CN103261891B

CN103261891B - The method selecting to treat the therapeutic regimen having attention deficit hyperactivity disorder patient

Info

Publication number: CN103261891B
Application number: CN201180061208.9A
Authority: CN
Inventors: D·A·马拉泽克
Original assignee: Mayo Foundation for Medical Education and Research
Current assignee: Mayo Foundation for Medical Education and Research
Priority date: 2010-10-21
Filing date: 2011-10-20
Publication date: 2016-11-30
Anticipated expiration: 2031-10-20

Abstract

Describing the method that patient selects therapeutic regimen, described method comprises with regard to one group of genetic testing Patient genotype, identifies the phenotype relevant to the genotype of each gene, and according to described Phenotypic Selection therapeutic regimen.

Description

The method selecting to treat the therapeutic regimen having attention deficit hyperactivity disorder patient

Cross reference to related applications

This application claims the priority of the U.S. Provisional Application No. 61/405,272 submitted on October 21st, 2010.Above-mentioned The disclosure of application is included in herein by reference of text.

Technical field

The application relates to the therapeutic regimen (medication) selecting treatment to have attention deficit hyperactivity disorder (ADHD) patient Method, and particularly relate to according to drug metabolism enzyme coding gene and the product encoding gene participating in such as nerve conduction Genotype selects the therapeutic regimen of patient.

Summary of the invention

The present invention is relevant to ADHD and have the qualification of Genetic polymorphism of pharmacological reaction to therapeutic regimen based on one group.Knot Really, the inventive method can measure the genotype of patient and according to the phenotype relevant to genotype, selects the patient having ADHD Suitably therapeutic regimen.The inventive method can integrate the output that multiple genotype is evaluated, it is provided that selects and gives therapeutic regimen Important and improve clinical information.Therefore, present approach provides and identify the therapeutic regimen causing patient peak optimization reaction Rational method.

On the one hand, qualitative ADHD patient is selected therapeutic regimen the method for the application.Described method comprises offer patient Biological sample (such as peripheral blood sample or saliva)；The genotype of one group of gene of patient is obtained from biological sample, wherein said Group comprises Cytochrome P450 2D6 (CYP2D6) gene, catechol-O-transmethylase (COMT) gene, noradrenaline Element transporter gene SLC6A2, Dopamine Transporter Gene SLC6A3 and dopamine receptor gene DRD4；Identify and institute State the phenotype that in one group of gene, the Patient genotype of each gene is correlated with；Each phenotype is made to be combined into the associating phenotype of patient；And basis The associating Phenotypic Selection therapeutic regimen of patient.Select therapeutic regimen can comprise the associating phenotype classification therapeutic regimen according to patient. Obtain patient's genotype for CYP2D6 can comprise mensuration described patient whether comprise CYP2D6*1A, 2D6*2,2D6*2N, 2D6*3,2D6*4,2D6*5,2D6*6,2D6*7,2D6*8,2D6*10,2D6*12 or 2D6*17 allele.Implement at some In mode, it is thus achieved that patient's genotype for CYP2D6 can comprise whether the described patient of mensuration comprises CYP2D6*1A, * 2A, * 2B, * 2N, * 3, * 4, * 5, * 6, * 7, * 8, * 9, * 10, * 11, * 12, * 15, * 17, * 35 or * 41 allele.Described genome is also Serotonin transporter gene SLC6A4, the ADRA2A gene of coding for alpha-2A adrenoreceptor, coding synapse can be comprised The SNAP25 gene of body associated protein 25 and/or the SLC1A1 gene of encoding nerve unit glutamate transporter.Described therapeutic regimen Can be methylphenidate, amphetamine (the most long-acting amphetamine or fugitive amphetamine) or atomoxetine.Described long-acting An Feita Bright energy is selected from dexamphetamine slow releasing capsule (spansule) preparation, the amphetamine salt pref of prolongation release and Lai Youan Fei Taming preparation.Described fugitive amphetamine can be selected from dextran amphetamine preparation, dexamphetamine and amphetamine Amphetamine salt pref and meth.

On the other hand, qualitative ADHD patient is selected therapeutic regimen the method for the application.Described method comprises computer Receiving patient's genotype for one group of gene in system, wherein said group comprises CYP2D6 gene, COMT gene, nor-kidney Upper parathyrine transporter gene SLC6A2, Dopamine Transporter Gene SLC6A3 and dopamine receptor gene DRD4, Qi Zhongsuo State computer system and comprise the multiple therapeutic regimen list being suitable to treat ADHD；Described computer system is used to identify and described group The phenotype that in gene, the genotype of each gene is relevant；Described computer system is used to make each phenotype be combined into the association list of patient Type；By quantitatively considering that each phenotype in associating phenotype selects to treat one or more therapeutic regimens of patient；With from described One or more therapeutic regimens selected by computer system output.The genotype of described patient can directly receive from for measuring trouble The equipment of person's genotype.In some embodiments, the Patient genotype during user inputs described computer system.Described method Before can also being included in output step, computer system is used to grade selected therapeutic regimen according to the associating phenotype of patient.

The application further relates to the non-transient computer-readable medium comprising executable instruction, can perform to refer to described in performing Making processor carry out comprising the operation of the Patient genotype receiving one group of gene when making, wherein said one group of gene comprises CYP2D6 Gene, COMT gene, norepinephrine transporter gene SLC6A2, Dopamine Transporter Gene SLC6A3 and DOPA Amine receptor gene DRD4；Identify the phenotype relevant to the genotype of each gene in described one group of gene；Each phenotype is made to be combined into trouble The associating phenotype of person；Identify and described patient in combination's phenotype in comprising the data base being suitable to treat the multiple therapeutic regimen of ADHD Relevant therapeutic regimen；Receive the genotype of patient with response and export the therapeutic regimen of qualification.

Unless otherwise defined, all technology used herein and scientific terminology have art ordinary skill people of the present invention The same implication that member is generally understood.Although or the method for equivalent similar with described herein and material can be used to implement the present invention, But it is described below suitable method and material.All publications, patent application, patent and other reference literary compositions addressed herein Offer and include in the most by reference of text herein.In case of conflict, it is as the criterion with this specification (in including being defined on).Additionally, material Material, method and embodiment are the most only illustrative, are not intended to be construed as limiting.

Other features, purpose and the advantage of the present invention can be apparent by description, accompanying drawing and claims.

Accompanying drawing explanation

Fig. 1 is the block diagram of the computer system 100 according to an embodiment.

Fig. 2 is the flow chart of the method 200 selecting therapeutic regimen for patient.

Detailed Description Of The Invention

Generally, the genotype of the gene that basis that the present invention is qualitative selects for therapeutic regimen, select treatment to have ADHD to suffer from The method of the therapeutic regimen of person.The gene wanting gene type generally encodes and affects therapeutic regimen metabolism or relevant to differential responses Product.A certain algorithm, the phenotype that initial imparting is relevant to Patient genotype for each gene in group can be used, and then make Each phenotype is combined into the associating phenotype of patient.So by application series of rules suitably to use prescription according to associating Phenotypic Selection Case.

For treat the therapeutic regimen of ADHD comprise psychostimulant (such as methylphenidate and amphetamine) and non-stimulated agent (as Atomoxetine (Strattera), selectivity NRI).The indefiniteness example bag of methylphenidate Containing effect fugitive, middle and durative action preparation.Such as, the short acting formulation of methylphenidate hydrochloride is (such as d, l-methylphenidate such as methylphenidate or first Spirit), middle effect (also referred to as extending release (ER) or sustained release (SR)) methylphenidate hydrochloride preparation such as methylphenidate SR, first spirit ER and Metadate ER, or long-acting (LA) Concerta such as methylphenidate osmotic oral release system (OROS) (be absorbed in and reach), Metadate controls to deliver (CD), methylphenidate LA or methylphenidate transdermal patch (Daytrana).The indefiniteness of amphetamine is shown Example comprises fugitive and durative action preparation.Such as, fugitive amphetamine preparation can be that dextran amphetamine preparation is (as non-in dextrorotation peace His bright or dextrorotation enlightening west volume), the amphetamine salt pref of the neural sulfate of dexamphetamine and amphetamine is (such as A get La (Adderall)), meth HCl preparation (such as noluder (Desoxyn)) or hydrochloric acid dexmethylphenidate preparation (d-piperazine Methyl ester, such as Focalin).Long-acting amphetamine preparation can be that dexamphetamine slow release capsule preparation is (as slow release glue is rolled up in enlightening west Capsule), ER amphetamine salt pref (such as A get La XR) or two methanesulfonic acids rely dexamfetamine (lisdexamfetamine Dimesylate) (it is metabolized to the prodrug of dexamphetamine, such as Vyvanse).

Multiple genes of encoding drug metabolic enzyme (such as Cytochrome P450 D6) and other target genes are (as participated in nerve Conduction gene) genomic testing provide safe method, impacted patient is avoided that the side effect of potential danger.

Organize gene more

Described method comprises and obtains biological sample from patient and one group of gene is obtained to the genotype of patient.Generally, carry out Described one group of gene of gene type comprises cytochrome P450 gene such as CYP2D6 and multiple target gene, and described gene is compiled Code responds the product that the ability of specific therapeutic regimen kind is relevant with patient.Such as, multiple target gene can be the adjacent benzene two of coding The gene of phenol-O-transmethylase (COMT), the gene of coding norepinephrine transporter (such as SLC6A2), coding DOPA The gene of amine transporter (such as SLC6A3) and the gene of coding dopamine receptor (such as DRD4).Therefore, at an embodiment In, described one group of gene can be CYP2D6 gene, COMT gene and SLC6A2 gene, SLC6A3 gene and DRD4 gene.This Each allele of a little genes is shown in table 1.

The substrate of CYP2D6 is typically cation binding site away from the weak base wanting carbonoxide atom.Especially, CYP2D6 Substrate comprise atomoxetine and amphetamine.Some individualities have the CYP2D6 gene order of change, and it causes synthesis to lack The enzyme that the enzyme of catalysis activity or catalysis activity reduce.Also been observed the repetition of function CYP2D6 gene, and cause medicine Ultra-rapid metabolism.Do not inactivate polymorphism, lack or the individuality that repeats has the phenotype of strong drug metabolism type (metabolizer), And referred to as CYP2D6*1.CYP2D6*2 allele has the enzymatic activity of the reduction that aminoacid replacement causes.Described CYP2D6*3 Occupy with * 4 allele cause weak metabolic pattern phenotype overall fault close to 70%.It is responsible for CYP2D6*3 (2549A > del) Polymorphism generate mRNA shifting frame.Participate in the allelic polymorphism of CYP2D6*4 (1846G > A) and destroy mRNA montage.This A little changes generate the clipped form CYP2D6 lacking catalysis activity.Other weak metabolic patterns (metabolizer) are CYP2D6*5, * 10 and * 17.CYP2D6*5 lacks owing to full gene.The polymorphism of CYP2D6*10 and * 17 generates the amino of CYP2D6 enzyme Acid replaces, and reduces the activity of enzyme.All these polymorphisms are autosomal recessives.As a result, it is only to these polymorphisms Say that the individuality isozygotying or being combined heterozygosis is weak metabolic pattern.The heterozygous individual having a normal gene and a Genetic polymorphism has Intermediate supersession (normally) and between weak metabolic pattern by force.As used herein, if it is weak or ultra-rapid metabolism type, identify that patient has Phenotype 1, if it is intermediate supersession type, is accredited as phenotype 2, if it is extensive (extensive) metabolic pattern, is accredited as phenotype 3.Table 2 lists CYP2D6 allele and related activity.

Table 1

Table 2

CYP2D6 allele and related activity

Allele	Activity level
		*1	Normally
*2A	Increase
		*2BD	Reduce
*3	Nothing
		*4	Nothing
*5	Nothing
		*6	Nothing
*7	Nothing
		*8	Nothing
*9	Reduce
		*10	Reduce
*11	Nothing
		*12	Nothing
*15	Nothing
		*17	Reduce
*35	Increase
		*41	Reduce

The Tandem Repeat Polymorphism of the known DRD4 gene promoter comprising 120 base pair repetitive sequences is various in the whole world Colony has different gene frequencies.See D ' Souza etc., Biol Psychiatry.56 (9): 691-7 (2004). This polymorphism of DRD4 promoter region and the performance solving mathematical problem when giving object more high dose methylphenidate improve phase Close.The official name of this variant is rs4646984.The more conventional form of rs4646894 is " 240 nucleotide allele ". Less common allele is " 120 nucleotide allele ", and reports this shorter allele and have higher Transcriptional activity.See D ' Sousa etc., 2004, ibid.When processing with the methylphenidate dosage being administered for mono-day three times more than 10mg, More high activity 120 is repeated child that allele isozygotys in mathematics test than there being one or two copy activity relatively low 240 Repeat those children allelic to perform better than.

COMT polymorphism (Val158Met) is relevant to the reaction of amphetamine.Especially, working memory efficiency is by just Val/val genotype (high COMT activity) gives amphetamine and strengthens, and amphetamine is with regard to (the low work of met/met genotype Property) for high workload memory loading condiction under generate side effect.See Froehlich etc., CNSDrugs, 24 (2): 99-117 (2010).The irritability of response methylphenidate is also relevant to this COMT polymorphism with physical symptom.See McCough etc., J.Am.Acad.Child Adolesc.Psychiatry,48(12):1155-1164(2009)。

Response methylphenidate is also relevant to the Variable bend tail vehicle of SLC6A3 gene 3 ' untranslated region (VNTR) polymorphism. According to the number of tandem sequence repeats in this unit, a minimum of 10 variants.Described 10 recurring units are more active common One of variant, and it is relevant to the increase of ADHD risk to report it.Repeat homozygote with regard to 10 and observe that the methylphenidate of improvement rings Should, and 9 are repeated homozygosity and react relevant to parent level (parent-rated) therapeutic regimen of minimizing.Other genes relatively 9 individualities repeating allele homologizing less can be experienced the effect of amphetamine by type.See Froehlich etc., 2010, ibid.

Zest therapeutic regimen (stimulant medication) blocks on norepinephrine transporter to be taken the photograph again Take.Several polymorphisms in SCL6A2 gene are relevant to ADHD and the reaction to amphetamine and methylphenidate.Such as, with G/A or G/G phenotype is compared, and the individuality that exon 9 isozygotys with regard to A/A genotype at 1278 in many dynamic impulsive behaviors but is not carelessness symptom Aspect, the reaction to methylphenidate reduces.C/C gene for amphetamine, after giving amphetamine, on 36001A/C Type is relevant to the active mood of higher self-report with the haplotype GCC of 28257G/C, 28323C/T and 36001A/C.This A little polymorphic positions are in transcript binding site.See Froehlich etc., 2010, ibid.

In some embodiments, described one group of gene can also comprise one or more of: serotonin transporter Gene SLC6A4, SNAP25 encoding gene, α-2A adrenoreceptor (ADRA2A) encoding gene, glutamate transporter (SLC1A1) encoding gene, carboxy-lesterase 1 (CES1) encoding gene, corticotropin releasing hormone (CRH) coding base Cause and tryptophan hydroxylase 2 (TPH2) encoding gene.In one embodiment, SLC6A4 gene be included in CYP2D6, In the group of COMT, SLC6A2, SLC6A3 and DRD4 gene.In one embodiment, SNAP25 gene has been included in In the group of CYP2D6, COMT, SLC6A2, SLC6A3 and DRD4 gene.In one embodiment, ADRA2A gene is included in Have in the group of CYP2D6, COMT, SLC6A2, SLC6A3 and DRD4 gene.In one embodiment, SLC6A4 gene and SNAP25 gene is included in the group of CYP2D6, COMT, SLC6A2, SLC6A3 and DRD4 gene.At an embodiment In, SLC6A4 gene and ADRA2A gene are included in the group of CYP2D6, COMT, SLC6A2, SLC6A3 and DRD4 gene. In one embodiment, SNAP25 gene and ADRA2A gene be included in CYP2D6, COMT, SLC6A2, SLC6A3 and In the group of DRD4 gene.In one embodiment, SLC6A4 gene, SNAP25 gene and ADRA2A gene have been included in In the group of CYP2D6, COMT, SLC6A2, SLC6A3 and DRD4 gene.

There is child's (being shown in Table 1) of the different VNTR polymorphic forms being positioned at SLC6A4 gene intron 2 to methylphenidate Therapeutic response is different.Modal variant is " 12 repeat " allele, and " 9 repeat " allele is relatively rare.With 10 weights Multiple alleles is compared, zooscopy instruction 12 repetition allele can up-regulated gene function (Lovejoy etc., Eur.J.Neurosci.17:417-420(2003).Therefore, the individuality having two copies 12 repetition can have the 5-of most highly active Hydroxytryptamine transport protein product is transcribed, and have two copy 10 repeat allelic those lower 5-hydroxy tryptamine can be had to turn Fortune albumen generates.Equally, described 12 reiterated genes types are relevant to the more preferable clinical response of methylphenidate.

Response methylphenidate is also relevant to SNAP25, and SNAP25 is to participate in the neurotransmitter born of the same parents from storage vesicles to synaptic space Exocrine neuronal specificity vesicle docking albumen.Especially, T1065G and T1069C polymorphism (being shown in Table 1) and ADHD it Between find association.The T allelic homozygote appropriateness of T1065G improves methylphenidate dose response, and with regard to T at T1069C Those isozygotied show poor methylphenidate reaction.At least one copy T is allelic compared with those, at 1065 with having There is sleep difficulty and big 2-3 times irritated of probability in the child isozygotied with regard to G allele.Compared with T allele carrier, Those generations isozygotied with regard to C allele at 1069 are twitched and big 2-4 times of the probability of other abnormal motions.See Froehlich etc., 2010, ibid；With McCough etc., 2009, ibid.

α-2A adrenoreceptor (ADRA2A) is to suppress cell discharge speed upon activation and limit noradrenaline The norepinephrine autologous recipient of element release.See Froehlich etc., 2010, ibid.Less common G is had at-1291 places Allelic object (seeing table 1) improves methylphenidate reaction in terms of carelessness scoring rather than many dynamic impulsion scorings.

As described herein, according to the genotype with upper 5 genes of group (such as CYP2D6 gene, COMT gene, SLC6A2 base Because of, SLC6A3 gene and DRD4 gene) relevant one group of Rule Generation Algorithm.Also can according to 6 genes (such as CYP2D6 base Cause, COMT gene, SLC6A2 gene, SLC6A3 gene, DRD4 gene and SLC6A4 gene, SNAP25 gene and ADRA2A One of gene) relevant one group of rule uses algorithm.Similarly, can according to 7 or 8 genes (such as CYP2D6 gene, COMT In gene, SLC6A2 gene, SLC6A3 gene, DRD4 gene and SLC6A4 gene, SNAP25 gene and ADRA2A gene Two or three) relevant one group of rule uses algorithm.According to these algorithms, given patient is provided according to the genotype of patient Therapeutic regimen or classification therapeutic regimen, make clinician can select acceptable treatment with regard to ADHD patient, and need not measure described Whether patient can respond or tolerate the repetition test of specific therapeutic regimen.

Measure genotype

Genomic DNA is generally used for measuring genotype, although could be used that mRNA.Genomic DNA is generally from biological sample As peripheral blood sample is extracted, but can extract from other biological sample, comprise saliva or the tissue (mucosa such as oral cavity wall Swipe or from kidney or hepatic tissue).Conventional method can be used to extract genomic DNA from blood, saliva or tissue sample, comprise example Such as extract with phenol.Or, genomic DNA can extract with test kit, such asTissue kit (California Look into the Kai Jie company (Qiagen) of thatch Butterworth (Chatsworth)),Genomic DNA purification kit (Pu Luomaige Company (Promega)) and A.S.A.P.^TMGenomic DNA Isolation Kit (the Bo Linge of Indianapolis, the state of Indiana Yin Gehan company (Boehringer Mannheim)).

Generally, before carrying out gene type, implement amplification step.Such as, polymerase chain reaction (PCR) technology can be used for from Patient obtains amplified production.PCR refers to program or the technology of enzymatic amplification target nucleic acid.Area-of-interest end or the sequence beyond it are believed Breath is commonly used to design oligonucleotides primer, and it is identical with the sequence of template opposite strand to be amplified.PCR can be used for from DNA and RNA expands particular sequence, including total genomic dna or the sequence of total cell RNA.Primer generally grows 14 40 nucleotide, but Be length range can be 10 nucleotide-hundreds of nucleotide.General round pcr is described in such as PCR Primer:A Laboratory Manual (" PCR primer: laboratory manual "), Dieffenbach C. and Dveksler G. compile, Cold SpringHarbor Laboratory Press (Cold Spring Harbor Laboratory Press), 1995.When using RNA as template source Time, reverse transcriptase can be used for synthesizing complementary DNA (cDNA) chain.Ligase chain reaction, strand displacement amplification, Autonomous maintenance sequence replicating Or amplification of based on nucleotide sequence can be used for obtaining the nucleic acid separated.See for example Lewis (1992) Genetic Engineering News 12(9):1；Guatelli etc. (1990) Proc.Natl.Acad.Sci.USA 87:1874-1878； With Weiss (1991) Science 254:1292-1293.

Primer is typically strand or the double chain oligonucleotide of 10 50 length of nucleotides, and works as and mammalian genes group When DNA combines and is used for PCR condition, can extend with the nucleic acid product of area-of-interest in the corresponding gene of generation.Generally, PCR produces Thing be at least 30 length of nucleotides (as 30,35,50,100,250,500,1000,1500 or 2000 or more polynucleotide long Degree).When oligonucleotide primers is to when reacting for identical PCR, can expand mammalian DNA specific region (as replicated thus Generate multiple copy accurately), one of them primer comprises the nucleotide sequence of nucleic acid coding chain, and another primer comprises core The nucleotide sequence of acid noncoding strand." coding strand " of nucleic acid is non-transcribed chain, has the nucleotide identical with specific rna transcription body Sequence (except rna transcription body comprises uracil to substitute thymidine residue), and " noncoding strand " of described nucleic acid is as transcribing The chain of template.

Single PCR reactant mixture can comprise a pair oligonucleotide primers.Or, single reactant mixture can comprise Multiple oligonucleotide primers pair, can generate in the case multiple PCR primer (as 5,10,15 or 20 primers to).Can amplification Each primer pair, such as 1 exon or the part of 1 exon.Also intron sequences can be expanded.

Exon or the intron of gene of interest, then direct Sequencing can be expanded.Dye primer order-checking can be used for increasing The accuracy of detection heterozygosis sample.Or, one or more technology hereinafter described can be used for measuring genotype.

Such as, allele specific hybridization can be used for detecting sequence variants, comprises whole haplotypes of mammal.Ginseng See Stoneking etc., 1991, Am.J.Hum.Genet.48:370-382；With Prince etc., 2001, Genome Res., 11 (1):152-162.In practice, DNA or RNA sample from one or more mammals can use primer pair amplifies, and institute Obtain amplified production can be fixed on substrate (such as zone of dispersion).Select hybridization conditions, thus nucleic probe can be specifically binding to sense On sequence of interest, such as variant nucleic acid sequences.This hybridization is generally carried out under high stringent condition, because some sequence variants are only Comprise single nucleotide difference.High stringent condition can comprise use LISS and high temperature for washing.Such as, Nucleic acid molecules can be (in 0.3M NaCl/0.03M sodium citrate/0.1% sodium lauryl sulphate (SDS) miscellaneous in 42 DEG C at 2X SSC Hand over, and in 65 DEG C of washings in 0.1X SSC (0.015M NaCl/0.0015M sodium citrate), 0.1%SDS.Can adjust miscellaneous Friendship condition, to consider the particular feature of described nucleic acid molecules, comprises length and sequence composition.Energy labelling (such as fluorescence) probe is with side Help detection.In some embodiments, one of primer used in amplified reaction is biotinylated the (5 ' ends such as reverse primer End), and gained biotinylation amplified production is fixed on the substrate of Avidin or Streptavidin coating (such as zone of dispersion).

Allele specific oligonucleotide restrictive diges-tion can be carried out in the following manner.To the nucleotide sequence introducing restriction site For variant, allele can be distinguished by the restrictive diges-tion of specific Restriction Enzyme.To the sequence not changing convenient restriction sites For row variant, when variation allele exists or in the presence of wild-type allele, can design and introduce restriction site Mutant primer.Mutant primer and wild primers can be used to expand nucleic acid moiety interested, then use suitable restriction enzyme Nuclease digestion.

Some variant such as inserts or deletes one or more nucleotide, changes the size of the DNA fragmentation comprising variant. The insertion of nucleotide or deletion can comprise region and mensuration size of amplified production compared with dimensional standard of variant by amplification Evaluate.The region of such as gene of interest can use the primer sets from variant either side to expand.One of primer is generally used Such as fluorescing fractions labelling is to help to measure size.Described amplified production can pass through acrylamide gel electrophoresis, has one group with not It is same as the dimensional standard of the fluorescing fractions labelling of primer.

Can exploitation only exist or only (MSPCR or allele in the presence of wild-type allele when variant allele Specific PCR) the PCR condition of amplified production and primer.Such as, patient DNA and comparison can use wild primers or to variation Allele specific oligonucleotide primer individually expands.Then amplified production is existed and use standard method detection often group reaction to observe DNA.Such as, described reaction can pass through agarose gel electrophoresis, and dyes by ethidium bromide or other DNA intercalative dyes Observe DNA.In the DNA of heterozygosis patient, product can be detected in each reaction.Only comprise the patient of wild-type allele Sample only has amplified production in the reaction using wild primers.Similarly, the allelic Patient Sample A of variation is only comprised Only in the reaction using variation primer, there is amplified production.ApoE gene could be used that and turns two Universal Energy The allele-specific primers moving labeled primer introducing primer sites carries out (being such as marked with the one of green colouring material such as fluorescein Individual primer and the primer being marked with orchil such as Sulforhodamine).The green of analysing amplified product on plate instrument can be read at plate Normal complexion red fluorescence.See Myakishev etc., 2001, Genome 11 (1): 163-169.

Could be used that then mismatch cleavage method is sheared with wild-type sequence hybridization and mismatch site to be expanded by PCR The different sequence of detection.Chemical reagent, such as carbodiimide or azanol and Osmic acid. can be used for the nucleotide modifying mispairing with side Help shearing.

Test kit is the most commercially to detect a lot of Cytochrome P450 variants.Such as, TAG-IT^TMTest kit is available from Tm Biological Science Co., Ltd (Tm Biosciences Corporation, Toronto, Ontario).

Select therapeutic regimen

After to genetic testing genotype each in group, therapeutic regimen can be selected.It is typically chosen and comprises CYP2D6 genotype It is associated with enzyme capacity with therapeutic regimen described in metabolism, i.e. distributes phenotype according to genotype.Such as, if patient is weak or ultrafast Metabolic pattern, identifies that this patient has phenotype 1.If patient is intermediate supersession type, identify that this patient has phenotype 2, or if wide General (extensive) metabolic pattern, is accredited as phenotype 3.

The gene of other target genes (such as COMT gene, SLC6A2 gene, SLC6A3 gene, DRD4 gene) in group Type, the ability that can respond therapeutic regimen with patient associates, and i.e. distributes phenotype according to genotype.Such as, for DRD4, if suffered from Person has 120 allele, identifies that this patient has positive phenotypes, and if it has 240 allele, be accredited as negative phenotype. For SLC6A3, if there being 10 recurring units, identify patient have positive phenotypes, and if have 9 recurring units, identify suffer from Person has negative phenotype.For SLC6A2, if patient has G/A or G/G genotype, identify that this patient has a positive phenotypes, and such as Really it has A/A genotype, is accredited as negative phenotype.For COMT, if patient has val/val genotype, identify this patient Active phenotype, and if it has val/met or met/met genotype, be accredited as active less phenotype.

After identifying phenotype relevant to Patient genotype for each gene in group, described phenotype is combined into associating phenotype, Reflect the phenotype relevant to the genotype of each gene in group.Such as, the associating phenotype of patient can be: DRD4 is positive, SLC6A3 sun Property, SLC6A2 is positive, COMT activity and the CYP2D6 positive 1.

Algorithm one group of rule based on associating phenotype can be used individual patient is selected most suitable therapeutic regimen.? Decision making algorithm quantitatively considers the change of each gene.Suitable use is strengthened by comprising target data and drug metabolism related data The selection of regimen.This can measure the impact on the clinical response of particular patient of the CYP product.Such as, target data and medicine are comprised Thing metabolism related data provides the amount of available medicine, patient uses the ability of medicine and about the quality of drug receptor target Information, it is provided that select therapeutic regimen rational method.

The example of this process can be that given patient selects suitable ADHD therapeutic regimen.If associating phenotype is DRD4 is positive, SLC6A3 is positive, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 1, and described algorithm can export methylphenidate (MPH) as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is positive, SLC6A2 is positive, COMT lives Property and CYP2D6 phenotype 1, described algorithm can export MPH as select therapeutic regimen.That if associating phenotype is DRD4 is positive, SLC6A3 is negative, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 1, and described algorithm can export MPH as the medication selected Scheme.If associating phenotype is DRD4 negative, SLC6A3 feminine gender, the SLC6A2 positive, COMT activity and CYP2D6 phenotype 1, described Algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is positive, SLC6A2 is negative, COMT activity and CYP2D6 phenotype 1, described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 Feminine gender, SLC6A3 are positive, SLC6A2 is negative, COMT is active and CYP2D6 phenotype 1, and described algorithm can export MPH as selecting Therapeutic regimen.If associating phenotype is DRD4 positive, SLC6A3 feminine gender, SLC6A2 feminine gender, COMT activity and CYP2D6 phenotype 1, Described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 feminine gender, SLC6A2 Feminine gender, COMT activity and CYP2D6 phenotype 1, described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype Being that DRD4 is positive, SLC6A3 is positive, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 2, described algorithm can export MPH conduct The therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is positive, SLC6A2 is positive, COMT is active and CYP2D6 Phenotype 2, described algorithm can export MPH as the therapeutic regimen selected.That if associating phenotype is DRD4 is positive, SLC6A3 negative, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 2, and described algorithm can export MPH as the therapeutic regimen selected.If connection Closing phenotype is that DRD4 is negative, SLC6A3 is negative, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 2, and described algorithm can export MPH is as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is positive, SLC6A2 is negative, COMT is active, With CYP2D6 phenotype 2, described algorithm can export MPH as the therapeutic regimen selected.That if associating phenotype is DRD4 is negative, SLC6A3 is positive, SLC6A2 is negative, COMT is active and CYP2D6 phenotype 2, and described algorithm can export MPH as the medication selected Scheme.If associating phenotype is DRD4 positive, SLC6A3 feminine gender, SLC6A2 feminine gender, COMT activity and CYP2D6 phenotype 2, described Algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is negative, SLC6A2 is negative, COMT activity and CYP2D6 phenotype 2, described algorithm can export amphetamine or atomoxetine as the therapeutic regimen selected.As Fruit associating phenotype is the DRD4 positive, the SLC6A3 positive, the SLC6A2 positive, COMT activity and CYP2D6 phenotype 3, described algorithm meeting Output MPH is as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is positive, SLC6A2 is positive, COMT lives Property and CYP2D6 phenotype 3, described algorithm can export MPH as select therapeutic regimen.That if associating phenotype is DRD4 is positive, SLC6A3 is negative, SLC6A2 is positive, COMT is active and CYP2D6 phenotype 3, and described algorithm can export MPH as the medication selected Scheme.If associating phenotype is DRD4 negative, SLC6A3 feminine gender, the SLC6A2 positive, COMT activity and CYP2D6 phenotype 3, described Algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is positive, SLC6A2 is negative, COMT activity and CYP2D6 phenotype 3, described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 Feminine gender, SLC6A3 are positive, SLC6A2 is negative, COMT is active and CYP2D6 phenotype 3, and described algorithm can export MPH as selecting Therapeutic regimen.If associating phenotype is DRD4 positive, SLC6A3 feminine gender, SLC6A2 feminine gender, COMT activity and CYP2D6 phenotype 3, Described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 feminine gender, SLC6A2 Feminine gender, COMT activity and CYP2D6 phenotype 3, described algorithm can export amphetamine or atomoxetine and use prescription as select Case.If associating phenotype is the DRD4 positive, the SLC6A3 positive, the SLC6A2 positive, the less activity of COMT, CYP2D6 phenotype 1, described Algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is positive, SLC6A2 is positive, The less activity of COMT and CYP2D6 phenotype 1, described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is The DRD4 positive, SLC6A3 feminine gender, the SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 1, described algorithm can export MPH and make For the therapeutic regimen selected.That if associating phenotype is DRD4 is negative, SLC6A3 negative, SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 1, described algorithm can export MPH as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 The positive, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 1, described algorithm can export MPH and use prescription as select Case.If associating phenotype is DRD4 feminine gender, the SLC6A3 positive, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 1, institute State algorithm and can export MPH as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is negative, SLC6A2 is cloudy Property, the less activity of COMT and CYP2D6 phenotype 1, described algorithm can export MPH as the therapeutic regimen selected.If association list Type is DRD4 feminine gender, SLC6A3 feminine gender, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 1, and described algorithm can export Low dosage atomoxetine is as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is positive, SLC6A2 is positive Property, the less activity of COMT and CYP2D6 phenotype 2, described algorithm can export MPH as the therapeutic regimen selected.If association list Type is DRD4 feminine gender, the SLC6A3 positive, the SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 2, and described algorithm can export MPH is as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is negative, SLC6A2 is positive, the less work of COMT Property and CYP2D6 phenotype 2, described algorithm can export MPH as select therapeutic regimen.That if associating phenotype is DRD4 is negative, SLC6A3 feminine gender, the SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 2, described algorithm can export amphetamine or atropic Xi Ting is as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is positive, SLC6A2 is negative, COMT is less Activity and CYP2D6 phenotype 2, described algorithm can export MPH as the therapeutic regimen selected.If it is cloudy that associating phenotype is DRD4 Property, SLC6A3 is positive, SLC6A2 negative, the less activity of COMT and CYP2D6 phenotype 2, described algorithm can export amphetamine or Atomoxetine is as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 is negative, SLC6A2 is negative, COMT Less activity and CYP2D6 phenotype 2, described algorithm can export amphetamine or atomoxetine as the therapeutic regimen selected.As Fruit associating phenotype is DRD4 feminine gender, SLC6A3 feminine gender, SLC6A2 feminine gender, the less activity of COMT, CYP2D6 phenotype 2, described algorithm Amphetamine or atomoxetine can be exported as the therapeutic regimen selected.That if associating phenotype is DRD4 is positive, SLC6A3 positive, The SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 3, described algorithm can export MPH as the therapeutic regimen selected.As Fruit associating phenotype is DRD4 feminine gender, the SLC6A3 positive, the SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 3, described calculation Method can export amphetamine or atomoxetine as the therapeutic regimen selected.If associating phenotype is the DRD4 positive, SLC6A3 the moon Property, SLC6A2 is positive, the less activity of COMT and CYP2D6 phenotype 3, described algorithm can export amphetamine or atomoxetine conduct The therapeutic regimen selected.That if associating phenotype is DRD4 is negative, SLC6A3 negative, SLC6A2 positive, the less activity of COMT and CYP2D6 phenotype 3, described algorithm can export amphetamine or atomoxetine as the therapeutic regimen selected.If associating phenotype is The DRD4 positive, the SLC6A3 positive, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 3, it is non-that described algorithm can export peace He is bright or atomoxetine is as the therapeutic regimen selected.If associating phenotype is DRD4 feminine gender, SLC6A3 is positive, SLC6A2 is cloudy Property, the less activity of COMT and CYP2D6 phenotype 3, described algorithm can export amphetamine or atomoxetine as the medication selected Scheme.If associating phenotype is DRD4 positive, SLC6A3 feminine gender, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 3, Described algorithm can export amphetamine or atomoxetine as the therapeutic regimen selected.That if associating phenotype is DRD4 is negative, SLC6A3 feminine gender, SLC6A2 feminine gender, the less activity of COMT and CYP2D6 phenotype 3, described algorithm can export amphetamine or atropic Xi Ting is as the therapeutic regimen selected.

The Similarity algorithm that can use based on relate to one group of 6 genes rule (i.e. CYP2D6 gene, COMT gene, One of SLC6A2 gene, SLC6A3 gene, DRD4 gene and SLC6A4 gene, SNAP25 gene and ADRA2A gene), or Based on relate to one group of 7 or 8 genes rule (i.e. CYP2D6 gene, COMT gene, SLC6A2 gene, SLC6A3 gene, Two or three in DRD4 gene and SLC6A4 gene, SNAP25 gene and ADRA2A gene).

In some embodiments, energy algorithm for design analysis to be divided into three classes by therapeutic regimen: 1) can connect for application The therapeutic regimen being subject to, the therapeutic regimen that i.e. homergy probability is high in the individuality having specific gene type, 2) can use with caution Therapeutic regimen (i.e. therapeutic regimen according to atypical metabolism may need some dose titration)；With 3) should avoid or be cautious use of With monitoring therapeutic regimen, such as the potential challenges caused due to dosage.

The data relevant with the therapeutic regimen reaction of patient's one-level or second degree relatives can input algorithm equation, described algorithm side Journey relates to selecting therapeutic regimen in the first kind medicine identified.Then can calculate dividing according to the clinical response of kinsfolk The adjustment of the suitable therapeutic regimen of level sequence (rank-order).

The output of algorithm also can be incorporated in historical data.Such as, if kinsfolk is good to the response of specific therapeutic regimen Good, this can prove that described therapeutic regimen can just can accept for application, if or one-level or second degree relatives this is used prescription The problematic reaction of case, can select substitute.

Computer system

Technology described herein can be run in the computer system having the processor performing computer program special instruction.Can To configure described computer system with output based on the therapeutic regimen overview receiving Patient genotype.Specifically, described computer Program can comprise system command to select most suitable therapeutic regimen (such as psychostimulant or non-stimulated medication single patient Scheme).

The examples of features being presented herein below in the system of may be embodied in.Can configure described computer program, thus described calculating Machine system according to receiving data authentication phenotype, and can provide the preliminary identification of the most possible therapeutic regimen.Described system energy according to In algorithm equation, specific cofactor is graded to sort and has been identified therapeutic regimen.The gene that described system can be loaded with according to patient Type polymorphism adjusts grading sequence.Described system can adjust grading row according to the kinsfolk of clinical response such as patient Sequence.

Fig. 1 is according to an embodiment, the block diagram of the computer system 100 that can use in aforesaid operations.Described system System 100 comprises processor 110, internal memory (memory) 120, storage device 130 and input-output apparatus 140.Each assembly 110, 120,130 and 140 interconnect with system bus 150.Described system can comprise analytical equipment 160 to detect the genotype of patient.

Described processor 110 can process the instruction for performing in described system 100.In one embodiment, Processor 110 is single screw socket processor.In another embodiment, described processor 110 is many screw sockets processor.Described place Reason device 110 can process the instruction preserved in internal memory (memory) 120 or storage device 130, comprises and is set by input/output Standby 140 receive or send information.Described internal memory (memory) 120 is at described system 100 inner storag information.An embodiment party In formula, internal memory 120 is computer-readable medium.In one embodiment, internal memory 120 is volatile memory unit.At another In embodiment, internal memory 120 is non-volatile memory cell.

Described storage device 130 can provide bulk storage for described system 100.In one embodiment, storage Equipment 130 is computer-readable medium.In various different embodiments, described storage device 130 can be floppy device, Hard disc apparatus, compact disk equipment or tape unit.

Described input-output apparatus 140 provides input/output operations for described system 100.In one embodiment, Input-output apparatus 140 includes keyboard and/or pointing device.In another embodiment, input-output apparatus 140 includes For showing the display unit of graphic user interface.

Described system 100 may be used for selecting therapeutic regimen.Fig. 2 shows the method 200 selecting therapeutic regimen for patient Flow chart.Preferably, described method 200 is carried out on the system 100.Such as, computer program can comprise and makes processor The instruction of 110 steps carrying out method 200.Described method 200 comprises the following steps.

Receive the Patient genotype for one group of gene in step 210.Described genotype can be by user by defeated Enter/outut device 140 inputs.Such as, described user can use analytical equipment 160 to obtain the Patient genotype of one group of gene (can connect and be free of attachment to described system 100).Described user can key on input-output apparatus 140 such as keyboard Patient genotype, to be received by described system 100.

Described genotype can directly receive from analytical equipment 160.Such as, analytical equipment 160 can comprise processor With suitable software, thus it can pass through net connection.Described system 100 can be fitted by input-output apparatus 140 such as network Orchestration is connected to analytical equipment 160, and directly receives Patient genotype.

Identify the phenotype 180 relevant to the genotype 170 of each gene in described group of gene in step 215.Such as, described System 100 can carry out database retrieval in storage device 130.

In a step 220 each phenotype 180 is combined into the associating phenotype 190 of patient.

One group of rule (as mentioned above) is applied to consider that each phenotype of associating phenotype 190 is to select with quantitative in step 230 Suitably one or more therapeutic regimens 195.Optional step 235 is as described below.

Response receives the genotype of patient and exports one or more therapeutic regimens 195 of qualification in step 240, and Apply described rule to consider associating phenotype.Described system can by input-output apparatus 140 export qualification one or Multiple therapeutic regimen 195.Such as, the therapeutic regimen identified can print in the suitable pattern user interface of display device or Display.Such as another example, described system 100 can use prescription by what network such as LAN or Internet transmission were identified Case, described input-output apparatus 140 is connected on network.

The form of one or more therapeutic regimens 195 exported by system 100 is flexible.Such as, institute's output information can comprise The classification of several therapeutic regimens.In this execution, described method 200 is adjusted before may be embodied in the therapeutic regimen that output is identified The optional step 235 of joint grading.Such as, described system 100 can be graded according to the associating Phenotypic modulation of patient.As another shows Example, step 235 can relate to adjusting grading according to clinical response.Described clinical response can by system 100 with patient's base The method identical because of type receives.Such as, described grading can adjust according to the clinical response of patient home member.

Other embodiments

Although being described it should be understood that the present invention has combined its detailed description, but above description being intended to illustrate and not limit this Bright scope, this scope is defined by the appended claims.Other aspects, advantage and amendment are at the model of following claims In enclosing.

Claims

1. for selecting a computer system for therapeutic regimen, described system bag for attention deficit hyperactivity disorder (ADHD) patient Contain

Data base, for storing patient's genotype for one group of gene, wherein said group comprises Cytochrome P450 2D6 (CYP2D6) gene, catechol-O-transmethylase (COMT) gene, norepinephrine transporter gene SLC6A2, Dopamine Transporter Gene SLC6A3 and dopamine receptor gene DRD4；Described group includes:

I () is selected from CYP2D6*2BD, * 3, * 4, * 5, * 6, * 7, * 8, * 9, * 10, * 11, * 12, * 15, * 17, * 35 or * 41 equipotential base One or more cytochrome P450 gene CYP2D6 of cause；

(ii) selected from 120 type allele and 240 types one or both dopamine receptor genes allelic of rs4646984 DRD4 allele；

(iii) exon 9 the 1278th is selected from one or both norepinephrine transporters gene SLC6A2 etc. of G and A Position gene；

(iv) Variable bend tail vehicle (i.e. VNTR) of SLC6A3 gene 3 ' untranslated region is selected from 9 recurring units and 10 weights One or both norepinephrine transporter gene SLC6A3 allele of multiple unit；

(v) the 158th one or both catechols-O-methyl transferase gene COMT allele selected from val and met；

It is configured to distribute the processor of the metabolic phenotype relevant to the Patient genotype of each described gene in described group of gene, wherein

The phenotype of CYP2D6 distribution is selected from phenotype 1, phenotype 2 and phenotype 3, wherein with regard to allele described in (i) for isozygotying or multiple The patient closing heterozygosis is assigned as phenotype 1, and (i) certain allele is that the patient of heterozygosis is assigned as phenotype 2, does not has any (i) Described in allelic patient be assigned as phenotype 3；

For DRD4, if isozygotying, 120 allele are then assigned as positive phenotypes, if there being 240 allele, divide Join for there being negative phenotype；

For SLC6A3, if there being 10 recurring units, being assigned as positive phenotypes, if only 9 recurring units, dividing Join for negative phenotype；

For SLC6A2, then it is assigned as positive phenotypes if G/A or G/G genotype, then distributes if A/A genotype For negative phenotype；

For COMT, then it is assigned as activity phenotypes if val/val genotype, and if val/met or met/met base Because type is being assigned as active less phenotype；

It is configured to each described phenotype to be combined into the processor of the associating phenotype of described patient, and

It is configured to the processor of therapeutic regimen described in the associating Phenotypic Selection according to described patient；Wherein with the combining of described patient The output of phenotype association is selected from following table:

2. computer system as claimed in claim 1, it is characterised in that described processor is further configured to work as associated patient Associating phenotype classification multiple therapeutic regimen according to described patient when the output of associating phenotype has a multiple therapeutic regimen.

3. computer system as claimed in claim 1, it is characterised in that described group of gene also comprises serotonin transporter Gene SLC6A4.

4. computer system as claimed in claim 1, it is characterised in that described group of gene also comprises coding for alpha 2A epinephrine The ADRA2A gene of energy receptor.

5. computer system as claimed in claim 1, it is characterised in that described group of gene also comprises coding synaptosome and be correlated with egg The SNAP25 gene of white 25.

6. computer system as claimed in claim 1, it is characterised in that described group of gene also comprises encoding nerve unit glutamic acid The SLC1A1 gene of transporter.

7. the computer system as according to any one of claim 1-6, it is characterised in that if associated patient associating phenotype It is methylphenidate that output has methylphenidate, described therapeutic regimen.

8. the computer system as according to any one of claim 1-6, it is characterised in that if associated patient associating phenotype Output display amphetamine or atomoxetine, described therapeutic regimen is amphetamine or atomoxetine.

9. computer system as claimed in claim 8, it is characterised in that described amphetamine is long-acting amphetamine.

10. computer system as claimed in claim 9, it is characterised in that described long-acting amphetamine is selected from dextrorotation An Feita Bright slow release capsule preparation, the amphetamine salt pref extending release and bad right amphetamine preparation.

11. computer systems as claimed in claim 8, it is characterised in that described amphetamine is fugitive amphetamine.

12. computer systems as claimed in claim 11, it is characterised in that described fugitive amphetamine is selected from: dextran The amphetamine salt pref of amphetamine preparation, dexamphetamine and amphetamine, and meth.

13. computer systems as according to any one of claim 1-6, it is characterised in that the genotype of described patient is by saliva Liquid sample or peripheral blood sample obtain.

14. computer systems as claimed in claim 1, it is characterised in that described group of gene also comprises 5-hydroxy tryptamine transhipment egg White gene SLC6A4, the SNAP25 gene of coding synaptosome associated protein 25 and encoding nerve unit glutamate transporter SLC1A1 gene.

15. computer systems as claimed in claim 1, it is characterised in that the genotype of described patient directly receive from for Measure the equipment of Patient genotype.

16. computer systems as claimed in claim 15, it is characterised in that also include the input for inputting Patient genotype Device.