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WO2020111169A1 - Procédé de test génétique pour maladie génétique multifactorielle et kit de test - Google Patents

Procédé de test génétique pour maladie génétique multifactorielle et kit de test Download PDF

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WO2020111169A1
WO2020111169A1 PCT/JP2019/046519 JP2019046519W WO2020111169A1 WO 2020111169 A1 WO2020111169 A1 WO 2020111169A1 JP 2019046519 W JP2019046519 W JP 2019046519W WO 2020111169 A1 WO2020111169 A1 WO 2020111169A1
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schizophrenia
disease
functional
test
gene
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雅臣 伊豫
信久 金原
賢吾 大石
正幸 高瀬
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Chiba University NUC
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to a method for testing a morbidity risk of a multifactorial genetic disease using a plurality of Single Nucleotide Polymorphisms (single nucleotide polymorphism, hereinafter referred to as SNP), an auxiliary diagnostic method, a test chip and a test kit.
  • SNP Single Nucleotide Polymorphism
  • SNP Diversity in which one base in the base sequence of the genome of a certain biological population is mutated is called SNP.
  • SNPs are present outside the gene region and their regulatory regions in genomic DNA, and do not cause changes in genetic characteristics.
  • SNPs that are clearly associated with these diseases have been proposed for application as markers that identify disease-related genes by linkage analysis and association analysis. Many SNPs associated with these diseases do not cause changes such as gene expression, but the expression and properties of disease-related genes such as gene expression levels, qualitative changes in proteins, and changes in non-coding RNA. It is known that there is a SNP called a functional SNP (functional SNP) that influences (non-patent document 1).
  • Multifactorial genetic disease is a disease that is caused by multiple factors such as environmental factors in addition to multiple genetic predispositions. It is considered difficult to predict morbidity risk because environmental factors are involved in onset in addition to multiple genetic predispositions. However, if the morbidity risk can be predicted in advance, the onset can be suppressed by various methods such as removing the environmental factors of the disease. As a result, it is possible to reduce the number of affected persons.
  • Multifactorial genetic diseases include various diseases such as diabetes, hypertension, ischemic heart disease, NASH (non-alcoholic steatohepatitis), rheumatoid arthritis, gout, and malignant tumors.
  • diseases such as diabetes, hypertension, ischemic heart disease, NASH (non-alcoholic steatohepatitis), rheumatoid arthritis, gout, and malignant tumors.
  • neuropsychiatric disorders schizophrenia, mood disorders (bipolar disorder, major depressive disorder, etc.), addictive diseases, autism spectrum disorders, attention deficit/hyperactivity disorder, Alzheimer's disease, narcolepsy , Panic disorder, social anxiety disorder, obsessive-compulsive disorder, generalized anxiety disorder, eating disorder, personality tendency and disorder are considered to be multifactorial diseases.
  • the genetic background of these diseases remains largely unknown, it is believed that there are multiple genetic predispositions. If the morbidity risk of these multifactorial diseases can be known in advance, the morbidity risk
  • diseases in the field of neuropsychiatry are considered to be extremely useful if an auxiliary diagnosis can be made by examination using SNP.
  • diagnosis is based on an inquiry. Unlike in the case of visceral diseases such as digestive organs, the diseases of the neuropsychiatric region cannot collect the brain tissue of the patient for examination and cannot be diagnosed by tissue biopsy. Although one depressive symptom may be a different disease, most of the diseases have been diagnosed by a doctor's inquiry, and establishment of an objective test method is desired.
  • Schizophrenia is a psychotic disorder that often develops from late adolescence to adolescence and has a chronic course.
  • the symptoms of schizophrenia are diverse, and many diseases exhibit similar symptoms such as mood disorders, and differential diagnosis is difficult especially for early symptoms.
  • Schizophrenia is a disease that can be expected to have a favorable prognosis if it is diagnosed and treated as accurately as possible at the earliest stage, and early diagnosis is desired. If there is a means for objectively making an auxiliary diagnosis in addition to the inquiry, it is possible to make a reliable diagnosis early.
  • Non-patent Reference 2 Non-patent Reference 2
  • Patent Document 1 is a test kit in which gene expression levels are comprehensively examined by a DNA microarray, and those having a change compared with healthy subjects are selected. Although the analysis was performed using samples from 5 acute patients, 12 chronic patients, and 9 healthy subjects, the number of samples in each group used in the analysis was small, and the gene expression level was the subject's health condition and environmental factors. Since it is highly likely to be affected by such factors, it is considered that the diagnostic accuracy is low.
  • Non-Patent Document 3 is an attempt to use a plurality of gene polymorphisms obtained by comprehensive gene analysis (Genome-Wide Association Study, GWAS) as a polymorphism risk for auxiliary diagnosis of schizophrenia and bipolar disorder.
  • GWAS Gene-Wide Association Study
  • each of the candidate genes has a very low effective dose, and there is a big problem in its validity. None of the results have been put to practical use, and new test methods and test kits are required.
  • various markers for examining morbidity risk have been proposed, but none of them has been put into practical use.
  • the present invention provides a new test method using a combination of a plurality of SNPs that cause a quantitative or qualitative change in gene expression as a disease marker.
  • An object of the present invention is to provide a method, a test chip, and a test kit for testing the risk of morbidity of a multifactorial genetic disease, which has been difficult to predict the risk of morbidity. It is another object of the present invention to provide a test method and a test kit for assisting diagnosis in diseases in the neuropsychiatric field for which there is no objective diagnostic criterion.
  • the present invention relates to an inspection method and an inspection kit for the following diseases.
  • the multifactorial genetic diseases include schizophrenia, bipolar disorder, mood disorders, addictive disorders, autism spectrum disorders, attention deficit/hyperactivity disorder, Alzheimer's disease, as neuropsychiatric disorders.
  • Narcolepsy, panic disorder, social anxiety disorder, obsessive-compulsive disorder, general anxiety disorder, eating disorder, personality tendency and disorder, and other areas of disease include diabetes, hypertension, ischemic heart disease, and NASH (non-alcoholic steatohepatitis).
  • the SNP is a functional polymorphism involved in dopamine fluctuation.
  • the functional polymorphisms involved in the fluctuation of dopamine are gene polymorphisms of tyrosine hydroxylase (TH) gene, catechol-O-methyltransferase (COMT) gene, and dopamine D2 receptor (DRD2) gene.
  • TH tyrosine hydroxylase
  • COMP catechol-O-methyltransferase
  • D2 receptor D2 receptor
  • a DNA of interest is analyzed for rs10770141, rs4680, and rs1800497, which are functional SNPs, and at least two of T(+) for rs10770141, Met( ⁇ ) for rs4680, and A1(+) for rs1800497 are combined. If you have schizophrenia, or you are at high risk of morbidity, if you have all three, you have bipolar disorder or you are at high risk of morbidity To test for schizophrenia and bipolar disorder.
  • a method for examining a patient suspected of schizophrenia which comprises analyzing the DNA of a target for functional SNPs rs10770141, rs4680, and rs1800497.
  • Is a T(+), or rs4680 has a combination of Met( ⁇ ) and rs1800497 has a combination of A1(+), a method of determining that the possibility of schizophrenia is high.
  • a method for assisting the dose determination of an antipsychotic drug in a schizophrenic patient by analyzing functional SNPs rs10770141, rs4680, and rs1800497.
  • It is recommended that patients with T(+) rs10770141 and Met( ⁇ ) rs4680 study high-dose dopamine receptor blockers.
  • Assist the dose determination of antipsychotic drugs Method.
  • a method for diagnosing a disease in a neuropsychiatric region which comprises examining functional SNPs of at least two or more genes known to be involved in a multifactorial genetic disease and sickness of the disease due to the functional SNP.
  • a diagnostic method that refers to and diagnoses risks.
  • the test method described in any one of (1) to (7) determines that the risk of developing a multifactorial genetic disease is high, administration of a prophylactic drug or non-drug therapy Preventive methods to suppress the onset.
  • the term “functional SNP” refers to an SNP existing in a gene region or its regulatory region, which causes some change such as increase/decrease in gene expression or qualitative change in translated protein. ..
  • the functional SNP in a certain disease includes not only a functional SNP directly involved in the disease but also a functional SNP of a gene group involved in the disease such as a signal transduction system or an enzyme cascade that is clearly involved in the disease.
  • a functional SNP of a gene group involved in the disease such as a signal transduction system or an enzyme cascade that is clearly involved in the disease.
  • a signal transduction system or an enzyme cascade that is clearly involved in the disease.
  • dopamine nervous system not only dopamine nervous system but also serotonin nervous system, noradrenaline nervous system, and other proteins related to other neurotransmission systems that have been reported to be involved in schizophrenia, and functional SNPs of proteins that will be found in the future. Can be included.
  • oligonucleotides complementary to a plurality of SNPs to be detected may be directly immobilized on a substrate, or may be immobilized on a carrier such as beads and then retained on the substrate.
  • Nucleic acid may be extracted from the blood of a patient and hybridized by a conventional method to detect the double-stranded nucleic acid.
  • a plurality of SNPs to be detected may be simultaneously detected by a known inspection method using PCR such as the invader method and the real-time PCR method.
  • a functional SNP capable of testing other diseases may also be fixed to one test chip so that a plurality of diseases can be tested at the same time.
  • test kit can include a primer for detecting functional SNPs, a reagent for use in PCR, or the above-mentioned test chip and necessary reagents.
  • the present invention will be described focusing on schizophrenia, but the analysis method using a combination of “functional SNPs” is effective for other diseases, particularly multifactorial genetic diseases.
  • schizophrenia, mood disorders, addictive diseases, diabetes, hypertension, and hyperlipidemia are diseases that have many patients all over the world, and early diagnosis and prevention are desired.
  • the combination of functional polymorphisms of genes is inherent and can be predicted before the onset, and of course, the prognosis and progress of the disease can be predicted without being affected by the condition and stage of the disease. In particular, being able to predict the risk of morbidity before onset is a very important test from the viewpoint of prevention.
  • Dopamine is synthesized by tyrosine hydroxylase (Tyrosine Hydroxylase, TH) and released into the synaptic cleft.
  • the dopamine released in the synaptic cleft is decomposed by catechol-O-methyltransferase (COMT) or reintroduced into the cell by the dopamine transporter (DAT).
  • DAT dopamine transporter
  • D2 dopamine D2 receptor
  • Non-patent Documents 7 and 8 In schizophrenia, it has been suggested that dopamine release is enhanced at nerve endings in limbic dopaminergic nerves and dopamine concentration in synaptic cleft is increased.
  • the group in which the positive symptoms are improved by the antipsychotic drug has an increased dopamine synthetic ability, and in the group that does not improve the synthetic ability is equivalent to that of a healthy person (non-patent document 9), and dopamine.
  • synthetic ability and dopamine concentration in the synaptic cleft are involved in symptoms and treatment responsiveness to antipsychotic drugs.
  • TH, COMT, and DRD2 proteins known to have functional polymorphisms.
  • Schizophrenia is formed by the repetitive hyperactivity and elimination of dopaminergic function. It is believed that this is a mechanism similar to psychosis that occurs with repeated administration of dopamine antagonists. Therefore, the risk of developing schizophrenia was examined using a gene set having a high correlation with the risk of developing DSP.
  • the SNP used is a polymorphism of the TH gene promoter region, COMT gene, DRD2 gene (Table 1). Specifically, C-824T gene polymorphism in the TH gene promoter region, polymorphism in which Val at position 158 of COMT gene is replaced with Met, -141C Ins/Del polymorphism in DRD2 gene, Taq1A polymorphism in ANKK1 gene is there.
  • the ANKK1 (the ankyrin repeat and kinase domain maintaining 1) gene is a gene close to the DRD2 gene, and the Taq1A polymorphism of ANKK1 is a polymorphism suggested to be associated with the DRD2 density.
  • Non-Patent Documents 10 to 13 We analyzed whether polymorphisms of these three genes are involved in schizophrenia risk.
  • dopamine neurotransmitter activity indicates dopamine neurotransmitter activity, from the left, high and low levels of dopamine synthesis, high and low levels of dopamine degradation, high and low receptor expression, specific combinations of polymorphisms, schizophrenia, number of healthy individuals, The appearance frequency and the appearance frequency ratio are summarized.
  • Table 4 shows the results of calculating the odds ratio by comparing the case of T(+), Met( ⁇ ), which is A1(+), or Del(+), with other combinations.
  • the odds ratio was 6.5 (p ⁇ 0.029), resulting in a high rate. The result was that they were prone to schizophrenia.
  • the P value was 0.00357 in the one-sided test, 0.00296 in the two-sided test, and the P-value was corrected by Bonferroni's method when the gene polymorphism was present.
  • the results were 0.02856 and 0.02368, which indicates that schizophrenia was significantly more likely to occur.
  • the risk of developing DSP increases (Non-Patent Document 4).
  • the DSP onset risk does not completely match the onset risk of schizophrenia because the onset risk increases not only in the combination of the above SNPs but also in other combinations.
  • a person with this combination has the following dopamine neurotransmission function.
  • a person with a functional SNP of this combination has a high ability to synthesize dopamine by the TH gene, and thus a large amount of dopamine is synthesized due to stress or the like.
  • DRD2 since DRD2 is low-expressed, release inhibition is less likely to occur, and a large amount of dopamine is released in the synaptic cleft.
  • the dopamine decomposing ability by COMT is high, there is a possibility that the dopamine has a dopamine transmitting function of being immediately decomposed.
  • the person with this combination has a dopamine neurotransmission function in which the dopaminergic nerve activity is rapidly enhanced and disappears naturally, and it is considered that repeated stress causes sensitization and manifests schizophrenia. This is consistent with the conventional pathological hypothesis of schizophrenia, and it is possible to select an appropriate treatment method, and it is highly likely to lead to the development of a prevention method.
  • antipsychotic drugs which are DRD2 blockers.
  • antipsychotic treatment it is considered that there is an optimal DRD2 occupancy rate by the antipsychotic and that there is an optimal dose for each antipsychotic.
  • the function of the gene is changed by the functional SNP, it is considered that the effect of the antipsychotic drug is also affected. Therefore, the correlation between functional SNP and antipsychotic dose was analyzed.
  • the chlorpromazine equivalent which is the value obtained by converting the prescribed amount of the prescribed oral drug into chlorpromazine, is used as a standard, so it was decided to analyze the correlation between the chlorpromazine equivalent and SNP.
  • the CP equivalent conversion tended to be high for T(+) for TH and Met(-) for COMT.
  • the result that the CP equivalent conversion amount was significantly high was obtained in the combination of T(+) of TH and Met( ⁇ ) of COMT (p ⁇ 0.05).
  • the CP equivalent conversion amount also tended to be high in the combination of T(+) of TH and A1(-) of TaqIA.
  • Antipsychotics do not exert antipsychotic effects at low doses.
  • overdose of antipsychotic drugs causes side effects such as extrapyramidal symptoms, depression, and discomfort, resulting in decreased medication adherence and recurrence, leading to a poor long-term prognosis.
  • overdose causes a compensatory increase in DRD2, induces dopamine hypersensitivity psychosis, and develops treatment resistance. While a biological index is needed to provide the optimal dose for each individual, it is also possible to use a combination of functional SNPs as a guide for determining the optimal dose.
  • the odds ratio of each SNP calculated by correlating with schizophrenia for age and sex is 1.24 for rs4680 (Met(-)) and 1 for rs1800497(A1(+)). 0.73 and rs10770141(T(+)) were 1.79, which were both significant.
  • the odds ratios of two genetic risk carriers were 2.01 respectively. A significant difference was observed with 1.87.
  • rs4680(Met(-)) has 53.0%
  • rs1800497(A1(+)) has 62.1%
  • rs10770141(T(+)) has 13.7%
  • all of these risk factors was 3.3%.
  • rs4680(Met( ⁇ )) was 38.8%
  • rs1800497(A1(+)) was 48.8%
  • rs10770141(T(+)) was 1.2%. 1.2% had all risk factors.
  • schizophrenia has a pre-symptomatic stage (at risk mental state, ARMS) or a pre-symptomatic phase called attenuated psychosis syndrome in the American Psychiatric Association diagnostic criteria DSM-5 before the onset of schizophrenia.
  • ARMS may develop not only schizophrenia but also bipolar disorder, and it is said that diagnosis of both diseases is often wrong even after the onset.
  • ARMS has been reported to be effective for some antipsychotic drugs, family intervention, and omega-3 fatty acids, and there is a high risk of developing schizophrenia by testing SNPs at the ARMS stage, or If it is possible to judge whether the risk of developing bipolar disorder is high, more appropriate measures can be taken.
  • Bipolar disorder known to have genetic factors other than schizophrenia, autism and ADHD, social anxiety disorder, dementia, etc. if functional SNPs can be used for testing, medication, family It is possible to take appropriate measures early or before the onset, such as intervention of.
  • psychiatric diseases become less responsive to antipsychotic drugs when the time from the onset of symptoms to the start of treatment becomes longer.
  • diagnosis is difficult in the early stage of onset, for example, it is difficult to distinguish bipolar disorder from schizophrenia.
  • the test using the functional SNP can obtain information that assists the diagnosis, and thus an appropriate treatment method can be selected earlier.
  • BP Bipolar disorder
  • CNT healthy person
  • serotonin transporter gene 5HTLTPR (l/s), serotonin 5HT 1A receptor gene 5HTR1 (C-1019G, Gly272Asp), serotonin 5HT 2A receptor gene 5HTR2A (T102C, A-1438G), tryptophan synthase TPH1.
  • functional dependent SNPs such as opioid receptor gene OPRM1 (A11G) are known in addition to gene polymorphisms of dopamine neurotransmission system in dependent diseases such as gene polymorphism of dopamine neurotransmission system (non-patent document 18 ⁇ 19), by combining these SNPs, morbidity risk can be similarly examined.
  • the analysis method shown here is a method capable of analyzing the morbidity risk of a multifactorial genetic disease by combining and analyzing the functional SNPs reported so far. , It is a very versatile analysis method.

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Abstract

La présente invention porte sur procédé pour tester le risque de morbidité ou pour dépister une maladie à partir d'un polymorphisme fonctionnel (SNP fonctionnel) d'un gène d'une protéine fonctionnelle qui est supposé être anormal ou responsable de la maladie. Etant donné que le risque de morbidité pour une maladie génétique multifonctionnelle peut être testé par analyse d'un SNP fonctionnel, la présente invention peut être utilisée pour aider au diagnostic et à la prévention de la maladie. L'invention concerne un procédé, une puce de test et un kit de test pour tester des SNP fonctionnels.
PCT/JP2019/046519 2018-11-28 2019-11-28 Procédé de test génétique pour maladie génétique multifactorielle et kit de test Ceased WO2020111169A1 (fr)

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