CN106399503A - Primers, kit and method for detection of SJS/TEN caused by AEDs - Google Patents
Primers, kit and method for detection of SJS/TEN caused by AEDs Download PDFInfo
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Abstract
The invention belongs to the technical field of gene engineering, and discloses a primer composition for detection of SJS/TEN caused by AEDs, a kit containing the primer composition and a method for detection of the SJS/TEN caused by the AEDs. The SJS/TEN caused by taking the AEDs and an AEDs tolerance sample are subjected to HLA-A and HLA-B locus Sanger sequencing typing, on the basis, primers for specific amplification of an HLA-A*24:02 gene and an HLA-B*15:02 gene are designed, and thus the method for detection of the SJS/TEN caused by the AEDs is designed. The method is rapid, simple, accurate, sensitive and intuitive, and the experimental cost is low. Through combined detection of the HLA-A*24:02 gene and the HLA-B*15:02 gene, the SJS/TEN caused by the AEDs is predicted, and the incidence rate of the SJS/TEN in Southern Han nationality population can be greatly reduced.
Description
Technical field
The present invention relates to gene engineering technology field is and in particular to be used for detecting the primer of SJS/TEN, examination that AEDs causes
Agent box and method.
Background technology
Aromatic series antiepileptic (aromatic antiepileptic drugs, AEDs) is to cause skin-type bad anti-
Answer one of the common factors of (cutaneous adverse drug reactions, cADRs).CADRs includes slight speckle mound
Rash (maculopapular exanthema, MPE), and dermoreaction (the severe cutaneous of serious threat to life
Reaction, SCR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (toxic
Epidermal necrolysis, TEN) and drug-induced hypersensitivity syndrome (drug hypersensitivity syndrome,
HSS).SJS and TEN belongs to same spectrum of disease, can be according to the degree different classifications of mucosa or skin exfoliation, SJS skin exfoliation face
The long-pending ratio with the skin gross area<10%, and TEN>30%.Skin-type untoward reaction the lighter affects the therapeutic effect of medicine, weight
Person is lethal, and fatality rate reaches more than 30%, and the wherein fatality rate of SJS/TEN is up to 40%.Serious skin reaction more than 90%
Occur two months after medication, no dose dependent, no predictability.Aromatic series antiepileptic AEDs, such as carbamazepine
(carbamazepine, CBZ), lamotrigine (lamotrigine, LTG) and phenytoin (phenytoin, PHT) are clinical conventional
In treatment epilepsy and neural class disease, three kinds of drug induced Stevens-Johnson syndrome (SJS) incidence rates are about
35.8/10,000, south China Chinese Han Population is even more group of people at high risk.
HLA gene is located at human chromosomal 6p21.3, is about 4,000Kb, is the genetic polymorphism system of most complex human,
Obvious population characteristics in distribution in different races or same race's different groups.In southern Chinese Han Population, HLA-
There is strong correlation in the SJS/TEN that B*1502 and carbamazepine (CBZ) lead to, U.S. FDA recommended asian ancestry before taking CBZ,
Carry out HLA-B*15:02 detection, to avoid the generation of SJS/TEN.The HLA related gene of the SJS/TEN that LTG, PHT lead to is still
Not clear and definite.Additionally, southern Chinese Han Population HLA-B*15:02 negative SJS Proportion of patients is up to 30.4%, therefore, except HLA-B*15:
Outside 02, it is understood that there may be other risks and assumptions, if before medication, carrying out the detection of risks and assumptions, for effective reduction medicine
High risk provides possibility.
Content of the invention
The present invention is directed to drawbacks described above present in prior art, using case-control study method, draws to taking AEDs
SJS/TEN the and AEDs tolerance sample rising carries out HLA-A site and HLA-B site Sanger sequencing and typing, sets on this basis
Count and be used for specific amplification HLA-A*24:02 gene and HLA-B*15:The primer of 02 gene, and thus devise AEDs is drawn
The method that the SJS/TEN rising is detected.The method of the present invention is quick, easy, accurate, sensitive, directly perceived, and experimental cost is low.
For this reason, one aspect of the present invention provides a kind of combination of the primer for detecting SJS/TEN that AEDs causes, it is by sequence
Primer composition shown in row 1-4, for specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
In a preferred embodiment of the present invention, this primer combination is made up of 2 groups of primers further, and the 1st group by sequence 1 He
Primer composition shown in 2, for specific amplification HLA-A*24:02 gene, the 2nd group of primer shown in sequence 3 and 4 forms,
For specific amplification HLA-B*15:02 gene.
In further preferred embodiment of the present invention, the concentration of every primer is 10pmol/l.
Another aspect of the present invention provides a kind of test kit for detecting SJS/TEN that AEDs causes, and it comprises this
Bright described primer combination, for specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
In a preferred embodiment of the present invention, in test kit, the concentration of every primer is 10pmol/l.
Another aspect of the present invention provides primer sets of the present invention and is combined in the SJS/TEN's that preparation detection AEDs causes
Application in test kit, this primer sets shares in specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
Further aspect of the present invention provides primer combination of the present invention, or test kit of the present invention is in detection
Application in the SJS/TEN that AEDs causes, the combination of this primer and test kit are used for specific amplification HLA-A*24:02 gene and
HLA-B*15:02 gene.
The method that on the one hand present invention finally provides the SJS/TEN that a kind of detection AEDs causes, it comprises the steps of：
1st, obtain testing sample DNA.
2nd, adopt primer combination of the present invention, or adopt test kit of the present invention, with obtain in step 1
DNA is template, enters performing PCR amplification.
3rd, Sanger sequencing is carried out to pcr amplification product.
4th, after obtaining sequencing peak figure, carry out result interpretation, judge HLA-A*24 in testing sample:02 gene and HLA-B*
15:The positive rate of 02 gene.
In a preferred embodiment of the present invention, in step 2, the concentration of every primer is 10pmol/l.
In further preferred embodiment of the present invention, carry out purification after also including sequencing reaction in step 3 and enter
The step of row degenerative treatments.
Seen from the above description, compared with prior art, the present invention possesses following advantage.
1st, the present invention adopts case-control study, carries out to taking SJS/TEN the and AEDs tolerance sample that AEDs leads to
HLA-A site and HLA-B site carry out Sanger sequencing and typing, find HLA-A*24:02 leads in CBZ, LTG and PHT
The positive rate of SJS/TEN, apparently higher than tolerance group, is the common risk factor of three kinds of medicines.The present invention is further discovered that HLA-A*
24:02 and HLA-B*15:The independent risks and assumptions of the SJS/TEN that 02 genotype causes for AEDs, and two genotype have
Synergistic effect.
2nd, the present invention is according to HLA-A*24:02 and HLA-B*15:02 gene order, devising can efficiently specifically
The primer of amplification both genes, has the specificity of height.And on this basis, devise and AEDs can be caused
Test kit and method that SJS/TEN is detected.
3rd, detection method joint-detection HLA-A*24 of the present invention:02 and HLA-B*15:02 gene, can be respectively increased
To 82.1% and 70.6%, specificity is tri- kinds of drug induced sensitivity of SJS/TEN and CBZ/LTG/PHT that CBZ leads to
70.6% and 69%.Meanwhile, the detection method of the present invention passes through joint-detection HLA-A*24:02 and HLA-B*15:02 gene, with
The SJS/TEN that prediction AEDs leads to, can reduce the incidence rate of southern Chinese Han Population SJS/TEN, be reduced to from 35.8/100000
13.0/100000.
Brief description
Fig. 1：The agarose gel electrophoretogram of pcr amplification product.
Fig. 2：A2F sequencing peak shape figure.
Fig. 3：A2R sequencing peak shape figure.
Fig. 4：A3F sequencing peak shape figure.
Fig. 5：A3R sequencing peak shape figure.
Fig. 6：A4F sequencing peak shape figure.
Fig. 7：B2F sequencing peak shape figure.
Fig. 8：B2R sequencing peak shape figure.
Fig. 9：B3F sequencing peak shape figure.
Figure 10：B3R sequencing peak shape figure.
Figure 11：B4F sequencing peak shape figure.
Specific embodiment
Below by embodiment, the present invention is described in further detail it is intended to be used for illustrating rather than restriction originally
Invention.It should be pointed out that to those skilled in the art, under the premise without departing from the principles of the invention, can also be to this
Bright carry out some improve and modify, these improve and modify similarly fall under the scope of the present invention.
Embodiment 1：Sample collection
Gather and in 8 weeks, take 91 (i.e. cases of patient that SJS/TEN untoward reaction in anti-aromatic series AED first
Group) and take the individuality 322 (i.e. antiepileptic tolerance matched group) that antiepileptic skin adverse reaction for 3 months
Peripheral blood, take 4ml, -80 DEG C of Refrigerator stores with EDTA anticoagulant tube.
Case group and matched group crowd are Han population of South China, and the nationality of proprietary grand parents, grand parents
Pass through and be southern area of China.
Embodiment 2：Experimental technique flow process
1st, DNA extraction
Extract people periphery using Quickgene DNA extraction agent box and supporting Quickgene-610LDNA extractor
Blood leukocytes DNA, step is carried out by operating instruction.Comprise the following steps that：
A, to 15ml centrifuge tube add 300 μ l protease (EDB), 2ml human peripheral specimen, 2.5mL lysis buffer
(Lysis Buffer,LDB)；
B, mixing 10-15 time of turning upside down；
C, eddy mixer 2500rpm/ divide × 15 seconds；
D, 56 DEG C of water-baths 5 minutes；
E, addition dehydrated alcohol 2.5mL；
F, mixing 10-15 time of turning upside down；
G, eddy mixer 2500rpm/ divide × 15 seconds；
H, pour the mixture into Quickgene 20ml purification column jecket；
I, for the first time operation " DNA WHOLE BLOOD " pattern, run " ISOLATE A " pattern second, can obtain two pipes
Required human peripheral leucocytes DNA；
Using concentration and the OD value of spectrophotometric determination DNA after J, fully mixing；Each specimen genomic DNA of gained
OD260/OD280It is respectively positioned between 1.7-2.0, DNA concentration is no less than 50ng/ul, total amount is no less than 10 μ g.
K, it is placed in -20 DEG C of Refrigerator stores.
2nd, design of primers, pcr amplification reaction and purification
The gene order announced according to GenBank, using the design of Primer Premier 5.0 primer-design software, by giving birth to
Work biological engineering (Shanghai) limited company synthesizes.For reducing sequencing peak figure bottom peak, ensure sequencing primer to greatest extent
Purity, by the optimization of primer reaction condition with compare, filter out the primer of high specificity.Specific primer sequence is referring to table
1.
Table 1：The amplimer sequence table of HLA-A and HLA-B gene
The PCR reaction system of each genomic DNA sample, performing PCR of going forward side by side in 96 hole Sptting plates, is prepared respectively according to table 2
Reaction.
Table 2 PCR amplification system
PCR response procedures are as follows：96 DEG C of denaturations 5min；98 DEG C of degeneration 10s, 65 DEG C of annealing 30s, 72 DEG C of extension 60s, 5
Individual circulation；96 DEG C of degeneration 20s, 60 DEG C of annealing 30s, 72 DEG C of extension 60s, 30 circulations；72 DEG C of extension 10min.4 DEG C of preservations.
Amplified production electrophoresis pattern is referring to accompanying drawing 1.
Product utilization SAP after amplification carries out purification.
3rd, Sanger sequencing and typing
Sanger be sequenced with ABI company Big Dye Terminator V3.1 as main agents (containing dNTP, ddNTP and
Fluorescein), it is template with the product after front PCR reaction purification, add specific primer to be circulated amplification.HLA-A、HLA-B
Sequencing primer be respectively A-2F/R, A-3F/R, A-4F, B-2F/R, B-3F/R, B-4F.Specific sequencing primer sequence referring to
Table 3.
Table 3 sequencing reaction amplimer sequence table
| Sequencing primer site | Sequence |
| A2F | CCTCTGYGGGGAGAAGCA |
| A2R | TCTCGGACCCGGAGACTG |
| A3F | CATTTTCAGTTTAGGCCAAAAAT |
| A3R | CCAATTGTCTCCCCTCCTTG |
| A4F | GGGTGTCCTGTCCATTCTCA |
| B2F | AGGAGCGAGGGGACCGCA |
| B2R | GATCTCGGACCCGGAGACT |
| B3F | GGGGCCAGGGTCTCACA |
| B3R | TGGGAGGCCATCCCCGGC |
| B4F | GGTCACATGGGTGGTCCTAG |
The reaction condition of sequencing amplification is as follows：96℃2min；96 DEG C of 10s, 50 DEG C of 20s, 60 DEG C of 2min (25 circulations)；15
℃∞.
The reaction system of sequencing amplification is 5ul, and as shown in table 4, wherein 2.5 × Bigdye and 5 × Buffer is equal for its composition
Purchased from Applied biosystems (Applied Biosystems, ABI).
Table 4 sequencing reaction system
Sequencing amplified production is through ethanol EDTA-Na2After deposition and purification is processed, dissolve degeneration with deionized formamide,
ABI 3730xl full-automatic DNA sequencer (U.S.) capillary electrophoresis simultaneously are analyzed to result processing automatically, obtain desirable tablet
Section base sequence, and presented with 4 color peak figure forms.Using the sequence to HLA-A, HLA-B for Vector NTI 6.0 (U.S.) software
Row are according to http:The online sequence announced of //www.ebi.ac.uk/imgt/hla is compared and is obtained result.
4th, statistical analysiss and result
Statistical analysiss are carried out using SPSS 16.0 statistical analysis software.
HLA-A*24 by case group and matched group:02 and HLA-B*15:02 positive rate chi-square criterion or exact probability
Method is compared, and P 0.05 is that difference is statistically significant, shows HLA-A*24:02 is the risk genes of CBZ, LTG and PHT,
Also it is the common risk gene of three kinds of medicines simultaneously；HLA-B*15:02 is the risk genes of CBZ, is also three kinds of medicines simultaneously
Common risk gene (concrete data is referring to table 5).
Table 5：The SJS/TEN risks and assumptions that CBZ, LTG, and PHT lead to
The reciprocal action of the SJS/TEN being led in AEDs using two allele of Logtistic analysis of regression model, is entered
Enter standard α=0.05 of equation, reject equation standard α=0.10, P<0.05 has statistical significance for difference, is retained in
Factor in Logistic regression model is defined as meaningful risk factor, finds that two genes are independent risk genes, and has
There is cumulative benefit (concrete data is referring to table 6).
Table 6：HLA-B*15:02 and HLA-A*24:The SJS/TEN accumulative effect that 02 couple of AED leads to
It is 35.8/100000ths according to three kinds of drug induced SJS incidence rates, detect HLA-A*24:02 and HLA-B*15:
02 genotype, HLA-A*24:02 gene masculine or HLA-B*15:02 positive patient avoids taking these three AEDS, can reduce
SJS incidence rate is to 13/100000ths.
Claims (10)
1. a kind of primer combination for detecting SJS/TEN that AEDs causes, its primer shown in sequence 1-4 forms, and is used for
Specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
2. primer combination according to claim 1, it is made up of 2 groups of primers further, and the 1st group shown in sequence 1 and 2
Primer forms, for specific amplification HLA-A*24:02 gene, the 2nd group of primer shown in sequence 3 and 4 forms, for special
Property amplification HLA-B*15:02 gene.
3. primer combination according to claim 1 and 2, the concentration of wherein every specificity amplification primer is 10pmol/
l.
4. a kind of test kit for detecting SJS/TEN that AEDs causes, it comprises drawing any one of claim 1-3
Thing combines, for specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
5. test kit according to claim 4, the concentration of wherein every primer is 10pmol/l.
6. the primer sets any one of claim 1-3 are combined in the test kit of SJS/TEN that preparation detection AEDs causes
Application, described primer sets share in specific amplification HLA-A*24:02 gene and HLA-B*15:02 gene.
7. the primer combination any one of claim 1-3, or the test kit described in claim 4 or 5 is in detection
Application in the SJS/TEN that AEDs causes, described primer combination or test kit are used for specific amplification HLA-A*24:02 gene and
HLA-B*15:02 gene.
8. the method for the SJS/TEN that a kind of detection AEDs causes, it comprises the steps of：
(1) obtain testing sample DNA；
(2) adopt the primer combination any one of claim 1-3, or using the test kit described in claim 4 or 5,
The DNA being obtained with step (1), as template, enters performing PCR amplification；
(3) Sanger sequencing is carried out to pcr amplification product；
(4), after obtaining sequencing peak figure, carry out result interpretation, judge HLA-A*24 in testing sample:02 gene and HLA-B*15:02
The positive rate of gene.
9. in method according to claim 8, wherein step (2), the concentration of every primer is 10pmol/l.
10. carry out purification after also including sequencing reaction in method according to claim 8 or claim 9, wherein step (3) and enter
The step of row degenerative treatments.
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Cited By (3)
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| TWI650423B (en) * | 2017-10-27 | 2019-02-11 | 長庚醫療財團法人林口長庚紀念醫院 | Risk assessment for lamotrigine-induced cutaneous adverse drug reactions and detecting agent thereof and use thereof |
| CN109628575A (en) * | 2019-01-07 | 2019-04-16 | 复旦大学附属华山医院 | Application of the HLA-A*24:02 allele in the drug rash risk caused by the raw metronidazole of detection human hair |
| CN113278687A (en) * | 2021-05-20 | 2021-08-20 | 广州医科大学附属第二医院 | Kit for detecting HLA-B1502 and HLA-A2402 genotypes |
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| TWI650423B (en) * | 2017-10-27 | 2019-02-11 | 長庚醫療財團法人林口長庚紀念醫院 | Risk assessment for lamotrigine-induced cutaneous adverse drug reactions and detecting agent thereof and use thereof |
| CN109628575A (en) * | 2019-01-07 | 2019-04-16 | 复旦大学附属华山医院 | Application of the HLA-A*24:02 allele in the drug rash risk caused by the raw metronidazole of detection human hair |
| CN109628575B (en) * | 2019-01-07 | 2021-11-05 | 复旦大学附属华山医院 | Use of HLA-A24: 02 allele for detecting the risk of a human developing drug eruption due to metronidazole |
| CN113278687A (en) * | 2021-05-20 | 2021-08-20 | 广州医科大学附属第二医院 | Kit for detecting HLA-B1502 and HLA-A2402 genotypes |
| CN113278687B (en) * | 2021-05-20 | 2023-11-24 | 广州医科大学附属第二医院 | Kit for HLA-B1502 and HLA-A2402 genotype detection |
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