CN104928394B - Intrauterine growth restriction diagnosis and treatment molecular marker - Google Patents
Intrauterine growth restriction diagnosis and treatment molecular marker Download PDFInfo
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- CN104928394B CN104928394B CN201510382768.4A CN201510382768A CN104928394B CN 104928394 B CN104928394 B CN 104928394B CN 201510382768 A CN201510382768 A CN 201510382768A CN 104928394 B CN104928394 B CN 104928394B
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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
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- 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
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/154—Methylation markers
Abstract
The invention discloses hypomethylation gene PIK3R1 application, one side hypomethylation gene PIK3R1 can be used for preparing intrauterine growth restriction diagnostic products, and another aspect hypomethylation gene PIK3R1 can be used for the medicine for preparing intrauterine growth restriction.Present invention experiment proves the PIK3R1 genes hypomethylation in the blood samples of patients with intrauterine growth restriction disease, the achievement in research provides strong molecular biology foundation for the diagnosis and treatment of intrauterine growth restriction patient, with far-reaching clinical meaning and generalization.
Description
Technical field
The invention belongs to biomedicine field, it is related to a kind of intrauterine growth restriction diagnosis and treatment molecular marker, specifically relates to
And PIK3R1 gene methylations and its detection reagent are in intrauterine growth restriction diagnostic products and medicine is prepared
Using.
Background technology
Intrauterine growth restriction (intrauterine growth restriction, IUGR), also known as fetal in utero
Hypoevolutism (intrauterine growth retardation, IUGR), refers to that birth weight is flat less than corresponding pregnant week fetus
The equal percentile of body weight the 10th or less than two standard deviations of average weight, is one of perinatal period major complications, its perinatal feruses disease
Dead rate is 8 times of normal youngster.Developing country there are about 30million IUGR neonates birth every year by inference.IUGR rear something lost
Disease is broadly divided into after life sequelae in the recent period and sequelae at a specified future date, and recent sequelae is mainly dysglycemia, temperature after IUGR lifes
Insufficiency of accommodation, respiratory distress syndrome, neonatal necrotizing enterocolitis and neonate's PVR are spent, is to cause new life
Youngster's main causes of death；Sequelae at a specified future date is mainly manhood obesity, insulin resistance, diabetes B, hypertension, painstaking effort
Pipe disease and asthma etc..2010, motrenko etc. was proposed " disease embryo origin theory ", it is believed that embry ogenesis period is extraneous not
Good factor can increase the incidence of chronic disease after adult, gamete, embryo and fetal tissue wherein caused by poor environment exposure
Epigenetics modification changes, it is considered to be one of important pathogenesis.Embryo growth and development is answered by multifactor regulation
Miscellaneous process, the undesirable condition such as malnutrition, infection, anaemia, hypoxia can all influence the growth of fetus when mother is pregnant, and make tire
Youngster causes fetus in terms of metabolism, allelotaxis, immunological stress in the growing environment of an improper regulation and control
Occur corresponding change, and cause related gene to occur the change in epigenetics, DNA methylation is the modification found earliest
One of approach, is also to cause epigenetic to adjust the startup factor in reaction chain.DNA methylation can cause chromatin Structure, DNA
Conformation, DNA stability and DNA and protein interaction mode change, dystopy methylate cause gene expression dose and under
Swim signal transmission to change, so as to regulate and control to have the expression of correlation gene.As can be seen here, DNA methylation gene transcription level modification,
Important function has been played in terms of biological development regulation.It is now recognized that the modification that methylates that gene promoter area occurs can be in space
It is upper to hinder transcription factor and DNA combination, therefore DNA methylation is typically associated with gene silencing.
Increasing research confirms that aberrant DNA methylation and IUGR are significantly correlated in recent years.Studies have reported that, IUGR is big
Mouse pancreas pancreas duodenum is with source capsule 1 (pancreatic duodenum homeobox gene-1, Pdx1) gene promoter area
Methylation level is significantly raised, and Pdxl gene expressions decline, and increase the onset risk of IUGR patient's diabetes B.
Einstein etc. has found the change that the cytimidine of IUGR neonate CD34+ candidate stem cells and progenitor cells is methylated.
The chip research that methylated with Illumina GoldenGate such as Yuen finds there is the first of 5 exceptions in IUGR placenta tissues
Base region.As can be seen here, the DNA methylation modification of several genes take part in IUGR pathogenic process, it is therefore desirable to from full base
Because of the relation that researching DNA methylation patterns occur with IUGR in group level, the base of the differential methylation related to IUGR is identified
Cause, and the mechanism of its abnormal methylation is analysed in depth, regulation mechanism of the DNA methylation in IUGR is specified, pin is taken
Improve fetus to property measure to grow, early prevention and treatment is given to manhood chronic disease.
The content of the invention
The invention provides a kind of intrauterine growth restriction diagnosis and treatment molecular marker, the molecular marker is hypomethylation
PIK3R1 genes.Had shown that by research, compared with normal crowd, PIK3R1 bases in intrauterine growth restriction blood samples of patients
The methylation level of cause is significantly lowered, according to both correlations, by the methylation level for detecting PIK3R1 genes in body fluid
It can determine whether whether subject suffers from intrauterine growth restriction or may determine that subject whether there is and suffer from fetal in utero
The risk of growth restriction, so as to realize the early diagnosis of intrauterine growth restriction, is the formulation of the precautionary measures of disease and faces
The formulation of personalized therapy program provides basis on bed.
Intrauterine growth restriction diagnosis production is being prepared present invention also offers the reagent of detection PIK3R1 gene methylations
Application in product, it is characterised in that the diagnostic products include the reagent of detection PIK3R1 gene methylations, the reagent passes through
The PIK3R1 gene methylations level in body fluid is detected to judge whether subject suffers from intrauterine growth restriction or presence
Risk with intrauterine growth restriction.
Further, the body fluid includes the neonatal body fluid after birth, also the body fluid including parent.The body fluid bag
Include any liquid of body generation, including but not limited to blood, blood plasma, serum, tissue fluid, cerebrospinal fluid, saliva, peritoneal fluid, cunning
Film liquid, amniotic fluid, urine, vaginal fluid, gastric juice, digestive juice, lymph, gall-bladder liquid, bile.
The method of detection gene methylation degree or frequency can be used for include but is not limited to full-length genome in the prior art
DNA methylation assay technology, such as full-length genome based on chip platform methylate screening, methylating based on high-flux sequence platform
Atlas analysis, the genome after specific site DNA methylation assay technology, such as methylation status of PTEN promoter (MSP), sulphite processing
PCR sequencing PCR (BSP), joint bisulfites restriction endonuclease analysis (COBRA), methylation-specific endonuclease digestion and
Quantitative polyase chain reaction combination method (MSRED-qPCR), fluorescent quantitation (Methylight), methylation sensitive high-resolution
Rate melting curve analysis method (MS-HRM), pyrosequencing method (Pyrosequencing).Therefore PIK3R1 gene methyl is detected
Required reagent when the reagent of change is using above method detection PIK3R1 gene methylation levels.
In specific embodiments of the present invention, required reagent includes amplification during detection PIK3R1 gene methylation levels
The primer sequence of the PIK3R1 genetic fragments including methylation sites is included, the primer sequence is as follows：
5 ' end primers：
aggaagagagTGTTTTTTTTAATGTGGTATATTTGTGA；
3 ' end primers：
cagtaatacgactcactatagggagaaggctAAAAAATATCACCAAACCACTCCTAC。
Further, the diagnostic products are including but not limited to kit, chip, microarray dataset.Wrapped in kit or chip
Containing the primer or probe available for detection PIK3R1 gene methylation levels.Microarray dataset is a kind of special diagnostic products, is led to
High-flux sequence detection full-length genome information is crossed, in the process it can be found that PIK3R1 gene methylations grow in fetal in utero
Limited to there is significant difference between patient and normal person, analysis understands to give birth to fetal in utero using the hypomethylation of PIK3R1 genes
It is long limited related so as to provide diagnosis report or provide treatment recommendations, the above be also contained in protection scope of the present invention it
It is interior.
Present invention also offers a kind of product for diagnosing fetal Fetal Growth Restriction, the product is included and can detected
The reagent of PIK3R1 gene methylation levels.
The method of detection gene methylation degree or frequency can be used for include but is not limited to full-length genome in the prior art
DNA methylation assay technology, such as full-length genome based on chip platform methylate screening, methylating based on high-flux sequence platform
Atlas analysis, the genome after specific site DNA methylation assay technology, such as methylation status of PTEN promoter (MSP), sulphite processing
PCR sequencing PCR (BSP), joint bisulfites restriction endonuclease analysis (COBRA), methylation-specific endonuclease digestion and
Quantitative polyase chain reaction combination method (MSRED-qPCR), fluorescent quantitation (Methylight), methylation sensitive high-resolution
Rate melting curve analysis method (MS-HRM), pyrosequencing method (Pyrosequencing).Therefore PIK3R1 gene methyl is detected
Required reagent when the reagent of change is using above method detection PIK3R1 gene methylation levels.
In specific embodiments of the present invention, required reagent includes amplification during detection PIK3R1 gene methylation levels
The primer sequence of the PIK3R1 genetic fragments including methylation sites is included, the primer sequence is as follows：
5 ' end primers：
aggaagagagTGTTTTTTTTAATGTGGTATATTTGTGA；
3 ' end primers：
cagtaatacgactcactatagggagaaggctAAAAAATATCACCAAACCACTCCTAC。
Present invention also offers hypomethylation gene PIK3R1 answering in intrauterine growth restriction medicine is prepared
With.The medicine can treat intrauterine growth restriction by improving the methylation level of PIK3R1 genes.
Further, the active component of the medicine is PIK3R1 gene methylation accelerator, the PIK3R1 genes methyl
The methylation level of PIK3R1 genes can be improved by changing accelerator.
The accelerator that methylates can activate the material or energy of DNA methylation transferase (DNMT)
The material of enough suppressor demethylases or be the two combination.
Present invention also offers PIK3R1 gene methylations accelerator in intrauterine growth restriction medicine is prepared
Application, the PIK3R1 gene methylations accelerator can improve the methylation level of PIK3R1 genes.
Further, the accelerator that methylates can activate DNA methylation transferase (DNMT) material, also may be used
To be to be capable of the material of suppressor demethylase or be the two combination.
Present invention also offers a kind of pharmaceutical composition for being used to treat intrauterine growth restriction, described pharmaceutical composition
Comprising PIK3R1 gene methylation accelerator, the PIK3R1 gene methylations accelerator can improve the methyl of PIK3R1 genes
Change level.The accelerator that methylates can be can activate DNA methylation transferase (DNMT) material or can
The material of suppressor demethylase or be the two combination.
In the context of the present invention, the methylation level of the PIK3R1 genes, which is significantly lowered, refers to that PIK3R1 genes are averaged
Methylation level is significantly lowered.
In specific embodiments of the present invention, find compared with normal group, the site of IUGR group PIK3R1 genes -98, -
244 sites, -332 site methylation levels are significantly lowered, and the average methyl level in three sites is also significantly lowered.
" diagnosis " includes judging whether subject includes judging tested with intrauterine growth restriction, also herein
Person whether there is the risk with intrauterine growth restriction.
, can be with by detecting the average methyl level of PIK3R1 genes it can be seen from the analysis of research achievements of the present invention
Judge whether subject suffers from intrauterine growth restriction, or may determine that subject whether there is with fetal in utero growth
Limited risk.Can also by detect respectively the site of PIK3R1 genes -98, -244 sites, -332 site methylation levels come
Judge whether subject suffers from intrauterine growth restriction, or may determine that subject whether there is with fetal in utero growth
Limited risk.
The advantages of the present invention：
1st, it is pioneering, with innovation present invention finds PIK3R1 gene methylations are related to intrauterine growth restriction
Property.
2nd, present invention discover that intrauterine growth restriction diagnosis molecular marker, can be by extracting the blood of subject
To detect its methylation level, with it is noninvasive, quick, special, sensitive the characteristics of.
Embodiment
With reference to embodiment, the present invention is further detailed explanation.Following examples be merely to illustrate the present invention and
It is not used in limitation the scope of the present invention.The experimental method of unreceipted actual conditions in embodiment, generally according to normal condition, for example
Sambrook et al., molecular cloning：Laboratory manual (New York:Cold Spring HarborLaboratory Press,
1989) condition described in, or according to the condition proposed by manufacturer.
The screening of the differential methylation gene of embodiment 1
1st, sample is collected：Collect the intrauterine growth hair that 2013-1-1 to 2013-6-30 is in hospital in Beijing Friendship Hospital's paediatrics
Educate limited (intrauterine growth restriction, IUGR) infant and the utility evaluation of the same period
(appropriate for gestational age, AGA) clinical data and blood specimen.Each patient endorsed informed
Letter of consent, the research obtains the license of Ethics Committee of Beijing.
Clinical data：No sex difference between IUGR 8, AGA 4, two groups, gestational age is with birth weight with median
(minimum value, maximum) represents that female pregnancy period is without special.Control group is the utility evaluation being admitted to hospital the same period, more because of jaundice, new life
The problems such as youngster's wet lung, is admitted to hospital, without other major diseases, with hypothermia, hypoglycemia and neonate when IUGR groups part infant is admitted to hospital
The complication such as Respiratory Distress Syndrome(RDS).Two groups of demographic informations and Clinical symptoms are shown in Table 1.
The clinical information of table 1
| IUGR n=8 | AGA n=4 | |
| Gestational age (week) | 34(31,35) | 39(34,40) |
| Birth weight (g) | 1625(1200,2050) | 3350(2650,3600) |
| Sex (man：Female) | 4:4 | 2:2 |
| Body temperature (<35℃) | 3 | Nothing |
| Merge NRDS | 3 | Nothing |
| Merge hypoglycemia | 2 | Nothing |
Note：Data are expressed as intermediate value (maximum, minimum value)
2nd, step
2.1 extract genomic DNA
The gDNA in blood is extracted using PureLink Genomic DNA kit (being purchased from Invitrogen companies), specifically
Operate and carried out according to the instruction of kit specification.
All DNA applications spectrophotometers carry out quality inspection, are higher than 75ng/ μ L with concentration, and total amount is higher than 1 μ g, electrophoresis master tape
Apparently without degraded, A 260/280=1.7-2.1 sample is qualified samples.All sample standard deviations of this experiment are qualified.Extract
DNA is placed in -20 DEG C of refrigerators and saved backup.
2.2 sulfurous hydrohalogenic acid salts are modified
Use EZ DNA MethylationTMKit (being purchased from Zymo Research, article No. is D5008) modification gDNA, tool
Gymnastics is made to carry out according to the instruction of kit specification.
2.3 chip hybridization
GDNA and Infinium Human Methylation450K after the sulfurous hydrohalogenic acid salt conversion that step 2 is obtained
BeadChip (being purchased from Illumina companies) is hybridized, and concrete operation step is carried out according to the instruction of chip specification.
2.4 data processing
Illumina Human Methylation450k chips obtain initial data by Illumina Iscan scannings.
The back of the body of data is carried out using GenomeStudio Methylation module version 1.0 (being purchased from Illumina companies)
Scape is corrected and Controls standardization, and using Illumina Custom methods screening differential gene, P values after selection BH corrections<
0.05(|diffscore|>13) difference site is used as significant differential methylation site.
3rd, experimental result
Experimental group IUGR is compared with control group A GA, and 5460, differential methylation site is filtered out altogether, is related to 2264
Gene, wherein 662 gene methylation level up-regulations, 1448 gene methylation horizontal down-regulations.Wherein, compared with AGA groups,
IUGR infant PI3KRl gene methylation levels are substantially lowered, and IUGR group average methyls rate is 0.8318, AGA group average methyls
Rate is 0.9049, and this species diversity has statistical significance (P values<0.05), diffscor values are -28.053.
The checking of the differential methylation gene of embodiment 2
Whether reliable for the data of clear and definite chip, we have collected 40 IUGR infants and 40 AGA, selection differences in addition
Methylated genes PI3KR1, is verified, specifically using MassARRAY Compact System (being purchased from Sequenom companies)
Operation instruction to specifications carry out.It is as follows in simple terms：
1st, gDNA extraction according to embodiment 1 the step of carry out.
2nd, the step of sulphite is modified according to embodiment 1 is carried out.
3rd, PCR expands chr5:67585758-675867575 ' fragments, amplimer is as follows：
5 ' end primers：
aggaagagagTGTTTTTTTTAATGTGGTATATTTGTGA；
3 ' end primers：
cagtaatacgactcactatagggagaaggctAAAAAATATCACCAAACCACTCCTAC。
4th, alkaline phosphatase treatment is carried out using Mass CLEAVE Kit kits, then using Spectro CHIP
Arrays and Clean Resin kit kits are purified.
5th, step 4 is obtained using MassARRAY Nanodispenser RS1000 point sample instruments (being purchased from Sequenom companies)
On the product point obtained to 384 hole Spectro-CHIP (being purchased from Sequenom companies) chip.
6th, the good chip of point sample is put into MassARRAY Compact System (being purchased from Sequenom companies) to be examined
Survey.
7th, Spectro-CHIP chips use MALDI-TOF technologies, and detection data (are purchased from by EpiTyper softwares
Sequenom companies) analyze and output result.
8th, statistical procedures：Detect that data, by EpiTYPER softwares (SEQUENOM) analysis and output result, are used
SPSS13.0 softwares carry out data processing, and statistical method uses Wilcoxon rank tests and chi-square criterion, with P<0.05 is poor
It is different statistically significant.
9th, result is as shown in table 2：
The methyl rate in the PIK3R1 gene methylations site of table 2
| Gene loci | IUGR (methyl rate) | AGA (methyl rate) |
| -98 | 0.6988 | 0.8233 |
| -244 | 0.7587 | 0.9033 |
| -289 | 0.7213 | 0.7167 |
| -332 | 0.9013 | 0.9633 |
Calculated and understood according to the above results, the average methyl rate of IUGR group PIK3R1 genes is 0.7700, AGA groups
The average methyl rate of PIK3R1 genes is 0.8516, and the difference has statistical significance (P<0.05).
10th, the correlation of PIK3R1 gene methylations and FGR
Using Logistic regression analysis PIK3R1 gene methylations and the correlation of FGR, as a result show：
PIK3R1 gene average methylizations and FGR have that significantly correlated (OR values are 1.6926, P<0.05)；PIK3R1 bases
Because -98 sites and FGR are present, significantly correlated (OR values are 2.0467, P<0.05)；The site of PIK3R1 genes -244 with
FGR exist it is significantly correlated (OR values be 2.9683, P<0.05)；The site of PIK3R1 genes -332 and fetal growth by
Limit exist it is significantly correlated (OR values be 2.6667, P<0.05).
Whether the above results show, can judge subject with fetus life by detecting PIK3R1 gene methylations rate
It is long to be limited or to judge that subject whether there is the risk with FGR.
The explanation of above-described embodiment is only intended to understand the method and its core concept of the present invention.It should be pointed out that for this
For the those of ordinary skill in field, under the premise without departing from the principles of the invention, some improve can also be carried out to the present invention
And modification, these are improved and modification will be also fallen into the protection domain of the claims in the present invention.
Claims (5)
- Application of the 1.PIK3R1 gene methylations detection reagent in intrauterine growth restriction diagnostic products are prepared, its feature exists In the diagnostic products include the reagent of detection PIK3R1 gene methylations, and the reagent is by detecting in subject's body fluid PIK3R1 gene methylations level come judge subject whether suffer from intrauterine growth restriction.
- 2. application according to claim 1, it is characterised in that the body fluid is blood.
- 3. application according to claim 1, it is characterised in that the reagent is the full-length genome methyl based on chip platform Change the gene order-checking after screening, the processing of the methylation profiles analytic approach based on chip, methylation status of PTEN promoter, sulphite Method, joint bisulfites restriction endonuclease analysis, methylation-specific endonuclease digestion and quantitative polyase chain reaction Combination method, fluorescent quantitation, methylation sensitive high-resolution melting curve analysis method, pyrosequencing method detection PIK3R1 bases Reagent needed for during because of methylation level.
- 4. the application according to any one of claim 1-3, it is characterised in that the reagent, which includes expanding including, to methylate The primer of PIK3R1 genetic fragments including site.
- 5. the application according to any one of claim 1-3, it is characterised in that the diagnostic products be kit, chip, Or microarray dataset.
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| Title |
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| DNA methylation: the pivotal interaction between early-life nutrition and;Jia Zheng et.al;《British Journal of Nutrition》;20141020;1850-1857页 * |
| Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.;Clea Bárcena et.al;《BMC Medical Genetics》;20141231;1-6 * |
| 宫内生长发育受限患儿血清糖皮质激素变化;丁瑛雪等;《中国优生与遗传杂志》;20141230;72-73页 * |
| 胎儿生长受限孕妇血清皮质醇浓度与胎盘组织IGF-1表达水平研究;王秀等;《实用妇产科杂志》;20050228;87-90页 * |
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