CN108179180A - A kind of method and kit that genotype detection is carried out to CYP3A5*3 sites - Google Patents
A kind of method and kit that genotype detection is carried out to CYP3A5*3 sites Download PDFInfo
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Abstract
A kind of method and kit that genotype detection is carried out to CYP3A5*3 sites, the present invention relates to molecular biology and medical domain, the present invention is directed to detects the type of SNP site using tacrolimus, the relevant gene SNP site design special primer of cyclosporine dosage related reactions risk, probe and the magnetic bead for writing correlation report probe, separable.Detection kit provided by the invention sensitive, quickly low can detect CYP3A5*3 (G in people's whole blood sample>A) type can provide reliable experimental evidence using tacrolimus, the adjustment of cyclosporine dosage for patient, reduce adverse reaction, guiding clinical treatment.
Description
Technical field
The present invention relates to molecular biology and medical domain, and more specifically, the present invention relates to tacrolimus, cyclosporine are bad
The kit of risk associated SNP positions is reacted, by detecting tacrolimus, the relevant chtochrome oxidase of cyclosporine adverse reaction
Mononucleotide polymorphism site (SNP) genotype of enzyme CYP3A5*3 genes assesses tacrolimus, cyclosporine in application process
Middle adverse reaction and dosage adjustment.
Background technology
Cytochrome P450 3A (CytochromeP450 3A, CYP3A) is internal most important CYP450 enzymes, is accounted for into
Important CYP enzymes in 25% and enteron aisle of people's cytochrome oxidase P450 total amount, mainly by CYP3A4, CYP3A5, CYP3A7 and
CYP3A43 is formed, and wherein CYP3A4 and CYP3A5 are even more important.It is clinical normal that CYP3A4 and CYP3A5 catalysis completes more than 60%
With the oxidation reaction of drug.There are apparent individual differences for CYP3A gene expressions.It is being grown up, the concentration of usual CYP3A4 is apparent
Higher than CYP3A5, but in part population, CYP3A5 is the CYP3A enzymes mainly expressed.Show Chinese Han nationality in previous research
The individual difference of CYP3A activity can reach 13 times in healthy population, it is now recognized that the individual difference of CYP3A activity may be to cause
One of the main reason for its metabolism substrate pharmacokinetics is different.
So far, in 39 allele being had determined in CYP3A4, the mononucleotide of most CYP3A4 is more
State property (SNP) will not lead to the change of enzymatic activity, only CYP3A4*18A (878T>C) point mutation can cause the raising of enzymatic activity, but
Incidence in Chinese population is only 1% or so.And most SNPs of CYP3A5 can cause the Splicing defect of protein expression,
It is substantially reduced the activity of CYP3A5.Wherein CYP3A5*3 is in intron3 (6986A>G mutation) causes montage to lack, so as to make
Saltant type homozygotic individual is obtained, i.e., it carries the people that gene is CYP3A5*3/*3 and does not express CYP3A5, causes in liver or small intestine
CYP3A5 proteinase activities seriously reduce or missing, its metabolism substrate clearance rate may thus declined, plasma drug level
Raising.Generation frequencies of the CYP3A5*3 in Chinese, Japanese, Korean, people from South Asia, black race, white people and Spaniard
Rate is 71%~76%, 71%~85%, 70%, 59%~61%, 27%~55%, 84%~95% and 62%~83%.
Activity difference caused by gene pleiomorphism makes CYP3A5 and its relevant research become one of current hot spot.
Cyclosporine (CyclosporineA, CsA) is the neutral ring type polypeptide containing 11 amino acid, belongs to calcineurin
Inhibitor family clinically obtains extensively should as the immunosuppressor for preventing solid organ transplantation and marrow rejection
With.Oral absorption is irregular, and differs greatly to Different Individual, is mainly combined after absorption with lipoprotein, with plasma protein
Percentage bound may be up to about 90%.The blood plasma T12 of adult is about 19h, and children are only 7h.CsA only has 6% through kidney excretion,
Middle about 01% is still discharged with original shape, other are produced by liver CYP3A4 and the CYP3A5 metabolism for be metabolized to more than 20 kinds or more
Object, metabolite in biliary excretion to excrement through discharging.It is mainly AM1 that CYP3A4, which is metabolized the metabolite to be formed, AM9 and
AM4N, and CYP3A5 only forms AM9, but each metabolic pathway can be converted mutually in human body, there is no single metabolic pathways.Face
On bed, CsA blood concentrations are too low, and expected immunosuppressive effect is not achieved and causes acute rejection, excessively high, can draw
Play many serious adverse reactions, such as Liver and kidney function damage.Because it is narrow with therapeutic index, pharmacokinetic difference between individual
The characteristics of larger, the detection that blood concentration is clinically periodically carried out to application cyclosporine patient have become routine.With to medicine
Object genomics research is goed deep into, it is now recognized that the difference of CsA drug metabolic enzymes CYP3A5, which may be it, forms individual difference
Main cause.
Tacrolimus was approved as the anti-injection drug of liver transfer operation in 1994 by FDA.It is a kind of macrolide, in T
Combination cell matter protein receptor FK Binding Protein 1s 2 (FKBP-12) in lymphocyte.The compound combination calcineurin,
The dephosphorylation of T cell nuclear factor of activation and core transposition are prevented, it is final to inhibit IL-2 generations and T lymphocyte activations.Such as
The present, tacrolimus are one of widely applied immunosuppressive drugs in solid organ transplantation and rheumatism treatment.Its Clinical practice
It is complicated due to the variability between its pharmacokinetics and its narrow therapeutic index.CYP3A5 genes have multiple
SNP, CYP3A5 are 71%~76% in the mutation rate of Chinese, and wherein CYP3A5 is in the 6986 site SNP (A ＞ G) of introne 3
It plays a major role.According to the nomenclature principle of CYP3A5 polymorphisms, wild homozygous (AA) name of the 6986 site SNP of CYP3A5
For CYP3A5*1/*1, mutant homozygous type (GG) is named as CYP3A5*3/*3, and heterozygous is named as CYP3A5*1/*3.Due to
The presence of 6986 site SNP (A ＞ G), mRNA shearing sites change, and produce a terminator codon, and translation shifts to an earlier date eventually
Only, product is a truncated protein matter；So that saltant type homozygotic individual CYP3A5*3/*3 genotype persons cannot express
There is enzymatic activity CYP3A5 protein, be slow FK506 metabolic patterns, make CYP3A5*3/*3 patient and CYP3A5*1/*1 and CYP3A5*
The pharmacokinetics of 1/*3 patient is dramatically different.The research about CYP3A5 genes is concentrated mainly on clinical renal transplantation at present.Have
Scholar has found that the weighted average that the non-express type patients of CYP3A5 take orally FK506 clearance rates compares expression type in renal allograft recipient
Low 48%, and the Genotyping by renal allograft recipient CYP3A5 etc. is wished accordingly to optimize the individuation of postoperative immunosuppression agent
Treatment.And have research, it is found that therefore the renal transplant recipients more than 70% are benefited.
Therefore, SNP site detection is carried out to CYP3A5 genes, contributed to application cyclosporine, tacrolimus drug therapy
Patient carry out dosage adjustment, reduces adverse reaction, progress individualized treatment.
Invention content
The present invention is directed to and is set using tacrolimus, the relevant gene SNP site of cyclosporine dosage related reactions risk
Special primer, probe and the magnetic bead for writing correlation report probe are counted, separable detects the type of SNP site.The present invention provides
Detection kit can CYP3A5*3 (G in sensitive, quick low detection people's whole blood sample>A) type can be that patient uses him
Ke Mosi, the adjustment of cyclosporine dosage provide reliable experimental evidence, reduce adverse reaction, guiding clinical treatment.
A kind of kit that genotype detection is carried out to CYP3A5*3 sites, the kit include drawing for following sequence
Object：
The kit includes the specific probe of following sequence：
The kit further includes the reporter probe of following sequence：TATCTCTTCC CTGTTTGGAC.
A kind of method that genotype detection is carried out to CYP3A5*3 sites, the method include the following steps：First into
Row PCR reacts, and realizes amplification；Multiple OLA reactions, label and connection are carried out again；Then hybridization reaction is carried out, finally carries out gene
The analysis of type.
Further, PCR reaction systems are as follows：2x qiagen Hotstar MM 5ul, primer mix 1ul, DNA
Sample 2ul, aqua sterilisa 2ul；Reaction condition be 95 DEG C, 15min, carry out 30 cycle 94 DEG C, 30 seconds, 60 DEG C, 30 seconds, 72
DEG C, 30 seconds；72 DEG C, 7 minutes, 4 DEG C of maintenances.
Further, multiple OLA reactions are as follows：2xOLA master mix are prepared, by OLA master mix and PCR
Reaction product mixes, and coupled reaction is carried out after mixing.
Further, 2xOLA master mix are prepared to include：10x Taq Ligase buffer 2ul,
Taq the DNA Ligase 0.25ul, wild-type probe mix 1ul, saltant type probe mix 2ul of 40000U/ml, deionized water
4.75ul。
Further, coupled reaction condition is as follows：96 DEG C of 2min, the 94 DEG C of 15s, 37 DEG C of 1min of 30 cycles；4 DEG C of dimensions
It holds.
Further, hybridization reaction program is as follows：Corresponding reporter probe magnetic bead is selected, and is resuspended, magnetic bead is mixed, and dilute
Up to 100u/ul is released, with 2X Tm hybridization buffer, is added in magnetic bead mix to every hole after mixing,
Add 1-5ul OLA reaction and 25ul dH2O carries out PCR reactions to each hole：96 DEG C of 90s, 37 DEG C of 30min, siphon away
Supernatant with 1x Tm hybridization buffer, is resuspended magnetic bead, siphons away supernatant again；1x Tm are used again
Hybridization buffer are resuspended magnetic bead, siphon away supernatant；With the 1x Tm comprising 2-8ug/ml SAPE
Magnetic bead is resuspended in hybridization buffer, and 15min is incubated at 37 DEG C, in 37 DEG C, adds in 50ul reaction products extremely
It is analyzed in LUMINEX.
Alternatively,
The process of hybridization reaction is as follows：1st, magnetic bead is selected, and is resuspended；2nd, each magnetic bead is mixed, and be diluted to 100u/
Ul, with 2X Tm hybridization buffer, oscillation mixing；3rd, it adds in magnetic bead mix to every hole；4th, sample is added
Into every hole；5th, PCR reactions are carried out：96 DEG C of 90s, 37 DEG C of 30min；6th, prepare 6ug/ml SAPE in 1x hybridization
buffer；7th, 100ul SAPE mix, mixing are added；8th, 37 DEG C of incubation 15min；9th, it adds in 100ul to 37 DEG C of luminex
Analysis.
The present invention is directed to and is set using tacrolimus, the relevant gene SNP site of cyclosporine dosage related reactions risk
Special primer, probe and the magnetic bead for writing correlation report probe are counted, separable detects the type of SNP site, helps to correspond to
Dosage adjustment is carried out with the patient of cyclosporine, tacrolimus drug therapy, reduces adverse reaction, carries out individualized treatment,
Guiding clinical treatment；And detection kit provided by the invention sensitive, quickly low can detect CYP3A5*3 in people's whole blood sample
(G>A) type.
Specific embodiment
Embodiment 1
The present invention provides a kind of kit, changes the primer that kit includes following sequence：
The specific probe of following sequence：
The reporter probe of following sequence：tatctcttcc ctgtttggac.
Embodiment 2
A kind of method that genotype detection is carried out to CYP3A5*3 sites, this method comprise the step of：Reaction tube into
Row PCR reacts, and the system of reaction is 10 μ l of total volume, includes 2x qiagen Hotstar MM 5ul, primer mix
1ul, DNA sample 2ul, aqua sterilisa 2ul.
It is reacted in ABI9700 type PCR amplification instruments, reaction condition is 95 DEG C, 15min, carries out the 94 of 30 cycles
DEG C, 30 seconds, 60 DEG C, 30 seconds, 72 DEG C, 30 seconds；72 DEG C, 7 minutes, 4 DEG C of maintenances.
Multiple OLA reactions：Prepare 2xOLA master mix：10x Taq Ligase buffer 2ul,Taq DNA
Ligase (40,000U/ml) 0.25ul, wild-type probe mix (100nM each) 1ul, saltant type probe mix (2.5uM
Each) 2ul, deionized water 4.75ul.OLA master mix are mixed with reaction product：2xOLA master mix 10ul,
The PCR product 5ul of amplification, sterile deionized water 5ul.Piping and druming mixing up and down, covers reaction tube, expand in ABI9700 types PCR
Increase coupled reaction on instrument.96 DEG C of 2min, the 94 DEG C of 15s, 37 DEG C of 1min of 30 cycles；4 DEG C of maintenances.
Hybridization reaction-washing procedure：The MagPlex-TAG magnetic beads of corresponding reporter probe are selected, and are resuspended, by each magnetic bead
Mixing, and 100u/ul is diluted to, with 2X Tm hybridization buffer, oscillation mixing 20s；Add in 25ul magnetic beads
(2500 pearls/each reaction should be provided) in mixture to every hole.Add 1-5ul OLA reaction and 25ul dH2O
To each hole, H is adjusted2The volume of O makes total volume close to 50ul.It closes the lid, carries out PCR reactions：96 DEG C of 90s, 37 DEG C
30min.30s-60s in magnetic board is put in, magnetic bead is sucked, supernatant is carefully siphoned away, does not siphon away magnetic bead；With 1x Tm
Hybridization buffer 75ul, are resuspended MagPlex-TAG magnetic beads, and magnetically attractive 30-60s carefully siphons away supernatant, do not siphon away
Magnetic bead；It repeats with 1x Tm hybridization buffer 75ul, is resuspended MagPlex-TAG magnetic beads, magnetically attractive 30-60s is small
The heart siphons away supernatant；With 75ul 1x Tm hybridization buffer (including 2-8ug/ml SAPE), magnetic bead is resuspended, 37
DEG C incubate 15min.In 37 DEG C, add in 50ul reaction products to LUMINEX and analyze.
Alternatively,
The washing procedure of hybridization reaction-not：1. the suitable MagPlex-TAG magnetic beads of selection, and be resuspended；2. each magnetic bead is mixed
It closes, and is diluted to 100u/ul, with 2X Tm hybridization buffer, oscillation mixing 20s；3. add in 20ul magnetic beads
(2500 pearls/each reaction should be provided) in mixture to every hole.4. it adds in 5uL samples to every hole；5. shut lid
Son carries out PCR reactions, PCR reactions：96 DEG C of 90s, 37 DEG C of 30min；6. prepare 6ug/ml SAPE in 1x hybridization
buffer；7. add 100ul SAPE mix, soft mixing；8.37 DEG C of incubation 15min；9. add in 100ul to 37 DEG C
It is analyzed in luminex.
Interpretation of result
It is compareed by plasmid and water, obtains background signal, when detecting sample results, after subtracting background, numerical value is more than 200
For positive reaction.
CYP3A5*3 (G can be provided in examining report>A) SNP types are miscellaneous as a result, the corresponding result of saltant type is shown as AA
The corresponding result of mould assembly is shown as GA, and the corresponding result of wild type is shown as GG.As shown in following formula heterozygote：
Claims (10)
1. a kind of kit that genotype detection is carried out to CYP3A5*3 sites, which is characterized in that the kit is included such as
The primer of lower sequence：
A kind of 2. kit that genotype detection is carried out to CYP3A5*3 sites as described in claim 1, which is characterized in that institute
The kit stated includes the specific probe of following sequence：
A kind of 3. kit that genotype detection is carried out to CYP3A5*3 sites as described in claim 1, which is characterized in that institute
The kit stated further includes the reporter probe of following sequence：tatctcttcc ctgtttggac.
A kind of 4. method that genotype detection is carried out to CYP3A5*3 sites, which is characterized in that the method includes following step
Suddenly：PCR reactions are carried out first, realize amplification；Multiple OLA reactions, label and connection are carried out again；Then hybridization reaction is carried out, most
The analysis of genotype is carried out afterwards.
A kind of 5. method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 4, which is characterized in that PCR
Reaction system is as follows：2x qiagen Hotstar MM 5ul, primer mix 1ul, DNA sample 2ul, aqua sterilisa 2ul；Instead
Condition is answered as 95 DEG C, 15min, carries out 94 DEG C, 30 seconds, 60 DEG C, 30 seconds, 72 DEG C, 30 seconds of 30 cycles；72 DEG C, 7 minutes, 4 DEG C
It maintains.
6. a kind of method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 4, which is characterized in that multiple
OLA reactions are as follows：2xOLA master mix are prepared, OLA master mix with PCR reaction products are mixed, are carried out after mixing
Coupled reaction.
7. a kind of method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 6, which is characterized in that prepare
2xOLA master mix include：The Taq DNA Ligase of 10x Taq Ligase buffer 2ul, 40000U/ml
0.25ul, wild-type probe mix 1ul, saltant type probe mix 2ul, deionized water 4.75ul.
A kind of 8. method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 6, which is characterized in that connection
Reaction condition is as follows：96 DEG C of 2min, the 94 DEG C of 15s, 37 DEG C of 1min of 30 cycles；4 DEG C of maintenances.
A kind of 9. method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 4, which is characterized in that hybridization
It is as follows to react washing procedure：Corresponding reporter probe magnetic bead is selected, and is resuspended, magnetic bead is mixed, and dilution up to 100u/
Ul with 2X Tm hybridization buffer, adds in magnetic bead mix to every hole after mixing, adds 1-5ul OLA
Reaction and 25ul dH2O carries out PCR reactions to each hole：96 DEG C of 90s, 37 DEG C of 30min, siphon away supernatant, with 1x Tm
Hybridization buffer are resuspended magnetic bead, siphon away supernatant again；Again with 1x Tm hybridization buffer, weight
Outstanding magnetic bead, siphons away supernatant；With the 1x Tm hybridization buffer comprising 2-8ug/ml SAPE, magnetic bead is resuspended, 37
DEG C incubate 15min, in 37 DEG C, add in 50ul reaction products to LUMINEX in analyze.
10. a kind of method that genotype detection is carried out to CYP3A5*3 sites as claimed in claim 4, which is characterized in that miscellaneous
The not washing process for handing over reaction is as follows：1st, magnetic bead is selected, and is resuspended；2nd, each magnetic bead is mixed, and is diluted to 100u/ul,
With 2X Tm hybridization buffer, oscillation mixing；3rd, it adds in magnetic bead mix to every hole；4th, addition sample is to every
Kong Zhong；5th, PCR reactions are carried out：96 DEG C of 90s, 37 DEG C of 30min；6th, prepare 6ug/ml SAPE in 1x hybridization
buffer；7th, 100ul SAPE mix, mixing are added；8th, 37 DEG C of incubation 15min；9th, it adds in 100ul to 37 DEG C of luminex
Analysis.
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Cited By (5)
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| CN108410961A (en) * | 2018-07-10 | 2018-08-17 | 默禾医疗科技（上海）有限公司 | A kind of kit and its method of detection CYP3A4, CYP3A5 polymorphic site |
| CN110643698A (en) * | 2019-10-16 | 2020-01-03 | 成都仕康美生物科技有限公司 | Tacrolimus metabolic gene detection kit and application method thereof |
| CN113930495A (en) * | 2021-10-18 | 2022-01-14 | 上海市第一人民医院 | Prediction model of tacrolimus initial dose after liver transplantation and individualized application thereof |
| CN114350788A (en) * | 2022-01-12 | 2022-04-15 | 武汉艾迪康医学检验所有限公司 | Group of probes and library construction kit for detecting polymorphism of pharmacogenomic related gene CYP3A5 by utilizing hybrid capture method |
| CN110964791B (en) * | 2019-12-26 | 2023-08-15 | 贵州中医药大学第二附属医院 | Method for detecting single nucleotide polymorphism and corresponding kit |
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