CN109055535A - Marker of the molecule as diagnosis of sepsis disease in blood - Google Patents
Marker of the molecule as diagnosis of sepsis disease in blood Download PDFInfo
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- CN109055535A CN109055535A CN201811071737.7A CN201811071737A CN109055535A CN 109055535 A CN109055535 A CN 109055535A CN 201811071737 A CN201811071737 A CN 201811071737A CN 109055535 A CN109055535 A CN 109055535A
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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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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
Abstract
The invention discloses a kind of diagnosis of sepsis product, which is to realize diagnostic purpose by the expression of LOC105371870 in detection blood.Research of the present invention has shown that compared with Healthy People, the expression of LOC105371870 is remarkably decreased in sepsis patient blood.According to the existing correlation between LOC105371870 and pyemia, the kit of diagnosis of sepsis disease can be prepared, which can clinically be widely applied.
Description
Technical field
The invention belongs to fields of biomedicine, are related to LOC105371870 answering as the molecular marker of diagnosis of sepsis disease
With.
Background technique
Pyemia, which refers to, causes systemic inflammatory response syndrome (Systemic by infection or height suspicious taint stove
Inflammatory response syndrome, SIRS), the then pathologic process and clinical syndrome of injuries of tissues and organs.
Pyemia can cause multiple organ failure (severe sepsis) and low blood pressure (septic body gram), be to move in Intensive Care Therapy disease
One of the major causes of death of room (intensive care unit, ICU) patient, and medical expense is quite high, gives patient house
Front yard brings great financial burden.However pyemia is at present mainly by clinical diagnosis, and its early clinical manifestation is without specificity,
Lack reliable early warning diagnosis index in time again, thus people be dedicated to finding a kind of or one kind can efficient diagnosis it is pyemic
Biomarker.
Being usually used in clinical or research pyemia associated biomarkers in recent years mainly has c reactive protein (Creactive
Protein, CRP), it is Procalcitonin (procalcitonin, PCT), interleukin-6 (interleukin-6, IL-6), soluble
Myeloid cell triggering receptor -1 (soluble triggering receptor expressed on myeloid cells-1,
STREM-1) etc..CRP is a kind of acute phase protein, not high to diagnosis of sepsis specificity, cannot be reflected pyemic tight
Weight degree, and dispute is also endured to the fullest extent with the relationship of prognosis.Concentration variation and infection severity and the pathogen type phase of PCT
It closes, however its concentration in some noninfectious diseases can also increase, clinical application has certain limitation.Research prompt
IL-6, sTREM-1 have also assisted in pyemic occurrence and development process, but its diagnostic value has not proved out, and need further
Research.In short, current pyemia associated biomarkers have more, sensibility is high or specific not strong deficiency, therefore
It is to be solved as current critical care medicine field letter to find out a kind of biomarker that can be used for pyemia early warning diagnosis
One of major issue.
With the continuous development of transcription group and genomics technologies, people gradually start the sight that will be explored and turn to non-volume
Code RNA (non-coding RNAs, ncRNAs).A series of research confirms microRNAs in cell differentiation and growth course
Take on the key player of post-transcriptional control, however the function of people 1ncRNAs many kinds of for substantial amounts is but known
It is few.It is more than 200nt that long-chain non-coding RNAs (long non-coding RNAs, 1ncRNAs), which are a kind of transcript length, is not compiled
The open reading frame of code protein.Concern correlative coding egg can often be compared when everybody traces to source disease reason in the past
The mutation problems of white matter gene, it is believed that ncRNAs does not have biological function, is subgenomic transcription " noise ".But this think of
Dimensional pattern there now have been very big transformation, and Recent study finds that 1ncRNAs can be after epigenetic, transcription and transcription
The expression of controlling gene in level is the key regulatory molecule of each important link of cellular physiological events, takes part in chromatin and repair
Decorations transport, genomic imprinting, X chromosome silencing and transcribe multiple regulation processes such as interference, transcriptional activation in core, with the mankind
The occurrence and development of disease close relationship there is compared with diagnosis and treatment.The research of current 1ncRNAs is concentrated mainly on tumour, mind
Through fields such as psychotic disorders, but there is no the relevant reports of 1ncRNAs and pyemia relationship.
Summary of the invention
For overcome the deficiencies in the prior art, the purpose of the present invention is to provide a kind of long-chain for diagnosis of sepsis disease is non-
Coding RNA marker.The present invention is using chip and QPCR experiments have shown that table of the LOC105371870 in sepsis patient blood
Up to the horizontal level significantly lower than in normal healthy controls crowd, therefore can be using LOC105371870 as point of diagnosis of sepsis disease
Sub- marker.
In order to test above-mentioned purpose, present invention employs following technical solutions:
The present invention provides application of the reagent of detection long-chain non-coding RNA expression in preparation sepsis diagnosis product；
The encoding gene Gene ID:105371870 (NC_000017.11 of the long-chain non-coding RNA
(68166525..68189296))。
Long-chain non-coding RNA of the invention is named as LOC105371870 in NCBI.Of the invention belongs to gene I/D:
The LOC105371870 of 105371870 coded products can have the transcript of different length: Genbank accession number XR_
934937.3 (length with 6490bp), Genbank accession number XR_001752982.2 (with 6439p length),
Genbank accession number XR_001752983.1 (length with 6508bp), Genbank accession number XR_001752981.1 (tool
There is the length of 6490bp)
Further, the reagent including the use of SYBR Green, TaqMan probe, molecular beacon, double cross probe or is answered
The reagent used when closing probe in detecting LOC105371870 expression quantity.
Further, the reagent includes the PCR amplification primer used when detecting LOC105371870 expression quantity.
In specific embodiments of the present invention, the PCR amplification primer sequence such as SEQ ID NO.1 and SEQ ID
Shown in NO.2.
The present invention provides a kind of product for sepsis diagnosis, the product passes through mentioned-above in detection sample
The expression of long-chain non-coding RNA carrys out diagnosis of sepsis disease.
Further, the product includes but is not limited to chip, kit, test paper or high-flux sequence platform；High pass measures
Sequence platform is a kind of special diagnostic tool, the building with the development of high throughput sequencing technologies, to the rna expression spectrum of a people
Very easily work will be become.Which by the rna expression of comparison Disease and normal population spectrum, it is easy that RNA analyzed
Exception it is related to disease.Therefore, know that LOC105371870 abnormal expression is related to pyemia in high-flux sequence also to belong to
In the purposes of LOC105371870, equally within protection scope of the present invention.
The kit includes the reagent for detecting LOC105371870 expression quantity, and the reagent includes and LOC105371870
Or its DNA sequence dna combine nucleic acid, the nucleic acid include SYBR Green, TaqMan probe, molecular beacon, double cross probe,
Or the primer and/or probe used when combined probe detection LOC105371870 expression quantity.
The chip include detect LOC105371870 expression quantity reagent, the reagent include with LOC105371870 or
The nucleic acid that its DNA sequence dna combines, the nucleic acid includes the primer and/or probe for being able to detect LOC105371870 expression quantity.
The test paper include detect LOC105371870 expression quantity reagent, the reagent include with LOC105371870 or
The nucleic acid that its DNA sequence dna combines, the nucleic acid includes the primer and/or probe for being able to detect LOC105371870 expression quantity.
Further, the primer sequence is as shown in SEQ ID NO.1 and SEQ ID NO.2.
Further, the samples sources of the invention are in blood.
The present invention also provides a kind of methods of diagnosis of sepsis disease, and described method includes following steps:
(1) sample of subject is obtained；
(2) expression of LOC105371870 in Samples subjects is detected；
(3) it associates whether by the expression of the LOC105371870 measured with the illness of subject.
(4) compared with normal healthy controls, the expression of LOC105371870 is significantly reduced, then the subject, which is judged, suffers from
Pyemia judges that the subject is high with pyemic risk or sepsis patient is judged as recurrence or pyemia
Patient is judged as prognosis mala.
In the context of the present invention, " diagnosis " include judge subject whether illness, judge whether subject deposits
Illness risk, judge whether patient has recurred, judge patient to the reactivity of drug therapy or judges that patient's is pre-
Situation afterwards.
Detailed description of the invention
Fig. 1 shows the statistical chart of the differential expression situation using QPCR detection LOC105371870.
Specific embodiment
The present invention is described in further detail with reference to the accompanying drawings and examples.Following embodiment is merely to illustrate this
It invents rather than limits the scope of the invention.Test method without specific conditions in embodiment, usually according to conventional strip
Part, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring HarborLaboratory
Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.
Embodiment 1 screens differential expression molecule
One, research object
Collect 3 hospital's division of respiratory diseases, emergency treatment Intensive Care Unit sepsis patient and 3 healthy volunteers.This research passes through hospital
Ethics Committee's examination & approval, all subjects and family members obtain and sufficiently inform and sign informed consent form.
Two, it is included in standard
Experimental group: sepsis patient.Diagnosis meets SCCM/ESICM/ACCP/ATS/SIS diagnostic criteria (Washington septicopyemia
Disease international conference common recognition), that is, have clear or suspected infection along with following some indexs:
1) overall health of patients:
Generate heat (DIE Temperature>38.3 DEG C) or hypothermia (DIE Temperature<36 DEG C>；
Heart rate > 90 beat/min are higher than 2 standard deviations of the age normal value；
It is short of breath, respiratory rate > 30 beat/min；
State of consciousness changes；
Typical oedema or positive fluid balance > 20m1/kg, continue 24 hours or more；
There is hyperglycemia (blood glucose > 110mg/dl or 7.7mmo1/L) in non-diabetic patients.
2) inflammatory parameters:
Leukocytosis (>12000/ μ l) or oligoleukocythemia (<4000/ μ l) or white blood cell count(WBC) it is normal but not at
Ripe leucocyte ratio > 10%；
Plasma C RP is higher than 2 standard deviations of normal value or more；
Level of procalcitonin is higher than 2 standard deviations of normal value or more.
3) hemodynamic index:
Low blood pressure (systolic pressure 90mmHg, mean arterial pressure<70mmHg, or adult contraction drops>40mmHg, or be lower than
Below 2 standard deviations of the age normal value)；
Mixed venous oxygen saturation > 70%；
Cardiac index (cardiac index, CI) > 3.5L/min/m2.
4) organ dysfunction index:
Hypoxemia (oxygenation index < 300)；
Acute oliguresis (urine volume < 0.5ml/kg/h or 45mmo1/L, at least 2 hours)；
Liquor-saturated increase > the 0.5mg/dl of flesh；
Dysfunction of blood coagulation (international standardization ratio > 1.5 or Activated partial thromboplastin time > 60s)；
Intestinal obstruction (gurgling sound disappearance)；
Decrease of platelet (< 100,000/ μ l)；
Hyperbilirubinemia (blood plasma total bilirubin > 4mg/dl or 70mmo1/L).
5) perfused tissue index:
Hyperlactacidemia (> 3mmo1/L)；
Mucocutaneous there is spot in prolonged capillary refill time.
Control group: the healthy volunteer of physical examination.
Three, exclusion criteria:
1) tumor patient；
2) age < 16 one full year of life；
3) pregnancy or nursing period；
4) merge HIV infection；
5) patient or family members refuse to participate in the research.
Four, experimental procedure
1, whole blood total serum IgE is extracted
1.1 homogenizeds: acquiring subject lml blood with the anticoagulant vacuum tube containing EDTA, is added according to the ratio of 1:3
3ml TRIpure LS Reagent (Bioteke) is cracked in blood with eddy mixer concussion vortex 15-20s to help
Cell.Open simultaneously high speed low temperature centrifugal machine pre-cooling.
1.2 are incubated for 5min so that ribosome decomposes completely under the conditions of 15-30 DEG C.
1.3 are added 0.6m1 chloroform, cover tightly sample tube cover, acutely shake 15s and are incubated at room temperature 3min.
1.4 are centrifuged 10min on the high speed low temperature centrifugal machine of 4 DEG C of 12000rpm, and sample can be divided into three layers later, at this time
RNA is just dissolved in the water phase on upper layer, supernatant is moved into new centrifuge tube.
1.5 are added 75% isometric ethyl alcohol, and gentle inversion mixes, and might have precipitating, together with liquid by precipitating
It pours into the adsorption column RA for covering collecting pipe by several times.
1.6 are centrifuged 45s in 4 DEG C of 10000rpm repeatedly, discard waste liquid, until all precipitatings and solution all cross column.
1.7 are added 500 μ l protein liquid removal RE (Bioteke), and 12000rpm is centrifuged 45s, discards waste liquid.
1.8 are added 700 μ l rinsing liquid RW (Bioteke), and 12000rpm is centrifuged 60s, discards waste liquid.
1.9 are centrifuged 2min in 4 DEG C of 12,000rpm, as far as possible removing rinsing liquid, in case residual ethanol inhibits downstream in rinsing liquid
Reaction.
1.10 take out adsorption column RA, are put into the centrifuge tube of RNase free, and 80 μ l RNase free water are added
(65-70 DEG C of heating bath in advance), places 2min at room temperature, and 12000rpm is centrifuged 1min.
2, RNA quality testing
Use the concentration and purity of NanoDropND-1000 type ultraviolet specrophotometer measurement total tissue RNA.
3, total tissue RNA integrity mensuration'
Through 1% denaturing formaldehyde agarose gel electrophoresis, is observed under ultraviolet transmission light, detect the integrality of RNA.
4, Agilent2100 measures RIN value.
LncRNA sequencing requires: sample requirements: >=200ng；Sample concentration: C >=20ng/ μ L；Sample purity: RIN >=
7.0,28S/18S >=1.0.
5, rRNA is removed
The long-chain non-coding RNA of intracellular a part (> 24%) is all the absence of traditional poly A tail, therefore using removal
The mode of rRNA, which builds library, can obtain more comprehensive lncRNA information.
6, fragmentation RNA
Illumina platform is sequenced for short sequence fragment, and the mRNA and lncRNA that removal rRNA is obtained are complete
RNA sequence, average length may reach several kb, it is therefore desirable to be interrupted at random to it.It, can be by RNA using metal ion
Random fracture at 200bp or so small fragment.
7, reversion synthesis cDNA
Under the action of reverse transcriptase, using random primer, one chain cDNA of synthesis is inverted by template of mRNA, carries out two chains
When synthesis, dTTP is replaced with dUTP in dNTPs reagent, making base in the second chain of cDNA includes A/U/C/G.
8, adaptor is connected
The cDNA structure of double-strand is cohesive end, and End Repair Mix is added and is mended into flat end, then at 3 ' ends
End adds an A base, for connecting the connector of Y-shaped.
9, bis- chain of UNG enzymic digestion cDNA
Before PCR amplification, the second chain of cDNA is digested with UNG enzyme, to make in library only comprising the first chain of cDNA.
10, machine is sequenced on Illumina Hiseq2500
Illumina Hiseq2500 microarray dataset carries out 2*150bp sequencing.
11, bioinformatic analysis
It is as follows that sequencing data obtains later rawdata analytic process:
(1) trim is carried out to the 5 ' of reads and 3 ' sections with cutadapt, trim falls the base of quality < 20, and deletes N
Reads greater than 10%；
(2) tophat is compared onto reference genome.Reference genome version used be GRCh38.p7, fasta and
Gff file download is from NCBI；
(3) expression quantity of cuffquant quantification of mrna and normalization output；Cuffquant quantifies the expression quantity of lncRNA
And normalization output；
(4) cuffdiff compares control group with the differential expression of disease group lncRNA and mRNA.
12, result
Significant difference lncRNA screening conditions: FDR < 0.01.Following result is obtained with the above standard screening: with normal healthy controls
Group is compared, and differential expression LncRNA is 74 in pyemia group blood, wherein raising is 59, downward is 15.
2 large sample of embodiment verifies the differential expression molecule filtered out
Based on sequencing early period as a result, according to the size of P value, we select LOC105371870 to verify.
1, sample collection
The peripheral blood of 45 sepsis patients and the peripheral blood of 45 healthy populations are collected according to the method for embodiment 1.
2, it is verified on transcriptional level
Reagent: reverse transcription reagent box (DDR037A) is purchased from precious bioengineering (Dalian) Co., Ltd.Real-time (the Real- of fluorescence
Time) SYBR Premix Ex Taq used in quantitative PCR (polymerase chain reaction)TM(Tli RNaseH
Plus) kit is the production of Takara company of Japan.
2.1 extract blood total serum IgE
Step is the same as embodiment 1.
2.2 reverse transcription
With the total serum IgE (1 μ g) of extraction for template, following reaction system is added, specifically:Buffer
4 μ L,1 μ L, Oligo dT Primer (50 μM) of RT Enzyme Mix, 1 μ L, Random 6mers (100 μM)
1 μ L, with the ddH of no RNA enzyme2O supplies reaction volume for 20 μ L.Above-mentioned mixed liquor is placed in 37 DEG C of 15min, 85 DEG C of 5s, i.e.,
Obtain cDNA.The cDNA can be used for lncRNA Real-time PCR detection.
2.3 QPCR
According to Japanese Takara companyPremix Ex TaqTM(Tli RNaseH Plus) kit explanation
Book is operated.
Reaction system: SYBR Premix Ex TaqTM(2 ×) 25 μ L, ROX Reference Dye (50 ×) 1 μ L, PCR
1 μ L, PCR downstream primer (10 μM) of upstream primer (10 μM), 14 μ L of μ L, cDNA, sterilize ddH2O 18μL。
Response procedures: 95 DEG C of 20s initial denaturations extend process circulation by 95 DEG C of 10s denaturation, 54 DEG C of 20s annealing, 70 DEG C of 10s
42 times, obtain Ct value.
As a result relative quantification method, formula 2 are used-△△ctIt calculates.Experiment is repeated 3 times.
Design of primers: it according to LOC105371870 sequence, is set by the design of primers tool (Primer BLAST) of NCBI
Meter is directed to the primer of cDNA, and primer sequence is as follows: upstream primer: 5 '-CCAAGGACAAGAAGTATGAG-3 ' (SEQ ID
NO.1)；Downstream primer: 5 '-GGCAGTGATAGACAATAACA-3 ' (SEQ ID NO.2).
According to GAPDH (reference gene) primers, upstream primer: 5 '-CTCTGGTAAAGTGGATATTGT-3 '
(SEQ ID NO.3)；5'-GGTGGAATCATATTGGAACA-3'(SEQ ID NO.4).
3, result
The results show that the LOC105371870 expression in 45 sepsis patients in all patients blood is substantially less than
The average level of healthy control group.Statistical result is as shown in Figure 1, compared with healthy control group, in sepsis patient blood
LOC105371870 expression is substantially reduced, and difference has statistical significance (P < 0.05).
The explanation of above-described embodiment is only intended to understand method and its core concept of the invention.It should be pointed out that for this
For the those of ordinary skill in field, without departing from the principle of the present invention, several improvement can also be carried out to the present invention
And modification, these improvement and modification will also be fallen into the protection scope of the claims in the present invention.
Sequence table
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Claims (10)
1. detecting application of the reagent of long-chain non-coding RNA expression in preparation sepsis diagnosis product；The long-chain non-coding
The encoding gene Gene ID:105371870 of RNA.
2. application according to claim 1, which is characterized in that the reagent is visited including the use of SYBR Green, TaqMan
Needle, molecular beacon, double cross probe or combined probe detect the reagent of the long-chain non-coding RNA expression.
3. application according to claim 2, which is characterized in that the reagent includes detecting the long-chain non-coding RNA table
Up to when the primer that uses.
4. application according to claim 3, which is characterized in that the primer sequence such as SEQ ID NO.1 and SEQ ID
Shown in NO.2.
5. a kind of product for sepsis diagnosis, which is characterized in that the product passes through described in claim 1 in detection sample
The expression of long-chain non-coding RNA carry out diagnosis of sepsis disease.
6. product according to claim 5, which is characterized in that the product includes chip, kit, test paper or high throughput
Microarray dataset.
7. product according to claim 6, which is characterized in that the chip include with mentioned-above non-coding RNA or
The nucleic acid that its DNA sequence dna combines；The kit includes the nucleic acid in conjunction with mentioned-above non-coding RNA or its DNA sequence dna；
The test paper includes the nucleic acid in conjunction with mentioned-above non-coding RNA or its DNA sequence dna；The high-flux sequence platform includes
Nucleic acid in conjunction with mentioned-above non-coding RNA or its DNA sequence dna.
8. product according to claim 7, which is characterized in that the nucleic acid includes primer and/or probe.
9. product according to claim 8, which is characterized in that the primer sequence such as SEQ ID NO.1 and SEQ ID
Shown in NO.2.
10. the product according to any one of claim 5-10, which is characterized in that the sample is blood.
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| CN201910866169.8A CN110408692A (en) | 2018-09-14 | 2019-09-12 | Marker of the molecule as diagnosis of sepsis disease in blood |
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| CN107541563B (en) * | 2017-05-19 | 2018-06-19 | 中南大学湘雅二医院 | A kind of molecular marked compound, kit and application for early diagnosing, predicting septicopyemia complicated with acute injury of kidney |
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