CN106191300A - The biomarker of prediction child patient severe drug skin adverse reaction and application - Google Patents
The biomarker of prediction child patient severe drug skin adverse reaction and application Download PDFInfo
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Abstract
The invention discloses biomarker and the application of prediction child patient severe drug skin adverse reaction.The measurable child patient of described biomarker uses beta-lactam class antibiotic (penicillin (Penicillin), cephalosporin (Cephalosporin)), carbamazepine (Carbamazepine), lamotrigine (Lamotrigine), oxcarbazepine (Oxcarbazepine), phenytoin (Phenytoin), allopurinol (Allopurinol), nevirapine (Nevirapine), Abacavir (Abacavir), methazolamide (Methazolamide), the risk of serious skin untoward reaction is there is during the medicines such as dapsone (Dapsone).
Description
Technical field
The invention belongs to biological technical field, be specifically related to predict the life of child patient severe drug skin adverse reaction
Thing mark and application.
Background technology
Drug skin untoward reaction (adverse cutaneous drug reaction, ACDRs) refers to by multiple medicine
The general name of the skin pathological changes that thing, medical herbs or other chemical drugss cause, its clinical manifestation is similar to other dermatosis, its
Middle maculopapule, accounts for the 90% of CARs, urticaria and severe drug skin adverse reaction (severe cutaneous adverse
Drug reactions, SCARs) account for the 2% of all ACDRs.ACDRs is most common adverse effect, accounts for adverse drug
The 18%-20% of reaction.ACDRs can be divided into A type drug skin untoward reaction and Type B drug skin untoward reaction, Qian Zheyu
The mechanism of action of medicine is relevant, generally in dose dependent, is foreseeable；The latter is general and drug pharmacokinetics mediating recipe
Measure unrelated, it is common that immune-mediated, be generally present in the listing post-evaluation of medicine, the most serious once occur, even jeopardize
Life.Owing to child's body weight is relatively light, the distribution of gene expression and quantity have the biggest difference with adult, drug skin is not simultaneously
Good reaction clinical manifestation is similar to other child skin disease, is difficult to distinguish, to hair of children crude drug physical property skin adverse reaction
Danger and the reason such as understanding of importance is not enough, occur SCARs risk higher and more dangerous.In child, ACDRs accounts for institute
Having the 35%-36% of children's adverse drug reactions, be only second to gastrointestinal symptom (39%), therefore, effective prevention SCARs is youngster
Generation in virgin patient, significant.Based on Pharmacogenetics Knowledge or/and the knowledge of pharmacogenomics, Wo Menfa
Existing genetic polymorphism has the strongest dependency with SCARs.But because these researchs are carried out mostly in adult, and it is grown up
Because of dietary life habits (as smoking, drink, high fat diet etc.), the impact of the factors such as complication (such as diabetes etc.) so that lose
Pass polymorphism limited to the predictive ability of adult SCARs.
Summary of the invention
We have found that genetic polymorphism is bigger to the effect of child's severe drug skin adverse reaction, this may be with child
Body weight is relatively light, the distribution of gene expression and quantity have the biggest difference with adult, and severe drug skin adverse reaction faces simultaneously
Bed behaves like other child skin disease, is difficult to distinguish, child occurs the danger of severe drug skin adverse reaction
The reasons such as dangerous and understanding of importance is not enough are correlated with.Therefore, the present invention is mainly based upon Pharmacogenetics Knowledge or/and medicine base
Because group is gained knowledge, use genetic polymorphism prediction severe drug skin adverse reaction occurrence risk in child patient, right
Clinical safety rational use of drug provides important guidance, it is to avoid medicine that application risk is high or must application risk high medicine time and
Early carry out risk management and control, reduce incidence rate and the extent of injury of untoward reaction of severe drug untoward reaction to greatest extent.This
The bright biomarker providing prediction child patient severe drug skin adverse reaction, it is pre-that this biomarker can be used for preparation
Survey child patient serious skin untoward reaction medicine and test kit.
The present invention refers to use Pharmacogenetics Knowledge or/and Drug Discovery is gained knowledge, it was predicted that and child patient use β-
Lactam antibiotics (penicillin (Penicillin), cephalosporin (Cephalosporin)), carbamazepine
(Carbamazepine), lamotrigine (Lamotrigine), oxcarbazepine (Oxcarbazepine), phenytoin
(Phenytoin), allopurinol (Allopurinol), nevirapine (Nevirapine), Abacavir (Abacavir), vinegar
The risk of serious skin untoward reaction is there is during the medicines such as methazolamide (Methazolamide), dapsone (Dapsone).Specifically
Including herein below:
1. beta-lactam antibiotic: 1. IL-13R130Q, IL-4RA I50V, IL-4RA S478P, IL-4RA
Q551R、IL-13 1055C>T、IL-13 1055C>T、IL-4RA Q551R、IL-4RαIle75Val、IL-10-819C>T、
IL-10-592C>A、IL-4RαQ576R AA、IL-4RαI75V AA、IL-4RαQ576/I75、IL-18-607A/C、IL-18-
At least one polymorphism in 137G/C gene pleiomorphism, the most measurable child patient uses beta-lactam antibiotic (penicillium sp
Element, cephalosporin) there is the risk of serious skin untoward reaction, if the polymorphism predictive ability of 2 or more than 2 occurs simultaneously
Higher.②IL-13R130Q、IL-4RA I50V、IL-4RA S478P、IL-4RA Q551R、IL-131055C>T、IL-13
1055C>T、IL-4RA Q551R、IL-4RαIle75Val、IL-10-819C>T、IL-10-592C>A、IL-4RαQ576R AA、
Multiple polymorphisms composition in IL-4R α I75V AA, IL-4R α Q576/I75, IL-18-607A/C, IL-18-137G/C polymorphism
Haplotype, it is possible to prediction child patient use beta-lactam antibiotic (penicillin, cephalosporin) occur serious skin not
The risk of good reaction.
2. carbamazepine: 1. at least in HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 gene pleiomorphism
Individual polymorphism, the most measurable child patient uses the risk of carbamazepine generation serious skin untoward reaction, if occur 2 simultaneously
Or the polymorphism predictive ability of more than 2 is higher.2. many in HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 polymorphism
The haplotype of individual polymorphism composition, it is possible to prediction child patient uses the risk of carbamazepine generation serious skin untoward reaction.
3. lamotrigine: 1. HLA-B*4403, HLA-B*15:02, HLA-A*6801, HLA-B*5801, HLA-C*0718,
At least one polymorphism in HLA-DQB1*0609, HLA-DRB1*1301 gene pleiomorphism, the most measurable child patient uses
, if there is the polymorphism predictive ability of 2 or more than 2 more simultaneously in the risk of lamotrigine generation serious skin untoward reaction
By force.②HLA-B*4403、HLA-B*15:02、HLA-A*6801、HLA-B*5801、HLA-C*0718、HLA-DQB1*0609、
The haplotype of multiple polymorphisms composition in HLA-DRB1*1301 polymorphism, it is possible to prediction child patient uses lamotrigine to occur
The risk of serious skin untoward reaction.
4. oxcarbazepine: 1. at least one polymorphism in HLA-B*15:02 gene pleiomorphism, the most measurable child patient
Use the risk of oxcarbazepine generation serious skin untoward reaction, if the polymorphism predictive ability of 2 or more than 2 occurs simultaneously
Higher.2. the haplotype of multiple polymorphisms composition in HLA-B*15:02 polymorphism, it is possible to prediction child patient uses oxcarbazepine
There is the risk of serious skin untoward reaction.
5. phenytoin: 1. at least one in HLA-B*15:02, CYP2C9*3 (rs1057910) gene pleiomorphism is polymorphic
Property, the most measurable child patient use phenytoin generation serious skin untoward reaction risk, if simultaneously occur 2 or 2 with
On polymorphism predictive ability higher.2. multiple polymorphism groups in HLA-B*15:02, CYP2C9*3 (rs1057910) polymorphism
The haplotype become, it is possible to prediction child patient uses the risk of phenytoin generation serious skin untoward reaction.
6. allopurinol: 1. HLA-B*58:01, HLA-B*58:01, HLA-B*58:01, HCP5 rs3099844, HCP5
rs3094011、HCP5 rs3131643、BATI rs2734583、MICC GA005234、PPIAP9 rs9267445、
PSORS1C1 rs9263726/rs17190526/rs2233945、CCHCR1 rs9263745、CCHCR1 rs130077/
rs9263781/rs9263785、TCF19 rs9263794、TCF19 rs1044870、POU5F1 rs9263796/
In rs9263800, HLA-C rs4084090, PSORS1C3 rs9263827, HLA-B rs1634776 gene pleiomorphism extremely
A few polymorphism, the most measurable child patient uses the risk of allopurinol generation serious skin untoward reaction, if go out simultaneously
The polymorphism predictive ability of existing 2 or more than 2 is higher.②HLA-B*58:01、HLA-B*58:01、HLA-B*58:01、HCP5
rs3099844、HCP5 rs3094011、HCP5 rs3131643、BATI rs2734583、MICC GA005234、PPIAP9
rs9267445、PSORS1C1 rs9263726/rs17190526/rs2233945、CCHCR1 rs9263745、CCHCR1
rs130077/rs9263781/rs9263785、TCF19 rs9263794、TCF19 rs1044870、POU5F1
Rs9263796/rs9263800, HLA-C rs4084090, PSORS1C3 rs9263827, HLA-B rs1634776 polymorphism
In multiple polymorphisms composition haplotype, it is possible to prediction child patient use allopurinol generation serious skin untoward reaction wind
Danger.
7. nevirapine: 1. HLA-B*35, HLA-C*04, HLA-C*04:01, HLA-DRB1*01, HLA-DRB1*0101,
HLB*35:05、HLB*14:02、HLA-Cw8、HLA-Cw8-B14、TRAF3IP2 rs76228616、ABCB1
At least one polymorphism in rs10276036TT gene pleiomorphism, it is serious that the most measurable child patient uses nevirapine to occur
The risk of skin adverse reaction, if occur simultaneously, the polymorphism predictive ability of 2 or more than 2 is higher.②HLA-B*35、HLA-
C*04、HLA-C*04:01、HLA-DRB1*01、HLA-DRB1*0101、HLB*35:05、HLB*14:02、HLA-Cw8、HLA-
The haplotype of multiple polymorphisms composition in Cw8-B14, TRAF3IP2 rs76228616, ABCB1 rs10276036TT polymorphism,
The most measurable child patient uses the risk of nevirapine generation serious skin untoward reaction.
8. Abacavir: 1. HLA-B*57:01, HLA-DR7, HLA-DQ3, HLA-B*5701, HLA-DR7, HLA-DQ3,
At least one polymorphism in HLA-B*57:01 gene pleiomorphism, it is serious that the most measurable child patient uses Abacavir to occur
The risk of skin adverse reaction, if occur simultaneously, the polymorphism predictive ability of 2 or more than 2 is higher.②HLA-B*57:01、
Multiple polymorphisms composition in HLA-DR7, HLA-DQ3, HLA-B*5701, HLA-DR7, HLA-DQ3, HLA-B*57:01 polymorphism
Haplotype, it is possible to prediction child patient use Abacavir generation serious skin untoward reaction risk.
9. methazolamide: 1. at least in HLA-B*59:01, HLA-B*59:01, HLA-C*01:02 gene pleiomorphism
Individual polymorphism, the most measurable child patient uses the risk of methazolamide generation serious skin untoward reaction, if occur 2 simultaneously
Or the polymorphism predictive ability of more than 2 is higher.2. many in HLA-B*59:01, HLA-B*59:01, HLA-C*01:02 polymorphism
The haplotype of individual polymorphism composition, it is possible to prediction child patient uses the risk of methazolamide generation serious skin untoward reaction.
10. dapsone: 1. at least one polymorphism in HLA-B*31:01 gene pleiomorphism, the most measurable child patient
Use the risk of dapsone generation serious skin untoward reaction, if the polymorphism predictive ability of 2 or more than 2 occurs more simultaneously
By force.2. the haplotype of multiple polymorphisms composition in HLA-B*31:01 state property, it is possible to it is tight that prediction child patient uses dapsone to occur
The risk of weight skin adverse reaction.
Detailed description of the invention
1. gather peripheral vein blood sample or mouth desquamated cells.
2. extract genomic DNA.
3. for different pharmaceutical beta-lactam antibiotic (penicillin, cephalosporin), carbamazepine, lamotrigine, Austria
Oxcarbazepine, phenytoin, allopurinol, nevirapine, Abacavir, methazolamide, dapsone select different gene test examinations
Agent box.
(1) beta-lactam antibiotic (penicillin, cephalosporin): comprise IL-13R130Q, IL-4RA I50V, IL-
4RA S478P、IL-4RA Q551R、IL-13 1055C>T、IL-13 1055C>T、IL-4RA Q551R、IL-4Rα
Ile75Val、IL-10-819C>T、IL-10-592C>A、IL-4RαQ576R AA、IL-4RαI75V AA、IL-4RαQ576/
One or more combinations in I75, IL-18-607A/C, IL-18-137G/C polymorphism or the gene detection reagent of haplotype
Box.
(2) carbamazepine: comprise in HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 polymorphism or many
Individual combination or the gene detecting kit of haplotype.
(3) lamotrigine: comprise HLA-B*4403, HLA-B*15:02, HLA-A*6801, HLA-B*5801, HLA-C*
0718, the gene test examination of the one or more combinations in HLA-DQB1*0609, HLA-DRB1*1301 polymorphism or haplotype
Agent box.
(4) oxcarbazepine: comprise the one or more combinations in HLA-B*15:02 polymorphism or the gene test of haplotype
Test kit.
(5) phenytoin: comprise the one or more combinations in HLA-B*15:02, CYP2C9*3 (rs1057910) polymorphism
Or the gene detecting kit of haplotype.
(6) allopurinol: comprise HLA-B*58:01, HLA-B*58:01, HLA-B*58:01, HCP5 rs3099844,
HCP5 rs3094011、HCP5 rs3131643、BATI rs2734583、MICC GA005234、PPIAP9 rs9267445、
PSORS1C1 rs9263726/rs17190526/rs2233945、CCHCR1 rs9263745、CCHCR1 rs130077/
rs9263781/rs9263785、TCF19 rs9263794、TCF19 rs1044870、POU5F1 rs9263796/
In rs9263800, HLA-C rs4084090, PSORS1C3 rs9263827, HLA-B rs1634776 polymorphism one or
Multiple combinations or the gene detecting kit of haplotype.
(7) nevirapine: comprise HLA-B*35, HLA-C*04, HLA-C*04:01, HLA-DRB1*01, HLA-DRB1*
0101、HLB*35:05、HLB*14:02、HLA-Cw8、HLA-Cw8-B14、TRAF3IP2 rs76228616、ABCB1
One or more combinations in rs10276036TT polymorphism or the gene detecting kit of haplotype.
(8) Abacavir: comprise HLA-B*57:01, HLA-DR7, HLA-DQ3, HLA-B*5701, HLA-DR7, HLA-
One or more combinations in DQ3, HLA-B*57:01 polymorphism or the gene detecting kit of haplotype.
(9) methazolamide: comprise in HLA-B*59:01, HLA-B*59:01, HLA-C*01:02 polymorphism or many
Individual combination or the gene detecting kit of haplotype.
(10) dapsone: comprise the one or more combinations in HLA-B*31:01 polymorphism or the gene test of haplotype
Test kit.
4. use the result of gene detecting kit according to detection, it was predicted that drug-induced serious skin untoward reaction generation wind
Danger.
(1) beta-lactam antibiotic (penicillin, cephalosporin): if IL-13R130Q, IL-occurs in child patient
4RAI50V、IL-4RA S478P、IL-4RA Q551R、IL-13 1055C>T、IL-13 1055C>T、IL-4RA Q551R、
IL-4RαIle75Val、IL-10-819C>T、IL-10-592C>A、IL-4RαQ576R AA、IL-4RαI75V AA、IL-4Rα
In Q576/I75, IL-18-607A/C, IL-18-137G/C polymorphism one, uses beta-lactam antibiotic to occur serious
The risk of skin adverse reaction is higher, and child patient is cautious use of beta-lactam antibiotic；If multiple polymorphism combination or single occurs
Times type positive, the risk using beta-lactam antibiotic generation serious skin untoward reaction is high, it is not recommended that child patient uses
Beta-lactam antibiotic；If said gene polymorphism is feminine gender, then use beta-lactam antibiotic generation serious skin
The risk of untoward reaction is low, and child patient can use beta-lactam antibiotic safely.
(2) carbamazepine: if child patient occurs in HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 polymorphism
One, use carbamazepine generation serious skin untoward reaction risk higher, child patient is cautious use of carbamazepine；If occurring
The combination of multiple polymorphisms or haplotype are positive, and the risk using carbamazepine generation serious skin untoward reaction is high, it is not recommended that youngster
Virgin patient uses carbamazepine；If said gene polymorphism is feminine gender, then use carbamazepine generation serious skin bad instead
The risk answered is low, and child patient can use carbamazepine safely.
(3) lamotrigine: if HLA-B*4403, HLA-B*15:02, HLA-A*6801, HLA-B* occurs in child patient
5801, in HLA-C*0718, HLA-DQB1*0609, HLA-DRB1*1301 polymorphism, uses lamotrigine to occur tight
The risk of weight skin adverse reaction is higher, and child patient is cautious use of lamotrigine；If the combination of multiple polymorphism or haplotype sun occur
Property, the risk using lamotrigine generation serious skin untoward reaction is high, it is not recommended that child patient uses lamotrigine；If it is above-mentioned
Gene pleiomorphism is feminine gender, then the risk using lamotrigine generation serious skin untoward reaction is low, and child patient can safety
Use lamotrigine.
(4) oxcarbazepine: if the one or more combinations in HLA-B*15:02 polymorphism or haplotype occurs in child patient
Gene detecting kit.In polymorphism one, the risk using oxcarbazepine generation serious skin untoward reaction is higher, youngster
Virgin patient is cautious use of oxcarbazepine；If occurring, the combination of multiple polymorphism or haplotype are positive, use oxcarbazepine generation serious skin
The risk of untoward reaction is high, it is not recommended that child patient uses oxcarbazepine；If said gene polymorphism is feminine gender, then use Austria
The risk of oxcarbazepine generation serious skin untoward reaction is low, and child patient can use oxcarbazepine safely.
(5) phenytoin: if in HLA-B*15:02, CYP2C9*3 (rs1057910) polymorphism occurs in child patient
Or multiple combination or the gene detecting kit of haplotype.In polymorphism one, uses phenytoin generation serious skin bad
The risk of reaction is higher, and child patient is cautious use of phenytoin；If occurring, the combination of multiple polymorphism or haplotype are positive, use phenytoin
The risk that serious skin untoward reaction occurs is high, it is not recommended that child patient uses phenytoin；If said gene polymorphism is the moon
Property, then the risk using phenytoin generation serious skin untoward reaction is low, and child patient can use phenytoin safely.
(6) allopurinol: if HLA-B*58:01, HLA-B*58:01, HLA-B*58:01, HCP5 occurs in child patient
rs3099844、HCP5 rs3094011、HCP5 rs3131643、BATI rs2734583、MICC GA005234、PPIAP9
rs9267445、PSORS1C1 rs9263726/rs17190526/rs2233945、CCHCR1 rs9263745、CCHCR1
rs130077/rs9263781/rs9263785、TCF19rs9263794、TCF19 rs1044870、POU5F1 rs9263796/
In rs9263800, HLA-C rs4084090, PSORS1C3 rs9263827, HLA-B rs1634776 polymorphism one or
Multiple combinations or the gene detecting kit of haplotype.In polymorphism one, uses allopurinol generation serious skin bad
The risk of reaction is higher, and child patient is cautious use of allopurinol；If occurring, the combination of multiple polymorphism or haplotype are positive, use the most fast
The risk of purine alcohol generation serious skin untoward reaction is high, it is not recommended that child patient uses allopurinol；If said gene polymorphism
Be feminine gender, then the risk using allopurinol generation serious skin untoward reaction is low, and child patient can use other purine safely
Alcohol.
(7) nevirapine: if child patient occur HLA-B*35, HLA-C*04, HLA-C*04:01, HLA-DRB1*01,
HLA-DRB1*0101、HLB*35:05、HLB*14:02、HLA-Cw8、HLA-Cw8-B14、TRAF3IP2 rs76228616、
One or more combinations in ABCB1 rs10276036TT polymorphism or the gene detecting kit of haplotype.In polymorphism
One, the risk using nevirapine generation serious skin untoward reaction is higher, and child patient is cautious use of nevirapine；If occurring many
The combination of individual polymorphism or haplotype are positive, and the risk using nevirapine generation serious skin untoward reaction is high, it is not recommended that child
Patient uses nevirapine；If said gene polymorphism is feminine gender, then use nevirapine generation serious skin untoward reaction
Risk low, child patient can use nevirapine safely.
(8) Abacavir: if HLA-B*57:01, HLA-DR7, HLA-DQ3, HLA-B*5701, HLA-occurs in child patient
One or more combinations in DR7, HLA-DQ3, HLA-B*57:01 polymorphism or the gene detecting kit of haplotype.Polymorphic
In property one, the risk using Abacavir generation serious skin untoward reaction is higher, and child patient is cautious use of Abacavir；If
Occurring that the combination of multiple polymorphism or haplotype are positive, the risk using Abacavir generation serious skin untoward reaction is high, does not builds
View child patient uses Abacavir；If said gene polymorphism is feminine gender, then use Abacavir generation serious skin not
The risk of good reaction is low, and child patient can use Abacavir safely.
(9) methazolamide: if child patient occurs in HLA-B*59:01, HLA-B*59:01, HLA-C*01:02 polymorphism
One or more combinations or the gene detecting kit of haplotype.In polymorphism one, uses methazolamide to occur serious
The risk of skin adverse reaction is higher, and child patient is cautious use of methazolamide；If occurring, the combination of multiple polymorphism or haplotype are positive,
The risk using methazolamide generation serious skin untoward reaction is high, it is not recommended that child patient uses methazolamide；If above-mentioned base
Because polymorphism is feminine gender, then the risk using methazolamide generation serious skin untoward reaction is low, and child patient can make safely
Use methazolamide.
(10) dapsone: if the one or more combinations in HLA-B*31:01 polymorphism or haplotype occurs in child patient
Gene detecting kit.In polymorphism one, the risk using dapsone generation serious skin untoward reaction is higher, child
Patient is cautious use of dapsone；If occurring, the combination of multiple polymorphism or haplotype are positive, use dapsone generation serious skin bad instead
The risk answered is high, it is not recommended that child patient uses dapsone；If said gene polymorphism is feminine gender, then dapsone is used to occur
The risk of serious skin untoward reaction is low, and child patient can use dapsone safely.
Case 1:3 example child patient medicine causes the gene type assay of serious skin untoward reaction
The most retrospective summary and the data of analysis 3 example child patient drug-induced serious skin untoward reaction, including: year
Age, sex, sensitizing drugs kind and quantity, incubation period, clinical manifestation, therapeutic scheme and lapse to.Drug-induced serious skin
Skin untoward reaction includes, fixed drug eruption (fixed drug eruptions, FDE), acute systemic dermexanthesis type impetigo
(acute generalized exanthematous pustulosis, AGEP), allergy syndrome
(hypersensitivity syndrome, HSS), Stevens-Johnson syndrome (Stevens-Johnson
Syndrome, SJS), toxic epidermal necrolysis (toxic epidermal necrolysis, TEN) (see table 1).
2. take 3 example child patient medicines to cause the peripheric venous blood of serious skin untoward reaction.
3. extract genomic DNA.
4. being respectively adopted prediction child patient uses carbamazepine to cause the detection examination of serious skin untoward reaction risk genes
Agent box, prediction child patient use lamotrigine to cause serious skin untoward reaction risk genes detection kit, detect Karma
Xiping, lamotrigine cause the genotype of serious skin untoward reaction child patient.
5. testing result is shown in Table 1, and 1. carbamazepine causes serious skin untoward reaction child patient genotype to be respectively as follows:
HLA-B*15:02, HLA-B*15:11.2. lamotrigine causes serious skin untoward reaction child patient genotype to be respectively as follows:
HLA-A*6801, HLA-B*5801, HLA-C*0718, HLA-DRB1*1301, HLA-B*4403/HLA-B*15:02 monoploid
Type.
Table 1
Case 2:10 example takes carbamazepine, lamotrigine does not occurs the gene type assay of serious skin untoward reaction infant
1. retrospective analysis 10 example child patient takes carbamazepine (5 example), lamotrigine (5 example) does not occurs serious skin
The data of untoward reaction, including: age, sex, sensitizing drugs kind and quantity, incubation period, clinical manifestation, therapeutic scheme and turn
Return.
2. collect the peripheric venous blood of 10 example child patients.
3. extraction genomic DNA.
4. genotype detection: 1. use prediction child patient to use carbamazepine to cause serious skin untoward reaction risk base
Because of detection kit, detect above-mentioned 5 examples and use carbamazepines that the child patient genotype of serious skin untoward reaction does not occurs.②
Use prediction child patient to use lamotrigine to cause serious skin untoward reaction risk genes detection kit, detect above-mentioned 5
Example uses lamotrigine that the child patient genotype of serious skin untoward reaction does not occurs.
5. testing result: 1. 5 examples do not find to cause serious skin not in taking the child patient genotype of carbamazepine
The related gene polymorphism of good reaction or haplotype (HLA-B*3802, HLA-DRB1*1302, HLA-DRB1*1302/DPB1*
0201 haplotype, HLA-DRB1*11, HLA-B*7301).2. 5 examples are not sent out in taking the child patient genotype of lamotrigine
Now can cause related gene polymorphism or haplotype (HLA-Cw*0401, STAT3 of serious skin untoward reaction
(rs4796793)、STAT3(rs4796793)、DAO 995C>T、GSTP1*A/A HLA-RB1*03:01-DQB1*02:01 is mono-
Ploidy).
Claims (4)
1. predict the biomarker of child patient severe drug skin adverse reaction, it is characterised in that described biomarker
Thing is: IL-13R130Q, IL-4RA I50V, IL-4RA S478P, IL-4RA Q551R, IL-13 1055C > T, IL-
131055C>T、IL-4RA Q551R、IL-4RαIle75Val、IL-10-819C>T、IL-10-592C>A、IL-4RαQ576R
In AA, IL-4R α I75V AA, IL-4R α Q576/I75, IL-18-607A/C, IL-18-137G/C gene pleiomorphism at least one
Individual polymorphism or the haplotype of multiple polymorphism composition；Or, HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 gene
At least one polymorphism in polymorphism or the haplotype of multiple polymorphism composition；Or, HLA-B*4403, HLA-B*15:02,
In HLA-A*6801, HLA-B*5801, HLA-C*0718, HLA-DQB1*0609, HLA-DRB1*1301 gene pleiomorphism extremely
A few polymorphism or the haplotype of multiple polymorphism composition；Or, HLA-B*15:02, CYP2C9*3 (rs1057910) gene
At least one polymorphism in polymorphism or the haplotype of multiple polymorphism composition；Or, HLA-B*58:01, HLA-B*58:
01、HLA-B*58:01、HCP5rs3099844、HCP5rs3094011、HCP5rs3131643、BATI rs2734583、MICC
GA005234、PPIAP9rs9267445、PSORS1C1rs9263726/rs17190526/rs2233945、
CCHCR1rs9263745、CCHCR1rs130077/rs9263781/rs9263785、TCF19rs9263794、
TCF19rs1044870、POU5F1rs9263796/rs9263800、HLA-C rs4084090、PSORS1C3rs9263827、
At least one polymorphism in HLA-B rs1634776 gene pleiomorphism or the haplotype of multiple polymorphism composition；Or, HLA-
B*35、HLA-C*04、HLA-C*04:01、HLA-DRB1*01、HLA-DRB1*0101、HLB*35:05、HLB*14:02、HLA-
At least one in Cw8, HLA-Cw8-B14, TRAF3IP2rs76228616, ABCB1rs10276036TT gene pleiomorphism is many
State property or the haplotype of multiple polymorphism composition；Or, HLA-B*57:01, HLA-DR7, HLA-DQ3, HLA-B*5701, HLA-
At least one polymorphism in DR7, HLA-DQ3, HLA-B*57:01 gene pleiomorphism or the haplotype of multiple polymorphism composition；
Or, at least one polymorphism or multiple many in HLA-B*59:01, HLA-B*59:01, HLA-C*01:02 gene pleiomorphism
The haplotype of state property composition；Or, at least one polymorphism in HLA-B*31:01 gene pleiomorphism or multiple polymorphism composition
Haplotype.
2. biomarker as claimed in claim 1, it is characterised in that described IL-13R130Q, IL-4RA I50V, IL-
4RAS478P、IL-4RA Q551R、IL-13 1055C>T、IL-13 1055C>T、IL-4RA Q551R、IL-4Rα
Ile75Val、IL-10-819C>T、IL-10-592C>A、IL-4RαQ576R AA、IL-4RαI75V AA、IL-4RαQ576/
At least one polymorphism in I75, IL-18-607A/C, IL-18-137G/C gene pleiomorphism or the list of multiple polymorphism composition
The severe drug skin adverse reaction that times type prediction beta-lactam antibiotic (penicillin, cephalosporin) causes；Described
At least one polymorphism in HLA-B*15:02, HLA-B*15:11, HLA-A*31:01 gene pleiomorphism or multiple polymorphism group
The severe drug skin adverse reaction that the haplotype prediction carbamazepine become causes；Described HLA-B*4403, HLA-B*15:
02, in HLA-A*6801, HLA-B*5801, HLA-C*0718, HLA-DQB1*0609, HLA-DRB1*1301 gene pleiomorphism
The severe drug skin that the haplotype prediction lamotrigine of at least one polymorphism or multiple polymorphism composition causes is bad instead
Should；At least one polymorphism or the haplotype prediction of multiple polymorphism composition in described HLA-B*15:02 gene pleiomorphism are difficult to understand
The severe drug skin adverse reaction that oxcarbazepine causes；Described HLA-B*15:02, CYP2C9*3 (rs1057910) gene is many
At least one polymorphism in state property or the severe drug skin of the haplotype prediction phenytoin initiation of multiple polymorphism composition
Untoward reaction；Described HLA-B*58:01, HLA-B*58:01, HLA-B*58:01, HCP5rs3099844, HCP5rs3094011,
HCP5rs3131643、BATI rs2734583、MICC GA005234、PPIAP9rs9267445、PSORS1C1rs9263726/
rs17190526/rs2233945、CCHCR1rs9263745、CCHCR1rs130077/rs9263781/rs9263785、
TCF19rs9263794、TCF19rs1044870、POU5F1rs9263796/rs9263800、HLA-Crs4084090、
At least one polymorphism in PSORS1C3rs9263827, HLA-B rs1634776 gene pleiomorphism or multiple polymorphism composition
Haplotype prediction allopurinol cause severe drug skin adverse reaction；Described HLA-B*35, HLA-C*04, HLA-C*
04:01、HLA-DRB1*01、HLA-DRB1*0101、HLB*35:05、HLB*14:02、HLA-Cw8、HLA-Cw8-B14、
At least one polymorphism in TRAF3IP2rs76228616, ABCB1rs10276036TT gene pleiomorphism or multiple polymorphism
The severe drug skin adverse reaction that the haplotype prediction nevirapine of composition causes；Described HLA-B*57:01, HLA-DR7,
At least one polymorphism in HLA-DQ3, HLA-B*5701, HLA-DR7, HLA-DQ3, HLA-B*57:01 gene pleiomorphism or
The severe drug skin adverse reaction that the haplotype prediction Abacavir of multiple polymorphisms composition causes；Described HLA-B*59:
01, at least one polymorphism in HLA-B*59:01, HLA-C*01:02 gene pleiomorphism or the list times of multiple polymorphism composition
The severe drug skin adverse reaction that type prediction methazolamide causes；In described HLA-B*31:01 gene pleiomorphism at least
The severe drug skin adverse reaction that the haplotype prediction dapsone of one polymorphism or multiple polymorphism composition causes.
3. biomarker predicts child patient severe drug skin adverse reaction medicine in preparation as claimed in claim 1 or 2
Application in thing.
4. as described in any one of claim 1 or 2, biomarker is bad at preparation prediction child patient severe drug skin
Application in reaction kit.
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| WO2020182189A1 (en) * | 2019-03-12 | 2020-09-17 | Chang Gung Memorial Hospital, Linkou | Methods for detecting or reducing the incidence of adverse drug reactions |
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| CN108728524A (en) * | 2017-04-18 | 2018-11-02 | 中南大学湘雅三医院 | One kind being based on JunoTMChildren's safety medication detection kit and chip |
| CN107447024A (en) * | 2017-09-11 | 2017-12-08 | 长沙都正医学检验有限责任公司 | Application of the HLA B allele in the detection reagent for preparing prediction Plant-Polygonum and its composition cause risk of liver injury |
| CN107447024B (en) * | 2017-09-11 | 2019-12-24 | 长沙都正医学检验有限责任公司 | Application of HLA-B allele in preparation of detection reagent for predicting risk of liver injury caused by plant polygonum multiflorum and components thereof |
| WO2019080077A1 (en) * | 2017-10-27 | 2019-05-02 | 长庚医疗财团法人林口长庚纪念医院 | Method for assessing the risk of cutaneous adverse drug reactions caused by anti-epileptic drug lamotrigine, detection reagent thereof and use thereof |
| CN111278990A (en) * | 2017-10-27 | 2020-06-12 | 长庚医疗财团法人林口长庚纪念医院 | Method for evaluating risk of skin drug adverse reaction caused by antiepileptic drug lamotrigine, detection reagent and application thereof |
| JP2021500083A (en) * | 2017-10-27 | 2021-01-07 | チャン グァン メモリアル ホスピタル，リンコウＣｈａｎｇ Ｇｕｎｇ Ｍｅｍｏｒｉａｌ Ｈｏｓｐｉｔａｌ，Ｌｉｎｋｏｕ | Methods for assessing the risk of skin side effects from drugs induced by the antiepileptic drug lamotrigine, their detection reagents, and their use |
| WO2020182189A1 (en) * | 2019-03-12 | 2020-09-17 | Chang Gung Memorial Hospital, Linkou | Methods for detecting or reducing the incidence of adverse drug reactions |
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