CN105219857B - A kind of Abacavir personalized medicine detection kit and its method - Google Patents
A kind of Abacavir personalized medicine detection kit and its method Download PDFInfo
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- CN105219857B CN105219857B CN201510670708.2A CN201510670708A CN105219857B CN 105219857 B CN105219857 B CN 105219857B CN 201510670708 A CN201510670708 A CN 201510670708A CN 105219857 B CN105219857 B CN 105219857B
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Abstract
The present invention provides a kind of Abacavir personalized medicine detection kit and its method, belongs to Abacavir medication detection technique field.The present invention uses Allele-Specific LAMP technology, devises special primer for the G allele of rs2395029, judges whether patient carries HLA-B*5701 allele using the G allele of rs2395029 and the relevance of HLA-B*5701.After test, the state change (variation for whether having precipitating or color) of observing response system can determine whether that positive reaction occurs, and can visually be judged, simple and easy to do without additional appliance arrangement.
Description
Technical field
The present invention relates to Abacavir medication detection technique fields more particularly to a kind of Abacavir personalized medicine to detect
Kit and its method.
Background technique
Abacavir (abacavir, abbreviation ABC, trade name: Ziagen) is a kind of anti-AIDS new drug, is new carbocyclic ring
2'- deoxyguanosine nucleoside medicine, oral administration biaavailability is high, easily infiltration central nervous system.It is reversed with other ucleosides
Transcriptase inhibitors are the same, and Abacavir is an inactive prodrug, are metabolized into three active phosphorus through 4 steps in vivo
Acid esters, and pass through the effect of following 2 approach performance HIV inhibiting (HIV) reverse transcriptase: 1. competitively press down
2'- deoxyguanosine triphosphate ester (dGTP) (one of DNA synthesis segment) processed is combined into nucleic acid chains；2. by preventing new base
It is added and effectively terminates the synthesis of DNA chain.
Recent studies indicate that the generation of HLA-B gene polynorphisms and adverse drug reaction is closely related.2008
U.S. Food and Drug Administration (FDA) issues the security information in relation to Abacavir and the drug containing Abacavir, it is indicated that takes
HIV infection person with HLA-B*5701 gene is easier to that Abacavir hypersensitivity (ABCHSR) occurs using Abacavir.A Ba
Card Wei hypersensitivity is a kind of multiple organ syndrome, it may appear that two or more S or S, including fever, skin
Rash, gastrointestinal reaction, respiratory response and systemic reaction.Hypersensitivity typically occurs in treatment early stage or treats beginning
The first six week, however, since symptom is more and the influence of drug combination, it is difficult to be made a definite diagnosis in early days.
CFDA is in " drug metabolic enzyme and the drug target technique of gene detection guide (tentative) " of publication in 2015
It points out: " it carries HLA-B*5701 allele person and Abacavir is used with caution, in order to avoid cause medicamentous liver lesion." therefore, HIV infection
Person is before using abc drug, it is necessary to which screening HLA-B*5701 gene, when testing result is feminine gender, i.e., patient does not carry HLA-
B*5701 gene can use abc drug.
The detection means of HLA-B*5701 mainly has serological detection method, PCR- direct sequencing (PCR-SBT) and fluorescence
PCR method, however HLA parting is carried out by Serologic detection, it is as a result and inaccurate.It is typically now then to be analyzed by being sequenced
The genotype of HLA, although this method can obtain most accurate gene sequence information, elapsed time is longer and cost compared with
Height is not appropriate for large-scale promotion when detecting, so clinically and being not suitable for；Although the opposite operation of fluorescent PCR method is easy,
Time-consuming is still difficult dependent on detection device and probe costly remote or economical also less than direct sequencing
Less-developed area popularizes.Therefore, it is necessary to which HLA-B*5701 can must quick and precisely be detected with extremely low cost by developing
Method.
Recently the study found that the G allele and HLA-B* of the SNP site rs2395029 near HLA-B locus
5701 height are chain, and the sensibility of the two is 100%, this provides a new visual angle for the detection of HLA-B*5701, i.e., I
Can be by avoiding the base situation directly analyzed the sequence of HLA-B, and only detect rs2395029 from learning inspection indirectly
Test sample sheet whether there is HLA-B*5701.
Ring mediated isothermal amplification (Loop-mediated Isothermal Amplification, LAMP) technology is Japan
A kind of isothermal amplification technology that scientist developed in 2000 draws for six regions, four specificity of design of target gene
Object, constant-temperature amplification under the action of strand displacement archaeal dna polymerase can generate 10 within more than ten minutes to one hour9-1010Quantity
The product of grade is determined the genotype of sample to be tested by the change of direct visual perception system status after reaction, is not necessarily to
Open pipe, therefore enormously simplify operating procedure, while again it is possible to prevente effectively from sample cross contamination, and, it is only necessary to common water-bath
Pot can carry out detection, and save a large amount of testing cost.Therefore, using the genotype of LAMP method detection HLA-B*5701
It is method that is a kind of novel and being suitable for large-scale use.
Summary of the invention
The problem to be solved in the present invention is that the method for existing detection HLA-B*5701 is undesirable, is unsuitable for large-scale promotion
It uses.
To solve the above problems, the present invention uses allele-specific ring mediated isothermal amplification on the basis of LAMP
(Allele-Specific LAMP) technology, is detected for the Tag SNP of HLA-B*5701, is provided a kind of suitable for promoting
The kit and detection method used.
The first purpose of this invention is to provide a kind of Abacavir personalized medicine detection primer, for detecting HLA-
The G allele of the Tag SNP of B*5701 --- rs2395029, including following primer:
5 '-GTGTGACAGCAGCCATGC-3 ' (SEQ ID No.1, hereinafter referred to as F3)
5 '-TCTCCCAAAACCACACTCTG-3 ' (SEQ ID No.2, hereinafter referred to as B3)
5′-ACCAGCGGGTGAGAAGAGGACCTCCTGGGGATCAGGATC-3′
(SEQ ID No.3, hereinafter referred to as FIP)
5′-GGACAGCTGTAATGTGTAGTTCAATGGAGGGTAGAAGGTCCT
GGATT-3 ' (SEQ ID No.4, hereinafter referred to as BIP).
In primer provided by the invention, BIP is the specific primer for rs2395029G allele.In order to avoid latent
Non-specific interference, a catastrophe point has artificially been introduced in BIP.This catastrophe point can increase the special of primer
Property, reduce non-specific amplification a possibility that, improve the accuracy of detection.
Preferably, described F3, B3, FIP, BIP are the primer of HPLC method of purification after purification.
Second object of the present invention is to provide a kind of Abacavir personalized medicine detection kit.The kit
Composition including detection rs2395029 loci gene type and then detection HLA-B*5701.The composition includes above-mentioned draws
Object further includes dNTP, buffer, Bst polymerase and ultrapure water.
Further, the composition further includes the indicator for showing composition color.
Preferably, the indicator is the composition of calcein and manganese chloride or is hydroxynaphthol blue.
Preferably, if indicator is the composition of calcein and manganese chloride, calcein is 25 μM, and manganese chloride is
0.5mM.It is 120 μM if indicator is hydroxynaphthol blue.
Further, the composition further includes additive.The additive is one in glycine betaine or dimethyl sulfoxide
Kind.If additive is glycine betaine, concentration is more than or equal to 0, is less than or equal to 1M.If additive is dimethyl sulfoxide, concentration is big
In being equal to 0, it is less than or equal to 10% (volume fraction).
Preferably, in the composition, F3 and B3 are 0.4 μM, and FIP and BIP are 1.6 μM.
Further, the buffer includes: Tris-HCl 20mM, KCl 50mM, (NH4)2SO410mM, MgSO44mM,
Tween-20 0.1% (volume fraction).
Preferably, dNTP is 1.4mM in the composition, and Bst polymerase is 8000U/mL.
Third object of the present invention is to provide a kind of Abacavir personalized medicine detection method.The detection side
Method, using above-mentioned Abacavir personalized medicine detection kit, specifically: nucleic acid to be detected is added to the combination
In object, obtained reaction system is reacted at 55~70 DEG C, observes the variation of system after reaction.
Further, the concentration of the nucleic acid to be detected in the reaction system is 0.8~4ng/ μ L.
Preferably, after reaction, reaction system is subjected to inactivation treatment.Inactivation treatment inactivates the enzyme in system,
It prevents that non-specific amplification occurs when system standing time is long.
Preferably, reaction temperature is 63 DEG C.
Preferably, the reaction time is 40~120min.
In reaction system of the invention, reacting precursor system is clear state, when positive reaction occurs, magnesium ion and by-product
Object pyrophosphoric acid forms precipitating, and system generates macroscopic precipitating, becomes cloudy state.The variation for observing system status can be straight
It connects and determines whether that amplified reaction occurs.
When there are when indicator in system: if (1) indicator is hydroxynaphthol blue, the magnesium ion in reacting precursor system with
Pansy is presented in dNTP chelating, system；When there is positive reaction, magnesium ion and by-product pyrophosphoric acid are formed and are precipitated, pH value of solution
It changes, color gradually becomes sky blue from pansy；(2) if indicator is the composition of calcein and manganese chloride
When, for calcein in conjunction with the manganese ion in manganese chloride, yellow is presented in system before reacting；When there is positive reaction, by-product is burnt
Phosphoric acid generates precipitating in conjunction with manganese ion, and for calcein in conjunction with the magnesium ion in system, color gradually becomes fluorescence from yellow
Green.The variation of observing response system color and/or state can directly determine whether that amplified reaction occurs.
The advantages and positive effects of the present invention are: (1) present invention uses Allele-Specific LAMP technology, needle
Special primer is devised to the G allele of rs2395029, utilizes the G allele of rs2395029 and the pass of HLA-B*5701
Connection property judges whether patient carries HLA-B*5701 allele, to instruct Abacavir personalized medicine, avoids directly surveying
Try HLA-B*5701.(2) present invention uses Allele-Specific LAMP technology, and the primer specificity of design is good.When detection,
Only this 4 primers could can cause subsequent amplification with clock synchronization with template to be detected completely, improve detection specificity,
Accuracy.(3) present invention uses Allele-Specific LAMP technology, devises special primer, after test, observing response body
The state change (variation for whether having precipitating or color) of system can determine whether that positive reaction occurs, can visually be sentenced
It is disconnected, it is simple and easy to do without additional appliance arrangement.(4) it is examined using detection primer provided by the invention, kit and method
It surveys, required equipment is only water-bath or metal bath or thermal cycler, and testing cost is low, detection is time-consuming shorter.And this inspection
Survey method does not need additional open pipe detection, therefore effectively prevents the generation of cross contamination, improves the accuracy of detection.
Kit provided by the invention is low in cost, detection time is short, accuracy is high, easy to spread.
Detailed description of the invention
Fig. 1 is the electrophoretogram for detecting the product that sample 1-5 is reacted through LAMP.
Fig. 2-Fig. 6 is the Sequencing chromatogram for detecting the site rs2395029 that sample 1-5 is obtained with PCR- PCR sequencing PCR respectively.
Specific embodiment
In order to better understand the present invention, the present invention is further retouched with attached drawing combined with specific embodiments below
It states.
A kind of Abacavir personalized medicine detection primer, for detecting the G allele of rs2395029, including it is following
Primer:
5 '-GTGTGACAGCAGCCATGC-3 ' (SEQ ID No.1, hereinafter referred to as F3)
5 '-TCTCCCAAAACCACACTCTG-3 ' (SEQ ID No.2, hereinafter referred to as B3)
5′-ACCAGCGGGTGAGAAGAGGACCTCCTGGGGATCAGGATC-3′
(SEQ ID No.3, hereinafter referred to as FIP)
5′-GGACAGCTGTAATGTGTAGTTCAATGGAGGGTAGAAGGTCCT
GGATT-3 ' (SEQ ID No.4, hereinafter referred to as BIP).
Above-mentioned F3, B3, FIP, BIP is the primer of HPLC method of purification after purification.
A kind of Abacavir personalized medicine detection kit, including detection rs2395029 loci gene type and then detection
The composition of HLA-B*5701.The composition includes above-mentioned primer, further includes dNTP, buffer, Bst polymerase, ultrapure
Water, indicator, additive.
The indicator is the composition of calcein and manganese chloride or is hydroxynaphthol blue.
The additive is one of dimethyl sulfoxide or glycine betaine.
The concentration that the concentration of each component can be reacted by normal LAMP in composition is arranged.Preferably, F3 and B3 are 0.4
μM, FIP and BIP are 1.6 μM, and dNTP 1.4mM, Bst polymerase is 8U.Buffer includes: Tris-HCl 20mM, KCl
50mM, (NH4)2SO410mM, MgSO44mM, Tween-20 0.1% (volume fraction).
If indicator is the composition of calcein and manganese chloride, calcein is 25 μM, manganese chloride 0.5mM.If referring to
Show that agent is hydroxynaphthol blue, is 120 μM.
If additive is to have glycine betaine, concentration is more than or equal to 0, is less than or equal to 1M；If additive is dimethyl sulfoxide,
Concentration is more than or equal to 0, is less than or equal to 10% (volume fraction).
A kind of Abacavir personalized medicine detection method uses above-mentioned Abacavir personalized medicine detection reagent
Box.Specifically: nucleic acid to be detected is added in above-mentioned composition, obtained reaction system.Reaction system is in 55~70 DEG C
40~120min of lower reaction.After reaction, reaction system is subjected to inactivation treatment.Inactivation treatment loses the enzyme in system
It is living, it prevents that non-specific amplification occurs when system standing time is long.The variation of system is observed after reaction.
Preferably, the concentration of nucleic acid to be detected in the reaction system is 0.8~4ng/ μ L.Reaction temperature is 63 DEG C,
Isothermal reaction.
When it is implemented, extracting 4 people 1ml venous blood with the preservation of EDTA anticoagulant tube, every pipe takes 200uL blood, with full formula gold
Or the DNA extraction kit of other companies, sample of the complete genome DNA as detection, sample are extracted referring to kit specification
Originally it is denoted as template T.Above-mentioned 4 samples distinguish serial number 1-4, in addition to above-mentioned 4 groups, are also added into the G etc. of known rs2395029
The plasmid of position gene masculine is as positive control, number 5.
Allele-Specific LAMP technology is used to template T, nucleic acid to be detected is made to carry out LAMP reaction, detection
The genotype in the site rs2395029.By template Tn(n is group number, 1-5) is added separately in composition, obtains reactant
System.Reaction system isothermal reaction 60min at 63 DEG C is warming up to 80 DEG C of progress inactivation treatment 20min later, cools down later, sees
Examine system color change.
As a kind of embodiment, reaction system total measurement (volume) is 25 μ L, each component and its specification such as following table institute in kit
Show:
Reaction is carried out according to above-mentioned detection method, and before reaction, system color is pansy, after reaction, each group
Color and the genotype judgement of reaction system are as shown in the table:
As seen from the above table, the sample reaction system that number is 1-4 keeps pansy, it was demonstrated that it does not occur positive anti-
It answers, prompts this 4 samples homozygous for T/T in the genotype in the site rs2395029.According to HLA-B*5701 and rs2395029
G allele relevance, detection sample 1-4 do not carry HLA-B*5701 allele, be applicable in Abacavir.
For the accuracy of further confirmatory reaction, electrophoresis test is carried out to above-mentioned group of other LAMP product.Condition are as follows: use
2% Ago-Gel, electrophoresis 30min under 6v/cm voltage.Obtained electrophoretogram is as shown in Fig. 1.5th group of positive reaction
Typical scalariform band is presented, and negative reaction is then without band.It is identical as the result of detection method of the invention.
The other template of above-mentioned 5 experimental groups is subjected to parting to rs2395029 with PCR- PCR sequencing PCR respectively, is obtained
The Sequencing chromatogram in the site rs2395029 compares the inspection of gene sequencing map and kit provided by the invention as shown in Fig. 2-Fig. 6
Result is surveyed it is found that the identical rate 100% of the detection of the two.It can verify that result of the invention is accurate.
The embodiments of the present invention have been described in detail above, but content is only the preferred embodiment of the present invention,
It should not be considered as limiting the scope of the invention.All changes and improvements made in accordance with the scope of the present invention, should all
It still belongs within this patent covering scope.
Claims (10)
1. a kind of Abacavir personalized medicine detection primer, it is characterised in that: including following primer:
5 '-GTGTGACAGCAGCCATGC-3 ' (SEQ ID No.1, hereinafter referred to as F3)
5 '-TCTCCCAAAACCACACTCTG-3 ' (SEQ ID No.2, hereinafter referred to as B3)
5 '-ACCAGCGGGTGAGAAGAGGACCTCCTGGGGATCAGGATC-3 ' (SEQ ID No.3, hereinafter referred to as FIP)
5 '-GGACAGCTGTAATGTGTAGTTCAATGGAGGGTAGAAGGTCCTGGATT-3 ' (SEQ ID No.4, it is simple below
Claim BIP).
2. Abacavir personalized medicine detection primer according to claim 1, it is characterised in that: the F3, B3, FIP,
BIP is the primer of HPLC method of purification after purification.
3. a kind of Abacavir personalized medicine detection kit, including Abacavir personalized medicine detection combination object, described
Composition includes primer of any of claims 1 or 2, it is characterised in that: the composition further includes dNTP, buffer, Bst poly-
Synthase and ultrapure water.
4. Abacavir personalized medicine detection kit according to claim 3, it is characterised in that: the composition is also
Including for showing the indicator of composition color change.
5. Abacavir personalized medicine detection kit according to claim 4, it is characterised in that: the indicator is
The composition of calcein and manganese chloride is hydroxynaphthol blue.
6. Abacavir personalized medicine detection kit according to claim 5, it is characterised in that: if indicator is calcium
The composition of yellowish green element and manganese chloride, calcein are 25 μM, manganese chloride 0.5mM；
It is 120 μM if indicator is hydroxynaphthol blue.
7. Abacavir personalized medicine detection kit according to claim 3, it is characterised in that: the composition is also
Including additive；The additive is one of glycine betaine or dimethyl sulfoxide；
If additive is glycine betaine, concentration is more than or equal to 0, is less than or equal to 1M；
If additive is dimethyl sulfoxide, concentration is more than or equal to 0, is less than or equal to 10% (volume fraction).
8. according to any Abacavir personalized medicine detection kit of claim 3-7, it is characterised in that: described group
It closes in object, F3 and B3 are 0.4 μM, and FIP and BIP are 1.6 μM.
9. according to any Abacavir personalized medicine detection kit of claim 3-7, it is characterised in that: described slow
Fliud flushing includes: Tris-HCl 20mM, KCl 50mM, (NH4)2SO410mM, MgSO4(the volume point of 4mM, Tween-20 0.1%
Number).
10. according to any Abacavir personalized medicine detection kit of claim 3-7, it is characterised in that: described
DNTP is 1.4mM in composition, and Bst polymerase is 320U/mL.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102209791A (en) * | 2008-11-12 | 2011-10-05 | 香港中文大学 | Detection of hla genotype |
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2015
- 2015-10-13 CN CN201510670708.2A patent/CN105219857B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102209791A (en) * | 2008-11-12 | 2011-10-05 | 香港中文大学 | Detection of hla genotype |
Non-Patent Citations (3)
| Title |
|---|
| A novel,high sensitive and rapid allele-specific loop-mediated amplification assay for the detection of the JAK2V617F mutation in chronic myeloproliferative neoplasms;Minnucci等;《HAEMATOLOGICA-THE HEMATOLOGY JOURNAL》;20120930;第97卷(第9期);第1394-1400页 |
| Development of an alle-specific,loop-mediated,isothermal amplification method(AS-LAMP) to detect the L1014F kdr-w mutation in Anopheles gambiae s.l.;Badolo等;《MALARIA》;20120706;第11卷;227 |
| Validation of the Loop-mediated Isothermal Amplification Method for Single Nucleotide Polymorphism Genotyping with Whole Blood;Iwasaki等;《Genome Letters》;20030930;第2卷(第3期);第119-126页 |
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