CN112322727B - Application of CDA gene SNP locus - Google Patents
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Abstract
The invention relates to the technical field of biology, in particular to application of a CDA gene SNP locus. The research of the invention shows that the SNP locus rs818202 of CDA can obviously influence the long-term antihypertensive curative effect of felodipine, and a genetic model constructed on the basis of rs818202 can better predict the antihypertensive curative effect. The kit prepared by taking the SNP locus of the CDA as a marker can play a good prediction effect on the administration effect of the antihypertensive drug.
Description
Technical Field
The invention relates to the technical field of biology, in particular to application of a CDA gene SNP locus.
Background
Hypertension is a clinical syndrome characterized mainly by the increase of systemic arterial pressure, or accompanied by functional or organic damages of organs such as heart, brain, kidney, etc., and is one of the most common chronic diseases, and is also the most important risk factor of cardiovascular and cerebrovascular diseases. The patients often show symptoms such as dizziness, headache, dim eyesight, tinnitus, insomnia, hypodynamia and the like.
Treatment modalities for hypertension primarily include lifestyle improvement and medication, and most patients may require lifelong medication. At present, various antihypertensive drugs available for clinical selection are available, but researches show that the antihypertensive curative effect of various antihypertensive drugs is greatly different from individual to individual. The pharmacogenetics and pharmacogenomics are important components of individualized medicine or precise medicine, and research shows that genetic factors play an important role in individual differences of therapeutic effects and adverse reactions of antihypertensive drugs.
At present, pharmacogenomics research on antihypertensive drugs is still rare, and further research on molecular markers for predicting the curative effect of the antihypertensive drugs has important significance for treatment, diagnosis and the like of hypertension.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide the use of the CDA gene SNP site in predicting the therapeutic effect of antihypertensive drugs.
The invention provides application of CDA gene SNP locus as a marker in preparation of a reagent for predicting the curative effect of a hypotensive drug.
The CDA gene is located in the region of chromosome 1 p36.2-p35, and consists of 4 exons and 3 introns, and codes for Cytidine deaminase (Cytidine deaminase). Cytidine deaminase is distributed and expressed in a large variety of tissues in the human body, with the highest expression levels in the liver. Cytidine deaminase is an important intracellular enzyme that physiologically catalyzes the deamination of cytidine and deoxycytidine to produce irreversible deamination reactions to uridine and deoxyuridine, playing an important role in the metabolism of DNA pyrimidine nucleosides. Cytidine deaminase can also catalyze deamination of antineoplastic nucleoside-like drugs to form inactive metabolites. The existing research shows that cytidine deaminase plays an important role in the metabolism of the antitumor drugs gemcitabine, cytarabine and azacitidine, and can directly degrade the gemcitabine, cytarabine and azacitidine into inactive metabolites. The CDA is found to be the main drug metabolism enzyme in the antineoplastic gemcitabine, and 90 percent of the gemcitabine is degraded and inactivated by CDA metabolism after entering a patient body. The CDA enzyme activity level in the body of the patient is obviously related to the serious adverse drug reaction caused by gemcitabine and cytarabine
The invention detects 3004 genetic variations on 406 genes through a large-scale clinical test 'felodipine treatment hypertension research' (FEVER) sample with a continuous follow-up period of 4 years, and incorporates 1197 samples and 76392 blood pressure phenotype data. Through two-stage research of preliminary screening and verification, the CDA rs818202 can obviously influence the long-term antihypertensive curative effect of felodipine, and a genetic model constructed on the basis of the rs818202 can better predict the antihypertensive curative effect. Therefore, in the invention, the SNP locus of the CDA gene is CDA rs 818202. The hypotensor is calcium channel antagonist. Specifically, the antihypertensive drug is felodipine.
The CDA rs818202 locus is located at 20590298 th basic group of chromosome 1, and has 3 genotypes, namely homozygous A/A, homozygous G/G and heterozygous A/G;
in the present invention, the prediction includes: the rs818202 locus genotype is A/A, so the antihypertensive drug has poor curative effect; the rs818202 locus genotype is G/G, so the antihypertensive drug has general curative effect; the rs818202 locus genotype is A/G, and the antihypertensive drug has good curative effect.
The CDA gene variation can be used for preparing a pre-testing agent for the treatment effect of the hypertension drug, is used for large-scale detection and screening of people, and finds whether a subject is suitable for taking a calcium ion antagonist or not; the treatment effect of partial essential hypertension patients on the calcium ion antagonist can be determined by detecting peripheral blood, the method is simple, convenient and easy to implement, has strong specificity, and can provide guidance for clinical treatment.
The invention also provides a reagent for predicting the curative effect of the antihypertensive drug, which comprises a primer pair and/or a probe for detecting the SNP locus of the CDA gene.
The detection method corresponding to the detection reagent can comprise the following steps: directly sequencing after PCR amplification, and carrying out enzyme digestion or PCR amplification-probe identification after PCR amplification. The enzyme digestion after the PCR amplification refers to that restriction enzyme digestion sites are searched at the SNP sites, homozygosity is cut or not cut, electrophoresis of cut genotype enzyme digestion products shows two bands, and electrophoresis of uncut genotype enzyme digestion products only shows one band. Three bands are generated after the enzyme digestion of the heterozygote type, so that different genotypes of the sample can be distinguished. The PCR amplification-probe identification adds a specific identification probe during amplification, a sequence identified by the probe reports fluorescence during amplification, a sequence not identified does not report fluorescence, and different genotype genotypes of a sample are judged according to fluorescence intensity.
In the embodiment of the invention, the detection adopts a method of direct sequencing after PCR amplification.
The reagent comprises a primer pair for detecting the CDA gene, wherein the primer pair comprises two primers of nucleotide sequences shown as SEQ ID NO. 1-2.
The two primers of SEQ ID NO. 1-2 of the invention are amplification primers. The detection reagent also comprises a sequencing primer, wherein the sequencing primer is a primer with a nucleic acid sequence shown as SEQ ID NO. 1.
The invention also provides a kit for predicting the curative effect of the antihypertensive drug, which comprises the reagent and a PCR amplification reagent.
In the invention, the PCR amplification reagent comprises dNTP, rTaq enzyme and PCR buffer solution.
In some embodiments, the kit for predicting the therapeutic effect of antihypertensive drugs comprises:
the invention also provides a method for predicting the curative effect of the antihypertensive drug, which comprises the following steps: and amplifying and sequencing the sample to be tested, and predicting the curative effect of the antihypertensive drug according to the sequencing result.
In the method, the sample to be tested is genomic DNA. Specifically, blood genomic DNA.
In this method, the amplified primers include primers to the nucleic acid sequence shown in SEQ ID NO. 1.
In this method, the procedure for amplification comprises:
the first step is as follows: pre-denaturation at 95 ℃ for 5 min
The second step is that: total 36 cycles
Denaturation at 95 ℃ for 30 seconds
Annealing at 61 ℃ for 45 seconds
Extension at 72 ℃ for 45 seconds
The third step: extension at 72 ℃ for 7 minutes.
Sequencing the amplified product after amplification, wherein the sequenced primer comprises a primer of the nucleic acid sequence shown in SEQ ID NO. 1.
The research of the invention shows that the SNP locus rs818202 of CDA can obviously influence the long-term antihypertensive curative effect of felodipine, and a genetic model constructed on the basis of rs818202 can better predict the antihypertensive curative effect. The kit prepared by taking the SNP locus of the CDA as a marker can play a good prediction effect on the administration effect of the antihypertensive drug.
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FIG. 1 shows a large sample long follow-up high throughput pharmacogenomics study procedure;
FIG. 2 showsCDAInfluence of rs818202 gene polymorphism on long-term hypotensive effect of felodipine (preliminary screening population), wherein A represents population with different genotypesThe reduction level of SBP response (systolic blood pressure) after the medicine is taken changes with time, the reduction level of DBP response (diastolic blood pressure) after the medicine is taken by people with different genotypes is shown as B, the reduction level of MAP response (mean arterial pressure) after the medicine is taken by people with different genotypes is shown as C, and the reduction level of PP response (pulse pressure difference) after the medicine is taken by people with different genotypes is shown as D;
FIG. 3 showsCDAThe influence of rs818202 gene polymorphism on felodipine long-term blood pressure lowering curative effect (verification population), wherein A shows that SBP response (systolic blood pressure) lowering level changes with time after different genotype populations take medicines, B shows that DBP response (diastolic blood pressure) lowering level changes with time after different genotype populations take medicines, C shows that MAP response (mean arterial pressure) lowering level changes with time after different genotype populations take medicines, and D shows that PP response (pulse pressure difference) lowering level changes with time after different genotype populations take medicines;
FIG. 4 showsCDAThe influence of rs818202 gene polymorphism on felodipine long-term blood pressure lowering curative effect (summary population), wherein A shows that SBP response (systolic blood pressure) lowering level changes with time after different genotype populations are taken, B shows that DBP response (diastolic blood pressure) lowering level changes with time after different genotype populations are taken, C shows that MAP response (mean arterial pressure) lowering level changes with time after different genotype populations are taken, and D shows that PP response (pulse pressure difference) lowering level changes with time after different genotype populations are taken.
Detailed Description
The invention provides the application of the SNP locus of the CDA gene, and the technical personnel in the field can appropriately improve the process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
The invention is further illustrated by the following examples:
example 1
Firstly, 3004 genetic variations on 406 genes are detected by applying an Illumina iSelect HD high-throughput chip to a large-scale clinical test felodipine treatment hypertension research sample with a continuous follow-up period of up to 4 years in random, double-blind, control and multi-center, 1197 samples and 76392 blood pressure phenotype data are included in total, and the specific experimental flow is shown in figure 1.
The correlation between 9 SNPs including CDA (rs818202) (fig. 2), IDE (rs35426658), CBR3-AS 1(rs 2835286), CYP4F 2(rs 2108622), CBR 1(rs 2835265), FMO3 (rs1736557), CYP20A1(rs1048013), CES2(rs4783745) and FMO6P (rs1736565) and the antihypertensive effect is corrected by multiple tests (P1736565)<8.14×10-5) It has statistical significance.
Subsequently, in the verification sample, the genetic polymorphism of CDA rs818202 is a site which can still significantly influence the curative effect of the antihypertensive drug (figure 3). Therefore, we found that only CDA rs818202 can significantly affect the long-term antihypertensive efficacy of felodipine through two-stage studies of preliminary screening (n =410) and validation (n =787) (fig. 4).
The therapeutic effect of CDA rs818202 on felodipine blood pressure reduction is shown as follows:
after rs818202 GG genotype population is administrated, the average SBP response (systolic blood pressure) reduction value is 21.3 mm Hg, the average DBP response (diastolic blood pressure) reduction value is 10.5 mm Hg, the average MAP response (mean arterial pressure) reduction value is 14.1 mm Hg, and the average PP response (pulse pressure difference) reduction value is 10.8 mm Hg, which indicates that the calcium ion antagonist is sensitive and has good curative effect and dosage reduction.
After rs818202 AG genotype people take the medicine, the average SBP response (systolic blood pressure) reduction value is 15.9 mm Hg, the average DBP response (diastolic blood pressure) reduction value is 8.7 mm Hg, the average MAP response (mean arterial pressure) reduction value is 11.1 mm Hg, and the average PP response (pulse pressure difference) reduction value is 7.2 mm Hg, which indicates that the curative effect is general, and the conventional dosage is given.
After rs818202 AA genotype population is administrated, the average SBP response (systolic blood pressure) reduction value is 14.1 mm Hg, the average DBP response (diastolic blood pressure) reduction value is 8.3 mm Hg, the average MAP response (mean arterial pressure) reduction value is 10.3 mm Hg, and the average PP response (pulse pressure difference) reduction value is 5.8 mm Hg, which indicates that the drug is not sensitive to calcium ion antagonists and has poor curative effect and needs to be changed.
Example 2
The CDA gene variation detection method comprises the following steps: genotyping was performed using PCR-direct sequencing (PCR-sequencing).
1. PCR primer sequences
The Primer Premier 5.0 Primer design software is used, the length of the PCR amplification product is limited to be 100-500bp according to a genome sequence (1001 bp in total) of 500bp before and after the CDA gene polymorphism site (rs818202) in the NCBI database as a reference sequence, and the Primer designed by the software is used for verifying the specificity of the amplification product in the NCBI database.
TABLE 1 CDA Gene PCR and sequencing typing primers
2. PCR amplification reaction system
TABLE 2 PCR amplification reaction System
3. PCR optimization conditions
The first step is as follows: pre-denaturation at 95 ℃ for 5 min
The second step is that: total 36 cycles
Denaturation at 95 ℃ for 30 seconds
Annealing at 61 ℃ for 45 seconds
Extension at 72 ℃ for 45 seconds
The third step: extension at 72 ℃ for 7 min
4. Electrophoresis
Preparing an electrophoresis working solution: 50 XTAE electrophoresis buffer preparation (stock)Liquid 500 mL): tris-base 121g, Na2EDTA·2H2018.6 g, glacial acetic acid 114.2mL, using ddH2And (3) diluting the solution to be lx TAE working solution during electrophoresis when the volume is 0 to 500 mL.
The agarose gel (1% -3% agarose gel for identifying or separating and purifying PCR amplification products) is prepared by the following steps:
diluting 50 XTAE electrophoresis stock solution into 1 XTAE working buffer solution;
1-3g of agar sugar powder is weighed into a clean conical flask, and 100ml of agar sugar powder is weighed into the conical flask.
Mix 1 XTAE with agar sugar powder in a conical flask, put in a microwave oven, and heat with medium fire to dissolve agarose completely (about 2 minutes).
Taking out the conical flask from the microwave oven, cooling to warm temperature at room temperature, shaking gently, and dissolving.
And placing the rubber mold and inserting the comb teeth. The warm agarose solution is poured gently into the gel mold tank, and the gel thickness is suitably maintained at 3-5 mm.
And standing for half an hour at room temperature until the gel is solidified, carefully removing the comb, taking out the gel, and gently placing the gel into an electrophoresis tank for sample loading.
The electrophoresis solution (1 XTAE) was poured to a depth of about 1 to 2mm higher than the upper surface of the gel.
5 mu.L of PCR amplification product is mixed with 6 × loading buffer uniformly and then added into the gel sample hole.
And covering the electrophoresis tank cover, and switching on the power supply until the xylene cyan and the bromophenol blue in the gel are completely separated.
And (5) turning off the power supply, taking out the gel, placing the gel under an ultraviolet lamp for photographing, and storing the picture.
5. Direct sequencing typing of PCR products
The PCR amplification product is subjected to band confirmation by using 1% -2% agarose gel, and then rs818202 is subjected to sequencing typing by using an upstream primer (5'-TGTGATAAGCACGGCAGGAG-3').
6. And (3) analyzing a detection result:
the predicting includes:
the rs818202 locus genotype is A/A, the antihypertensive drug has poor curative effect (the calcium ion antagonist is not sensitive, and the drugs are changed);
the rs818202 locus genotype is A/G, so the antihypertensive drug has a common curative effect (conventional dose);
the rs818202 locus genotype is G/G, so the hypotensor has good curative effect (calcium ion antagonist is sensitive and the dosage is reduced).
The results show that the results completely coincide with the actual medication results.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Sequence listing
<110> Xiangya II Hospital of Zhongnan university
<120> use of SNP site of CDA gene
<130> MP2035894
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 20
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 1
<210> 2
<211> 20
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Claims (1)
- The application of the CDA gene SNP locus rs818202 as a marker in preparing a reagent for predicting the curative effect of felodipine;the CDA rs818202 locus is located at 20590298 th basic group of chromosome 1, and has 3 genotypes, namely homozygous A/A, homozygous G/G and heterozygous A/G;the predicting includes: the rs818202 locus genotype is A/A, so the antihypertensive drug has poor curative effect; the rs818202 locus genotype is G/G, so the antihypertensive drug has general curative effect; the rs818202 locus genotype is A/G, and the antihypertensive drug has good curative effect.
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| CN101717816A (en) * | 2009-03-09 | 2010-06-02 | 中南大学 | Gene detection chip of OATP1B1 major gene mutation |
| CN101665837A (en) * | 2009-09-27 | 2010-03-10 | 中国医学科学院阜外心血管病医院 | Reagent kit and application of NEDD4L gene polymorphism position point on preparation of reagent kit for predicting curative effect of hydrochlorothiazide |
| US20200181623A1 (en) * | 2017-05-18 | 2020-06-11 | The Broad Institute, Inc. | Systems, methods, and compositions for targeted nucleic acid editing |
| CN109182510A (en) * | 2018-11-06 | 2019-01-11 | 宁波艾捷康宁生物科技有限公司 | Hypertension individuation drug therapy genotype detection SNP site and matched reagent box |
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