KR101559626B1 - Kit for predicting of therapeutic effect of affective disorder medicine - Google Patents

Abstract

The present invention relates to a kit for predicting therapeutic response of a therapeutic agent for affective disorder, and a method for detecting a polymorphic polymorphism for predicting therapeutic response of a therapeutic agent for affective disorder. According to the present application, it is possible to predict the therapeutic effect of a therapeutic agent for affective disorder in patients with affective disorder, to provide basic information on personalized treatment, and to treat the affective disorder scientifically and effectively.

Description

[0001] The present invention relates to a kit for predicting the therapeutic response of a therapeutic agent for affective disorder,

The present invention relates to a kit for predicting therapeutic response of a therapeutic agent for affective disorder, and a method for detecting a polymorphic polymorphism for predicting therapeutic response of a therapeutic agent for affective disorder.

The serotonin neurotransmitter system is one of the most important factors in the pathogenesis and treatment of depressive disorder. To date, at least 14 serotonin receptors have been found, and these receptors are divided into different families, denoted 1 to 7, and subtypes such as a, b and c. The number of these receptors is associated with the onset of various mental illnesses. In particular, one of the most studied receptors for association with depressive disorder is the serotonin 1A receptor (5-HT Receptor 1A; HTR1A). HTR1A, a G-protein coupled receptor, is a key protein that regulates serotonin signaling in the central nervous system and the central serotonin nervous system is located in the raphe nuclei of the brain stem. HTR1A is extensively present in the frontal cortex, septum, amygdala, hippocampus, and hypothalamus, which receive serotonin signals from the seam nucleus. In addition, HTR1A is a somatodendritic autoreceptor of the septal nucleus, which decreases the excitatory rate of nerve cells, the amount of serotonin secreted by action potentials, and the production of neurotransmitters, Lt; RTI ID = 0.0 > serotonin < / RTI > Furthermore, activation of HTR1A in cell dendrites inhibits the production of tyrosine hydroxylase and initiates at the medial prefrontal cortex (mPFC) to inhibit the glutamatergic pathway to the seam nucleus Thereby indirectly reducing serotonergic neurotransmission. Thus, HTR1A not only dynamically regulates serotonin activity, which affects various functions such as cognition and emotion, but also plays an important role in neuronal migration, neurite outgrowth, and synapse formation in neuronal development It is thought to play a role.

The roles of HTR1A in major depressive disorders have been elucidated through a variety of pharmacological studies, post-analysis studies, neuro-receptor imaging studies, and genetic studies. In particular, the expression of HTR1A at both synapses and post-synapses is regulated differently, and this change in expression is thought to be important in the pathophysiology of major depressive disorder and in the control of the serotonin system. In other words, the amount of posterior synaptic HTR1A located in the marginal cortex of the major depressive disorder is decreased, whereas the amount of HTR1A self-receptor present in the septal proximal of the septal nucleus increases. Conclusions: This conflicting expression of HTR1A ultimately reduces the activity of serotonin system and strongly suggests that it plays an important role in the pathogenesis of major depressive disorder.

On the other hand, the serotonin transporter (5-HTT) plays a role of resupplying the synaptic secretion of serotonin to the synapse, and abnormal decrease of the serotonin transporter in the brain region is observed in the depressive disorder . Many antidepressants also have therapeutic effects by inhibiting this serotonin transporter activity. Many depression and antidepressant drug genetics studies have been focused on serotonin transporters. The serotonin transporter gene, SLC6A4 (Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4), is present on chromosome 17q11.1-q12 and is a major therapeutic target for selective serotonin reuptake inhibitors (SSRIs). The most intensively studied polymorphism was found in the 5-HTT LPR (5-Hydroxytriptamine transporter-linked polymorphic region), in which the 43 base pairs of the promoter region were inserted / deleted. The S allele L allele (Long allele). In the STARD (Sequenced Treatment Alternatives to Relief Depression) study, the direct association between 5-HTT LPR and antidepressant treatment was not confirmed, but the combination of the S allele and L allele was SSRI (selective serotonin reuptake inhibitor) Citalopram has been reported to have a high likelihood of side effects. In addition, it has recently been reported that additional polymorphisms, including the 5-HTT LPR, as well as the serotonin transporter intron 2, are associated with antidepressant treatment responses.

However, the effect of serotonin 1A receptor gene polymorphism or serotonin 1A aminotransferase gene polymorphism and serotonin transporter gene polymorphism on the antidepressant treatment response is not known.

1. Horstmann S, Binder EB. Pharmacogenomics of antidepressant drugs. Pharmacol Ther 2009 124 (1): 57-73 2. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002 Apr; 71 (4): 533-554.

The purpose of this application is to predict the effect of serotonin 1A receptor gene polymorphism alone or serotonin 1A receptor gene polymorphism and serotonin transporter gene polymorphism on the therapeutic response of amyotrophic disorders treatment.

The present application provides a kit for predicting therapeutic response of a therapeutic agent for affective disorder comprising a probe capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).

The present application also provides a microarray for predicting therapeutic response of a therapeutic agent for affective disorder comprising a probe capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).

The present application also provides a method for detecting the polymorphism rs1800042 of the serotonin 1A receptor from a sample isolated from an individual for prediction of the therapeutic response of a therapeutic agent for affective disorder.

According to the present application, it is possible to predict the therapeutic effect of a therapeutic agent for affective disorder in patients with affective disorder, to provide basic information on personalized treatment, and to treat the affective disorder scientifically and effectively.

Figure 1 shows the association of 5-HTT VNTR (1A) and HTR1A (1B) polymorphisms with rates of depression symptom reduction represented by percent reduction of HAMD-17 scores in the treatment of major depressive disorder drugs.
Figure 2 shows the association of the combination of 5-HTT VNTR and HTR1A polymorphisms with the rate of depression symptom reduction represented by percent reduction of HAMD-17 score in the treatment of major depressive disorder treatment.

Treatment response rates for antidepressant drugs, including Mirtazapine, an antidepressant, are typically around 60%. The difficulty in treating mood disorders is that the rate of failure and the rate of adverse events are higher when compared to other drugs and the individual differences in drug reactions are very large. In addition, continuous treatment for at least 2-4 weeks is required until the therapeutic effect of the therapeutic agent appears, which leads to an increase in the economic, physical burden and social cost of the patient.

Therefore, in order to find out the predictors of treatment response in patients with affective disorder, we have selected indications that can be selected according to the constitution and situation of individuals. However, most of them are single gene based studies, There is little contribution to the treatment of depression and there are no indications that have been practically used because of low reproducibility of the results of the study.

In this application, we investigated the interaction between genetic polymorphisms that may affect the therapeutic effect of depression, one of the affective disorders. Specifically, we investigated the relationship between 1) serotonin transporter gene polymorphism and treatment response of major depressive disorder, 2) to investigate the association between serotonin receptor 1A gene polymorphism and treatment response of major depressive disorder, and 3) We examined the effect of gene polymorphism interaction on the treatment response of major depressive disorder treatment.

The term polymorphism in the present application refers to the coexistence of one or more forms of nucleic acids, including exons and introns, or portions thereof. That is, when two or more alleles exist in one locus, the single nucleotide polymorphism (SNP) is called a single nucleotide polymorphism. The polymorphic region may also be several nucleotides in length.

The term allele in the present application refers to an alternative form of a gene comprising introns, exons, intron / exon junctions and 3 'and / or 5' untranslated regions associated with a gene or a portion thereof. Generally, an allele refers to several types of genes that are located on the same gene locus on a homologous chromosome. When an individual has two identical alleles of the gene, the individual is said to be homozygous for the gene or allele. When an individual has two different alleles of the gene, the individual is said to be heterozygous for the gene. Alleles of a particular gene may differ from each other by a single nucleotide or several nucleotides and may include substitution, deletion and insertion of nucleotides.

Term in this application, the polymorphism "rs1800042" means the SNP is identified by its accession number in the SNP database (dbSNP, www.ncbi.nlm .nih.gov / projects / SNP /) and c.818G of HTR1A gene> A It is located in the locus corresponding to the locus.

In this application, the term variable number tandem repeat (VNTR) means a sequence in which 9 to 80 bases are repeated. The variable number tandem repeat (VNTR) of the second intron of the serotonin transporter (5-HTT) gene is located on human chromosome 17, chromosome 25,570,101-25,570,300. The polymorphism of the chain repetition sequence in the second intron of the serotonin transporter (5-HTT) gene corresponds to a DNA sequence (12-repeat allele) consisting of 204 nucleotides from RP1 of SEQ ID NO: 1 to RP 12 of SEQ ID NO: 12, The polynucleotide of SEQ ID NO: 9 and the sequence of SEQ ID NO: 10 are missing, for example, the sequence of SEQ ID NO: 9 and the sequence of SEQ ID NO: 10 are missing.

SEQ ID NO: 1: GGCTGTGACCCAGGGTG (repeat number; RP1)

SEQ ID NO: 2: GGCTGTGACCCGGAGTG (repeat number; RP2)

SEQ ID NO: 3: GGCTGTGACCCGGGGTG (repeat number: RP3)

SEQ ID NO: 4: GGCTGTGACCCG GGTG (repeat number: RP4)

SEQ ID NO: 5: GGCTGCGACCTGGGGTG (repeat number: RP5)

SEQ ID NO: 6: GGCTGTGACCTGGGATG (repeat number; RP6)

SEQ ID NO: 7: GGCTGTGACCCG GGTG (repeat number; RP7)

SEQ ID NO: 8: GGCTGTGACCTGGGGTG (repeat number; RP8)

SEQ ID NO: 9: GGCTGTGACCCG GGTG (repeat number: RP9)

SEQ ID NO: 10: GGCTGTGACCTGGGGTG (repeat number: RP10)

SEQ ID NO: 11: GGCTGTGACCCG GGTG (repeat number: RP11)

SEQ ID NO: 12: GGCTGTGACCTGGGATG (repeat number; RP12)

The term " probe " in the present application means a composition capable of determining the presence or absence of the polymorphism by identifying the polymorphism site of the gene through a hybridization reaction specifically. The specific method of such gene analysis is not particularly limited, and may be by any known gene detection method.

The present application will be described in detail below. Mirtazapine was selected as a treatment for major depressive disorder, and 1) the association of serotonin transporter gene polymorphism with the treatment of mirtazapine was divided into two groups according to 50%. It was confirmed that the patient with the genotype showed a higher reactivity by treatment with the mirtazapine (Example 1).

We also investigated the association between serotonin receptor 1A gene polymorphism and the treatment of mirtazapine. The HAM-D17 reduction rate was 50%, and the results were divided into two groups: the HTR1A + 272G> A genotype and the HTR1A + 272G> A genotype. This means that a single gene marker of the serotonin receptor 1A gene polymorphism can be used as a genetic marker for predicting the therapeutic response of a major depressive disorder treatment (Example 2).

In addition to single gene markers, 3) the effect of gene polymorphism on serotonin transporter and serotonin receptor 1A gene on the treatment of mirutazin therapy was investigated. As a result, it was confirmed that the Mirtazapine treatment response can be predicted even more efficiently when the two gene polymorphisms are judged by the combination of the single gene polymorphism and the marker polymorphism. That is, 12.12. Patients with major depressive disorder who had both genotype and HTG1A +272 and GG at the same time showed excellent therapeutic effects in the treatment of Mirtazapine (Example 3).

In other words, even when the gene polymorphism of serotonin transporter or serotonin receptor 1A is used as a single index, it is possible to obtain a significant effect in predicting the therapeutic response of the treatment for major depressive disorder. However, in the case of predicting the combination of both polymorphisms, Which means that the therapeutic response to the treatment of depressive disorder can be predicted much more effectively.

Accordingly, the present application provides a kit for predicting therapeutic response of a therapeutic agent for affective disorder comprising a probe capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).

In the present application, the affective disorder includes both major depressive disorder and bipolar disorder, and the sedative disorder therapeutic agent includes a major depressive disorder therapeutic agent and a bipolar disorder therapeutic agent. The major depressive disorder in the present application can be used interchangeably as the same meaning as depression. In one embodiment, the treatment for affective disorder can be a major depressive disorder treatment.

In one embodiment, the kit for predicting therapeutic response of the treatment for affective disorder includes a probe capable of detecting a polymorphism of a variable number tandem repeat (VNTR) in a second intron of a serotonin transporter (5-HTT) gene As shown in FIG.

In one embodiment, the probe capable of detecting the polymorphism of VNTR in the second intron of the serotonin transporter gene comprises a nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in a sequence comprising the nucleotide sequence of SEQ ID NO: A polynucleotide comprising a defective sequence, or a polynucleotide comprising a sequence complementary to the polynucleotide. For example, a polynucleotide consisting of a sequence lacking the nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in the repeated sequence consisting of the nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO: 12 or a polynucleotide consisting of the sequence complementary to the polynucleotide .

In one embodiment, the probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 can be a polynucleotide comprising the 32nd base of the serotonin 1A receptor gene or a polynucleotide complementary to said polynucleotide. For example, it may be a polynucleotide consisting of 5 to 40, 10 to 35, or 20 to 30 consecutive DNA sequences comprising the 32nd base of the serotonin 1A receptor gene, or a complementary polynucleotide thereof. In this case, the 32nd base of the serotonin 1A receptor gene is A.

In one embodiment, the probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 may be a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

SEQ ID NO: 13: ctg ggc gtg gag agc aag gct ggg ga

SEQ ID NO: 14: cac cgc gcc att ggc gca cag agc at

In one embodiment, the sedative disorder therapeutic agent is selected from the group consisting of citalopram, escitalopram, paroxetine, fluoxetine, dawoxetheline, fluvoxamine, sertraline, atomocetin, reboxetine, , Dexloaxacin, duloxetine, milnacifran, venlafaxine, etoparidone, napazodone, trazodone, bupropion, agomelatine, amitriptyline, clomipramine, doxepin, imipramine, Pramine, protryptiline, nortriptyline, tianeptine, amiepentin, opipramol, indolindine, or zimellidine.

In the present application, the kit can be used without restriction as long as it is a kit capable of detecting the presence or absence of the gene polymorphism. For example, the kit may be a DNA chip kit or a real time-polymerase chain reaction (RT-PCR) kit.

The present application also provides a microarray for predicting therapeutic response of a therapeutic agent for affective disorder comprising a probe capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).

In one embodiment, the microarray for predicting the therapeutic response of the treatment for affective disorder comprises a probe capable of detecting polymorphism of a variable number tandem repeat (VNTR) in a second intron of a serotonin transporter (5-HTT) gene May be further included.

In one embodiment, the probe capable of detecting the polymorphism of VNTR in the second intron of the serotonin transporter gene comprises a nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in a sequence comprising the nucleotide sequence of SEQ ID NO: A polynucleotide comprising a defective sequence, or a polynucleotide comprising a sequence complementary to the polynucleotide. For example, a polynucleotide consisting of a sequence lacking the nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in the repeated sequence consisting of the nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO: 12 or a polynucleotide consisting of the sequence complementary to the polynucleotide .

In one embodiment, the probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 can be a polynucleotide comprising the 32nd base of the serotonin 1A receptor gene or a polynucleotide complementary to said polynucleotide. For example, it may be a polynucleotide consisting of 5 to 40, 10 to 35, or 20 to 30 consecutive DNA sequences comprising the 32nd base of the serotonin 1A receptor gene, or a complementary polynucleotide thereof. In this case, the 32nd base of the serotonin 1A receptor gene is A.

In one embodiment, the probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 may be a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

The microarray in the present application can use any known microarray without limitation, and methods for manufacturing microarrays are well known in the art. In addition, hybridization of nucleic acids on a microarray and detection of hybridization results are also well known in the art. For example, a nucleic acid sample may be labeled with a labeling substance capable of generating a detectable signal such as a fluorescent substance, And detecting a hybridization result by detecting a signal generated from the labeling substance.

The present application also provides a method for detecting the polymorphism rs1800042 of the serotonin 1A receptor from a sample isolated from an individual for prediction of the therapeutic response of a therapeutic agent for affective disorder. In addition, in order to improve the therapeutic response prediction effect of the treatment for affective disorder, the VNTR polymorphism in the second intron of the serotonin transporter gene can be additionally detected in addition to the polymorphism of serotonin 1A receptor gene.

Herein, the 32nd base of the serotonin 1A receptor gene is A and the VNTR of the second intron of the serotonin transporter gene comprises the nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO: 12, the nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: In the case of a polynucleotide consisting of a defective sequence, it can be judged that the treatment response of the treatment for affective disorder is low.

Hereinafter, the present application will be described in detail by way of examples. The following examples are illustrative of the present application and the scope of the present application is not limited to the following examples. These embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art to which the present application belongs. Only.

[ Example ]

[ Example  One] HTT VNTR and Mirtazapine ( Mirtazapine ) Association of therapeutic response

A total of 283 patients with major depressive disorder (depression) (psychiatric department of cancer hospital, Korea University) were recruited. A skilled psychiatrist examined all patients and included patients with a score of 18 or higher on a 17-item Hamilton depression rating scale (HAMD-17).

All subjects were given 15 to 60 mg daily dose of Mirutazin (trade name: Remeron). DNA was extracted from peripheral blood mononuclear cells of the patients and polymerase chain reaction (PCR) was performed to analyze the polymorphism. Analysis of the relationship between HAMD17 reduction rate and HTT VNTR for 12 weeks after treatment with Mirtazapine showed significant results (FIG. 1A). That is, 12.12. The HAMD17 reduction rate in patients with major depressive disorder with recurrent genotype was 34.7 ± 1.9% after 4 weeks of treatment with mirtazapine, which was significantly higher than that of 24.8 ± 4.0 in patients with 10-repeat allele (10-repeat allele) = 0.030), 12.12. Patients with genotypes were found to have a better therapeutic effect on mirtazapine. This association was also observed at 8 and 12 weeks. That is, 12 weeks after 8 weeks of treatment with Mirtazapine. The HAM-D17 reduction rate of patients with recurrent genotype was 36.4 ± 2.0, which was significantly higher than that of patients with 10-repeat allele (P = 0.020) and 12.12 at 12 weeks. The HAM-D17 reduction rate in patients with genotype was 37.8 ± 2.1%, which was significantly higher than that in patients with 10-repeat allele (27.9 ± 4.6%, P = 0.046).

Based on the above results, we divided the response group and the non-response group based on the 50% reduction rate of HAMD17. The proportion of patients with the genotype was 90%, while the proportion of patients with the 10-repeat allele was 10.0% (odds ratio (OR) = 0.41, 95% confidence interval (CI) = 0.195 to 0.862, P = 0.019), 12.12. Patients with genotypes were found to be more responsive to treatment with Mirtazapine (Table 1).

[Table 1]

[ Example  2] HTR1A  + 272G> A Mirtazapine  Relevance of therapeutic response

The same patients as in Example 1 were tested. HTR1A + 272G> A genotyping was performed by restriction enzyme Fok I (New England Biolabs, Ipswich, MA, USA). A 12-week HAM-D17 reduction rate after treatment with Mirtazapine was compared according to the HTR1A + 272G> A genotype, indicating a significant association (FIG. 1B). The HAMD17 reduction rate in patients with major depressive disorder with GG genotype was 34.1 ± 1.8% at 4 weeks after treatment with Mirtazapine, which was significantly higher than that of 21.8 ± 5.9 patients with A allele (p = 0.042) The patient was found to have a better therapeutic effect on the mirtazapine. These associations also showed that patients with GG genotype tended to have a higher rate of HAM-D17 decline at 8 and 12 weeks. HAMD17 reduction in patients with major depressive disorder with GG genotype was 35.7 ± 1.9% after 8 weeks of treatment and 37.3 ± 2.0% after 12 weeks, and 23.5 ± 6.5% (8 weeks) of patients with A allele (P = 0.056 for 8 weeks, P = 0.053 for 12 weeks) (see Table 2).

[Table 2]

[ Example  3] HTT VNTR and HTR1A  + 272G> According to combination A Mirtazapine  Relevance of therapeutic response

In the above results, we evaluated the interaction between these genetic polymorphisms because HTT VNTR and HTR1A + 272G> A were significantly associated with the rate of HAM-D17 reduction by mirthapine. In other words, we tried to confirm whether the genetic effects of HTT and HTR1A are related to each other in the treatment of mirthapine. As a result, 12.12. In patients with major depressive disorder with genotype and GG at the same time with HTR1A + 272, the HAM-D17 reduction rate at 1 week of treatment with Mirtazapine was 20.1 ± 1.5%, and the HTT VNTR 10-repeat allele and HTR1A + (Fig. 2, P = 0.031) and 12.12 after two weeks in the HTT VNTR. The HAM-D17 reduction rate in patients with major depressive disorder with genotype and HTR1A +272 at the same time was 29.5 ± 1.8%, which was significantly higher than 20.7 ± 3.3% (P = 0.018) 12.12. Patients with genotype and GG genotype were 36.1 ± 2.0%, which was significantly higher than that of 23.5 ± 3.5% (P = 0.002). Further, 12.12. The reduction of HAM-D17 at the 8th week of treatment with Mirtazapine + GG genotype combination was 37.8 ± 2.0% at week 12 and 39.2 ± 2.12% at week 12, and 24.5 ± 3.8% of patients with 10-repeat + A allele combination 8 weeks) and 26.5 ± 4.0% (12 weeks) (P = 0.002 at the 8th week and P = 0.004 at the 12th week).

The results of the analysis of the HAMD17 reduction rate and the non-responsive group were also the same (Table 3). There was no difference in genotype distributions between the 1 and 2 weeks after treatment with mirutazin treatment, but the 12.12. The proportion of patients with major depressive disorder with genotype and having GG at the same time with HTR1A +272 was 83.7%, and patients with other genotypic combinations, ie HTT VNTR 10 repeat allele and HTR1A + 272A allele (OZ ratio = 0.50, 95% confidence interval = 0.23 ~ 0.83, P = 0.035), respectively. These differences were consistently observed at 8 weeks (84.8% versus 15.2%) and 12 weeks (42.2% versus 25.8%) (8-week odds ratio = 0.44, 95% confidence interval = 0.23-0.83, P = 0.011; OZ ratio = 0.47, 95% confidence interval = 0.25 to 0.86, P = 0.015).

[Table 3]

<110> KOREAN UNIVERSITY RESEARCH AND BUSINESS FOUNDATION <120> Kit for predicting the therapeutic effect of affective disorder          medicine <130> P130810 <160> 14 <170> Kopatentin 2.0 <210> 1 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 1 <400> 1 ggctgtgacc cagggtg 17 <210> 2 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 2 <400> 2 ggctgtgacc cggagtg 17 <210> 3 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 3 <400> 3 ggctgtgacc cggggtg 17 <210> 4 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 4 <400> 4 ggctgtgacc cgggtg 16 <210> 5 <211> 17 <212> DNA <213> Artificial Sequence <220> &Lt; 223 > 5-HTT VNTR repeat number 5 <400> 5 ggctgcgacc tggggtg 17 <210> 6 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 6 <400> 6 ggctgtgacc tgggatg 17 <210> 7 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 7 <400> 7 ggctgtgacc cgggtg 16 <210> 8 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 8 <400> 8 ggctgtgacc tggggtg 17 <210> 9 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 9 <400> 9 ggctgtgacc cgggtg 16 <210> 10 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 10 <400> 10 ggctgtgacc tggggtg 17 <210> 11 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 11 <400> 11 ggctgtgacc cgggtg 16 <210> 12 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> 5-HTT VNTR repeat number 12 <400> 12 ggctgtgacc tgggatg 17 <210> 13 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> rs1800042 probe <400> 13 ctgggcgtgg agagcaaggc tgggga 26 <210> 14 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs1800042 probe <400> 14 ggctgtgacc cagggtg 17

Claims (14)

A kit for predicting the therapeutic response of a mirtazapine comprising a probe capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).
The method according to claim 1,
A kit for estimating the therapeutic response of a mirtazapine additionally comprising a probe capable of detecting a polymorphism of a variable number tandem repeat (VNTR) in a second intron of a serotonin transporter (5-HTT) gene.
3. The method of claim 2,
A probe capable of detecting the VNTR polymorphism in the second intron of the serotonin transporter gene includes a sequence lacking the nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in the sequence including the nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO: 12 Or a polynucleotide comprising a sequence complementary to the polynucleotide.
The method according to claim 1,
A probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 is a polynucleotide comprising the 32nd base of the serotonin 1A receptor gene or a polynucleotide complementary to the polynucleotide, wherein the 32nd base of the serotonin 1A receptor gene is A And a kit for predicting the therapeutic response of the mirtazapine.
5. The method of claim 4,
Wherein the polynucleotide is a polynucleotide consisting of 20 to 30 consecutive DNA sequences comprising the 32 &lt; th &gt; base of the serotonin 1A receptor gene, or a polynucleotide complementary to the polynucleotide.
5. The method of claim 4,
A kit for predicting the therapeutic response of a mirtazapine, which is a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13 or SEQ ID NO: 14, is a probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042.
delete The method according to claim 1,
Kit is a DNA chip kit or real time-polymerase chain reaction (RT-PCR) kit for estimating the therapeutic response of mirtazapine.
A microarray for predicting the therapeutic response of mirtazapine, including probes capable of detecting the polymorphism rs1800042 of the serotonin 1A receptor (HTR1A).
10. The method of claim 9,
A microarray for predicting the therapeutic response of mirtazapine, further comprising a probe capable of detecting a polymorphism of a variable number tandem repeat (VNTR) in a second intron of a serotonin transporter (5-HTT) gene.
11. The method of claim 10,
A probe capable of detecting the VNTR polymorphism in the second intron of the serotonin transporter gene includes a sequence lacking the nucleotide sequence of SEQ ID NO: 9 and SEQ ID NO: 10 in the sequence including the nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO: 12 Or a polynucleotide comprising a sequence complementary to said polynucleotide, wherein said polynucleotide is a polynucleotide comprising a sequence complementary to said polynucleotide.
10. The method of claim 9,
A probe capable of detecting the serotonin 1A receptor gene polymorphism rs1800042 is a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13 or SEQ ID NO: 14, and a microarray for predicting the therapeutic response of the mirtazapine.
A method for providing information for predicting the therapeutic response of mirtazapine, comprising detecting the polymorphism rs1800042 of the serotonin 1A receptor from a sample isolated from an individual.
14. The method of claim 13,
A method for providing information for predicting a therapeutic response of a Mirtazapine, comprising detecting VNTR polymorphism in a second intron of a serotonin transporter gene.

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