specifically derived from cell types playing a core role in the occurrence and development of placenta-related diseases, have high specificity and great significance for early diagnosis of the diseases, and meanwhile, the further research on the serum markers is expected to provide therapeutic targets for early intervention of the placenta-related diseases.
Some embodiments of the invention screen differentially expressed genes at the placenta of the nuclear lesion tissue in the onset of preeclampsia based on gene chip technology, and combine with single cell transcriptome sequencing technology to establish genes that are significantly differentially expressed in extravillous trophoblast cells (EVT) and syncytium trophoblast cells (SCT) in intimate contact with maternal blood at the maternal-fetal interface. The secretory protein enters the blood circulation system of the mother body in the development process of preeclampsia so as to provide a high-specificity marker for early identification of preeclampsia. In addition, the secretion source and pathogenic mechanism of the serum marker screened by the method are clear, further research on the serum marker is expected to provide a treatment target for early intervention of preeclampsia, and the serum marker has high treatment application value.
According to some embodiments of the invention, when the differential diagnosis of preeclampsia is carried out on the suspected pregnant woman, only a maternal blood or urine sample is needed, the detection operation is convenient, and the detection result is reliable.
Drawings
FIG. 1 is a schematic representation of a gestational placental interface; SV, helical vein; SA, helical artery; HB, hofbauer cells; FB, fiber cells; VCT, villous trophoblast cells; EVT, extravillous trophoblast cells; SCT, syncytium trophoblast cells; endo, endothelial cells.
FIG. 2 is a diagram of the screening volcano results of the high differential expression genes of the placenta of early preeclampsia (EOPE, <34 week) and premature pregnant women and late preeclampsia (LOPE, ≧ 34 week) and normal pregnant women;
FIG. 3 is a thermographic analysis of differentially expressed genes from the placenta of LOPE, EOPE, normal pregnant women, and premature pregnant women;
FIG. 4 is a cluster plot of single cell sequencing of different types of cells from normal pregnant woman placental tissue; HB, hofbauer cells; FB, fiber cells; VCT, villous trophoblast cells; EVT, extravillous trophoblast cells; SCT, syncytium trophoblast cells; endo, endothelial cells, M, macrophages; epi, epithelial cells.
FIG. 5 is a Wien diagram of early (late) onset preeclampsia up-regulated and down-regulated genes screened by chip data and cell type specific expressed genes identified by single cell sequencing data;
FIG. 6 shows that the ELISA verifies the serum content of the potential serum marker EBI3 in EOPE, LOPE and the corresponding normal pregnant women. (chip data, left; experimental data, right) (Student t test;. P < 0.05;. P < 0.01;. P < 0.001).
FIG. 7 shows that EBI3 in the patient serum has a linear correlation trend with the clinical indicators (uric acid and urine protein) of the patient.
Detailed Description
The technical scheme of the invention is further explained by combining specific experiments. The following examples are intended to illustrate the invention only. They should not be construed as limiting the scope of the invention in any way.
Screening for novel diagnostic markers
1) Preeclampsia is a disease derived from placental dysgenesis in which the placenta, located at the maternal-fetal interface, secretes a number of factors into the maternal-fetal blood circulation during the onset. The remodeling of the uterine spiral artery plays an important role in the normal development of the placenta, and the occurrence of preeclampsia is caused by insufficient blood supply of the placenta and hypoxia and oxidative stress caused by insufficient remodeling. The core role of trophoblasts in helical arterial remodeling makes them the type of core diseased cells in the onset of preeclampsia. Therefore, screening for proteins specifically derived from EVT and SCT (see fig. 1) in intimate contact with maternal blood provides a potential marker with high clinical utility value for early diagnosis of preeclampsia, greatly reduces data throughput, improves screening efficiency, and has unexpected effects.
2) Searching a preeclampsia placenta Expression chip database (GSE 74341) in Gene Expression Omnibus (GEO) [11] . EOPE and preterm delivery and LOPE and term pregnant women are respectively compared to screen differential expression genes (Fold Change is more than or equal to 1.5 and P-value is less than 0.05), and as shown in figure 2, the number of the differential expression genes of EOPE is obviously more than that of LOPE. Further heat map analysis also confirmed that EOPE showed significant differences in gene expression patterns relative to the other three groups, as shown in figure 3. Therefore, the EOPE placenta has high specificity of the differential expression gene and has high application value for further serum marker screening.
3) To screen for differentially expressed genes specifically expressed in EVT and SCT, we tested Roser Vento [12] A published study on single cell transcriptome sequencing of maternal-fetal interfaces performed the reintegration and clustering of data from the fetal disc fraction, as shown in figure 4.
4) The comparative analysis is respectively carried out on the gene which is screened by the chip data and differentially expressed in EOPE and LOPE and the gene which is identified by the single cell sequencing data and specifically expressed in cell types to obtain a figure 5, wherein the specific up-regulated gene of the cell types in the EOPE is 94, the down-regulated gene is 206, the up-regulated gene of the LOPE is 16, and the down-regulated gene is 6, which also reflects that the pathogenesis of the EOPE is more closely related to the placenta, and the detection of the protein components from the placenta has high application value for the diagnosis of the EOPE. Subsequent marker screening therefore focused on 94 up-regulated genes and 206 down-regulated genes specifically expressed by cell types in EOPE.
5) We used GeneCard and published data on secreted proteins [13] The 94 up-regulated genes were screened for secreted proteins to obtain 24 secreted protein markers specifically up-regulated in the pre-eclampsia placenta, as shown in table 1.
6) Also, 11 secreted protein markers specifically down-regulated in the pre-eclampsia placenta were obtained by the same screening method, as shown in table 2.
7) To verify the possibility of the selected markers in practical clinical application, we tested the plasma levels of the secreted protein EBI3 specifically expressed in EVT in EOPE, LOPE and their corresponding normal pregnant women by ELISA, as shown in FIG. 6.EBI3 was significantly higher in the amount of EOPE than its control group, while there was no significant difference between LOPE and its corresponding control group.
8) Meanwhile, correlation analysis is carried out on the content of the EBI3 in serum of a patient and clinical indexes (uric acid and urine protein) of the serum of the patient to show a positive correlation trend, as shown in figure 7, the method lays a foundation for further carrying out a large clinical double-blind random test, and also embodies that the screened marker has extremely high application value for early diagnosis of diseases.
The inventor screens high-difference expression genes from a preeclampsia placenta tissue and a control group thereof by a gene chip technology, screens 94 high-difference up-regulated and 206 high-difference down-regulated genes with cell type specific expression by combining a single cell sequencing technology, screens secretory proteins derived from EVT and SCT closely contacted with maternal blood from the genes, and classifies the secretory proteins by retrieving the degree of reports related to preeclampsia to obtain 24 up-regulated and 11 down-regulated serum markers for early preeclampsia diagnosis, thereby verifying the great potential of the secretory protein EBI3 in the early preeclampsia clinical diagnosis application by an enzyme-linked immunosorbent assay and the correlation analysis with clinical indexes. Therefore, the serum marker obtained by the combined screening has high specificity, and can be used for early diagnosis of early eclampsia and reduce missed diagnosis if the serum marker is verified by clinical random tests.
Table 1:24 secreted proteins specifically up-regulated in placenta before early eclampsia
I has been reported to play an important role in the onset of preeclampsia and has been evaluated in clinical diagnosis;
II has been reported to play a role in the development of preeclampsia;
III reports related to preeclampsia are temporarily absent.
Table 2:11 secreted proteins specifically down-regulated in preeclampsia placenta
I has been reported to play a role in the development of preeclampsia;
II reports related to preeclampsia are temporarily absent.
The screening method and the marker at least have the following applications:
1) The screening method is possibly also suitable for screening serum markers of placenta syndrome disorder, such as diseases of placental prematurity, fetal growth restriction, spontaneous abortion and the like;
2) Diagnosing the suspected preeclamptic pregnant woman by detecting the screened serum markers;
3) Aiming at the secreted protein of the patent, the secreted protein is directly or after being modified to be designed as a therapeutic target for preventing and treating preeclampsia and gestational hypertension;
4) The pathogenesis of preeclampsia is not clear, the current widely thought is caused by placenta development limitation and insufficient uterine spiral artery remodeling, and the deep research on the screened high differential expression genes specific to the placenta lays a foundation for the research on the pathogenesis of the preeclampsia;
5) The pre-eclampsia disease condition shows continuous change, and the continuous detection of the screened serum marker is a good auxiliary method for monitoring the progress of the disease condition;
6) The clinical manifestations of preeclampsia are similar to those of other hypertensive diseases in gestation period and chronic nephritis, but the pathogenesis of the preeclampsia is different, and the detection of the serum marker has high clinical value for differential diagnosis of the preeclampsia;
7) Preeclampsia is not limited to the gestational period of a pregnant woman, the pregnant woman after delivery is always at the risk of new hypertension (postspecific hypertension), and the continuous monitoring of the serum markers after delivery has a certain reference value for monitoring the postpartum complications;
8) The screened serum marker is not limited to early diagnosis of preeclampsia, and further research on the serum marker can provide a new target and strategy for treatment and prevention of preeclampsia;
9) According to the invention, the secretory protein is used as a detection target to design a kit or a detection instrument for early and rapid diagnosis of preeclampsia.
Reference documents:
1.Brosens,I.,et al.,The"Great Obstetrical Syndromes"are associated with disorders of deep placentation.Am J Obstet Gynecol,2011.204(3):p.193-201.
2.Phipps,E.A.,et al.,Pre-eclampsia:pathogenesis,novel diagnostics and therapies.Nat Rev Nephrol,2019.15(5):p.275-289.
3.Nishizawa,H.,et al.,Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients.Mol Hum Reprod,2008.14(10):p.595-602.
4.Levine,R.J.,et al.,Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.N Engl J Med,2006.355(10):p.992-1005.
5.Verlohren,S.,et al.,The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients.Am J Obstet Gynecol,2012.206(1):p.58.e1-8.
6.Maynard,S.E.,et al.,Excess placental soluble fms-like tyrosine kinase 1(sFlt1)may contribute to endothelial dysfunction,hypertension,and proteinuria in preeclampsia.J Clin Invest,2003.111(5):p.649-58.
7.Zamarian,A.C.,et al.,Evaluation of biochemical markers combined with uterine artery Doppler parameters in fetuses with growth restriction:a case-control study.Arch Gynecol Obstet,2016.294(4):p.715-23.
8.Cignini,P.,et al.,Predictive value of pregnancy-associated plasma protein-A(PAPP-A)and free beta-hCG on fetal growth restriction:results of a prospective study.Arch Gynecol Obstet,2016.293(6):p.1227-33.
9.Liu,Y.,et al.,Predictive value of serumβ-hCG for early pregnancy outcomes among women with recurrent spontaneous abortion.Int J Gynaecol Obstet,2016.135(1):p.16-21.
10.Kleinrouweler,C.E.,et al.,Accuracy of circulating placental growth factor,vascular endothelial growth factor,soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia:a systematic review and meta-analysis.Bjog,2012.119(7):p.778-87.
11.Liang,M.,et al.,Gene expression profiling reveals different molecular patterns in G-protein coupled receptor signaling pathways between early-and late-onset preeclampsia.Placenta,2016.40:p.52-9.
12.Vento-Tormo,R.,et al.,Single-cell reconstruction of the early maternal-fetal interface in humans.Nature,2018.563(7731):p.347-353.
13.Uhlén,M.,et al.,Proteomics.Tissue-based map of the human proteome.Science,2015.347(6220):p.1260419.
Claims (4)
1. a set of markers for use in the diagnosis of early onset preeclampsia, the set of markers consisting of a set of up-regulated markers and a set of down-regulated markers, wherein: the group of up-regulating markers is ADAM12, AMD1, CGB, EBI3, FLT4, FSTL3, GFOD2, GREM2, HIPDA, HTRA1, HTRA4, INHBA, MIF, NPB, PAM, PLIN2, PRSS8, PSG9, SEMA7A and TFPI; and the set of down-regulating markers is ADAMTS1, ADAM28, COL4A1, GADD45A, GPC, GPC4, IGF2, LOXL1, MAPT, PTN and PCSK5; the screening method of the marker comprises the following steps:
screening differential expression profiles of female subjects with early-onset preeclampsia and normal female subjects without placenta-related diseases;
screening differential expression profiles with placenta cell specific sources by using a single cell transcriptome sequencing technology;
screening secretory proteins of extravillous trophoblast cells or syncytiotrophoblast cells derived from placenta;
taking the intersection of the two as a candidate potential marker;
the sample for differential expression profile screening is selected from the group consisting of serum of female subjects;
screening for differential expression profiles using at least one of protein chip, gene chip, mass spectrometry and single cell transcriptome sequencing techniques;
potential markers that differ significantly across multiple samples are identified as risk predictive markers.
2. The application of the detection kit in preparing the early eclampsia diagnosis kit is characterized in that: the detection kit can quantify the marker of claim 1.
3. A system for early onset preeclampsia diagnosis, comprising:
a data storage device: for storing information on the amount of expression of an early-onset preeclampsia diagnostic marker as set forth in claim 1;
a data analysis device: calculating the risk of early eclampsia based on the expression amount information of the early eclampsia pre-diagnosis marker;
a result output device: and outputting the result of the data analysis device.
4. The system of claim 3, wherein: and (4) the up-regulation marker is obviously up-regulated or the down-regulation marker is obviously reduced, and the early eclampsia is judged to be high risk.
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| EP3458861A4 (en) * | 2016-05-17 | 2019-12-11 | LDX Prognostics Limited Co. | Methods and compositions for providing preeclampsia assessment |
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