EP1278892A1 - Detection de variations dans le profil de methylation de l'adn - Google Patents

Detection de variations dans le profil de methylation de l'adn

Info

Publication number
EP1278892A1
EP1278892A1 EP01940158A EP01940158A EP1278892A1 EP 1278892 A1 EP1278892 A1 EP 1278892A1 EP 01940158 A EP01940158 A EP 01940158A EP 01940158 A EP01940158 A EP 01940158A EP 1278892 A1 EP1278892 A1 EP 1278892A1
Authority
EP
European Patent Office
Prior art keywords
receptor
alpha
damage
consequences
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP01940158A
Other languages
German (de)
English (en)
Inventor
Kurt Berlin
Christian Piepenbrock
Alexander Olek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Epigenomics AG
Original Assignee
Epigenomics AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Epigenomics AG filed Critical Epigenomics AG
Publication of EP1278892A1 publication Critical patent/EP1278892A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • 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
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/154—Methylation markers

Definitions

  • the invention relates to a set of oligonucleotides as probes for the detection of relevant variations of DNA methylation in a target group of genes, the use thereof for the detection of gene variants with regard to DNA methylation, a medical device which uses a set of oligonucleotides, a method for Investigation of the methylation status of an individual and a method for creating a model for evaluating the probability of occurrence of an individual's health impairment.
  • the present invention describes sets of oligomers and methods for detecting relevant variations of DNA methylation in a target group of genes that are associated with adverse events for patients / individuals or certain diseases.
  • 5-methylcytosine is the most common covalently modified base in the DNA of eukaryotic cells. For example, it plays a role in the regulation of transcription, in genetic imprinting and in tumorigenesis. The identification of 5-methylcytosine as a component of genetic information is therefore of considerable interest. However, 5-methylcytosine positions cannot be identified by sequencing because 5-methylcytosine has the same base pairing behavior. exhibits like cytosine. In addition, in the case of PCR amplification, the epigenetic information which the 5-methylcytosines carry is completely lost.
  • a relatively new and the most frequently used method for the investigation of DNA for 5-methylcytosine is based on the specific reaction of bisulfite with cytosine, which is converted into uracil after subsequent alkaline hydrolysis, which corresponds in its base pairing behavior to thymidine.
  • 5-methylcytosine is not modified under these conditions.
  • the original DNA is thus converted in such a way that methylcytosine, which originally cannot be distinguished from the cytosine by its hybridization behavior, can now be detected by "normal" molecular biological techniques as the only remaining cytosine, for example by amplification and hybridization or sequencing.
  • the prior art As far as sensitivity is concerned, it is defined by a method that includes the DNA to be examined in an agarose matrix, thereby preventing the diffusion and renaturation of the DNA (bisulfite only reacts on single-stranded DNA) and all precipitation and purification steps by rapid dialysis (Olek, A. et al., Nucl. Acids. Res. 1996, 24, 5064-5066).
  • This method can be used to examine individual cells, which illustrates the potential of the method.
  • Base pair length examined a global study of cell n on thousands of possible methylation analyzes is not possible.
  • this method too, cannot reliably analyze very small fragments from small sample quantities. These are lost despite the diffusion protection through the matrix.
  • Fluorescent-labeled probes have been used in many cases for scanning an immobilized DNA array.
  • the fluorescence of the hybridized probes is detected, for example, via confocal optics.
  • Genomic DNA is obtained by standard methods from DNA from cell, tissue or other test samples. This standard methodology can be found in references such as Fritsch and Maniatis eds., Molecular Cloning: A Laboratory Manual, 1989.
  • the object of the present invention is to compile sets of oligomer probes which bind to genes which are of importance for adverse events for patients or certain disease groups in such a way that comprehensive prognostic statements for the respective patient are possible by analyzing the respective methylation state of these genes become.
  • the data collected in the process are combined into methylation patterns.
  • a method is to be created which enables the analysis of methylation positions on a large scale using the oligomer probes mentioned.
  • the object is achieved by a set of nucleotide probes and a method for examining the methylation profile of a patient or individual.
  • the set of oligonucleotide probes and / or the method With the help of the set of oligonucleotide probes and / or the method, the presence or absence of the relevant methylation variants from the target group of the genes is detected.
  • a diagnosis results from the methylation pattern by comparison with methylation patterns in a database, which are already assigned to certain phenotypes, prognoses or effects on the patient.
  • this object is achieved by a set of nucleotide probes according to one or more of the claims.
  • a method or a device can be used to achieve the object, which contains a set of the nucleotide probes mentioned.
  • Advantageous embodiments of the invention are characterized in the respective subclaims.
  • CNS FeU functions damage or illness aggressive symptoms or behavioral disorders clinical, psychological and social consequences of brain injuries psychotic disorders and personality disorders dementia and / or associated syndromes cardiovascular disease, FeM function and damage malfunction, damage or illness of the gastrointestinal tract FeW function, damage or illness of the respiratory system Injury, inflammation, infection, immunity and / or convalescence Malfunction, damage or illness of the body as a deviation in the development process
  • FeM function damage or disease of the skin, muscles, connective tissue or bone endocrine and metabolic FeWfunction, damage or disease headache or sexual FeMfunction. This list is not exhaustive and it is clear to the person skilled in the art that any disease or FeM function of an organism or individual can be used by means of the inventive idea.
  • the oligomer probes include sequences that bind to the genes associated with these adverse events.
  • the oligomer probes bind to the sequences as they are after treatment of the DNA sample, which converts unmethylated cytosine into uracil.
  • the genes are detailed in the claims. According to the invention, these genes belong to at least one of the following protein connotations: enzymes, transport, storage, structure, immunity, nerve transmission, growth and differentiation.
  • the following describes the method that uses the set of oligomer probes to assess whether adverse events will or are likely to occur in a patient, individual or population.
  • a DNA sample is taken from patients or individuals who have been diagnosed with an adverse event or not diagnosed in the control group.
  • the DNA samples pretreated by means of the solution of a bisulfite, bisulfite or disulfite are hybridized in the second step of the method for the detection of relevant gene variants with regard to DNA methylation with a set of oligonucleotides as probes which are used within the respective target group of genes after the bisulfite treatment bind present sequences in which cytosine methylation can potentially be present.
  • the result is a hybridization pattern, which is translated into a methylation pattern of the genes of the respective DNA sample in the third step of the method.
  • these genes belong to at least one of the following protein functions: enzymes, transport, storage, structure, immunity, nerve transmission on, growth and differentiation.
  • the said genes are associated with a variety of adverse events, including:
  • CNS FeM functions damage or illness aggressive symptoms or behavioral disorders clinical, psychological and social consequences of brain injuries psychotic disorders and personality disorders dementia and / or associated syndromes cardiovascular disease, malfunction and damage FeM function, damage or illness of the gastrointestinal tract FeM function, damage or illness of the respiratory system Injury, inflammation, infection, immunity and / or convalescence FeMfunction, damage or illness of the body as a deviation in the development process
  • FeM function damage or disease of the skin, muscles, connective tissue or bone endocrine and metabolic FeM function, damage or disease headache or sexual FeM function.
  • the oligonucleotide probes are characterized in that they are complementary to, or correspond to, DNA sequences of the target group of genes, as is the case after a chemical treatment which converts unmethylated cytosines to uracil, preferably treatment with sodium bisulfite.
  • the frequency of the alleles is calculated using a different methylation pattern and the frequencies of the alleles in patients and individuals with adverse events and the corresponding control group are compared. At least one of the steps of the method is preferably carried out with a computer.
  • the methylation pattern of an individual is compared with the entries already present in the database or with a model derived therefrom in order to assess the risk of the occurrence of disadvantageous events.
  • the set of oligonucleotides preferably consists of oligonucleotides which are arranged on a support at known locations in a rectangular or hexagonal grid.
  • This carrier consists of silicon, glass, polystyrene, aluminum, StaM, iron, copper, nickel, silver or gold.
  • a medical device which contains the set of oligonucleotides used is preferably used to detect the gene variants with regard to methylation and various gene expression.
  • said oligonucleotide set or a device containing the same is used to predict likely therapeutic consequences or adverse events as a result of a therapeutic intervention or as a result of taking specific medications.
  • one uses a set of oligonucleotides or a device for predicting probable symptoms when the above-mentioned adverse events occur and the likelihood of the occurrence of secondary diseases or further symptoms.
  • said oligonucleotide set or device is used for the following purposes:
  • kits for performing an assay which can be used to assess the risk of a patient or individual experiencing adverse events.
  • This kit includes test options for the presence or absence of relevant variations in DNA methylation of the genes listed above in a sample of genomic DNA.
  • Reagents for use in the detection process are also included, as is a script that describes the likelihood of a patient or individual experiencing adverse events.
  • the object of the invention is therefore achieved by a set of oligonucleotides as probes for the detection of relevant variations in DNA methylation in a target group of genes, characterized in that the oligonucleotides are complementary to the DNA sequence of the target group of genes or correspond to them, as they follow a chemical treatment which converts unmethylated cytosines into uracil, the target group essentially comprising genes which are associated with an individual's health impairment.
  • the set of oligonucleotides is characterized in that the health impairments have undesirable drug effects; Cancer; CNS FeM functions, injury or illness; aggressive symptoms or behavioral disorders; clinical, psychological and social consequences of brain injury; Dementia and / or associated syndromes; psychotic disorders and personality disorders; cardiovascular disease, FeM function or injury; FeMfiintation, damage or disease of the gastro- testinal Tracks; Damage or disease of the respiratory system; Injury, inflammation, infection, immunity and / or convalescence; FeM function, damage or loss of body as a result of a deviation in the development process, FeM function, damage or disease of the skin, muscles, connective tissue or bones; endocrine and metabolic FeM function; A headache; sexual FeM functions are.
  • the set of oligonucleotides is characterized in that the genes associated with undesirable drug effects are selected from Table 1, the cancer-related genes are selected from Table 2, which are associated with symptoms and consequences of CNS FeM function-related genes are selected from Table 3, genes related to aggressive symptoms or behavioral disorders are selected from Table 4, and the genes related to the consequences of clinical, psychological and social consequences of a gene injury are shown in Table 5 with genes related to dementia and / or associated syndromes are selected from Table 6, the genes related to psychotic disorders and personality disorders are selected from Table 7, those related to cardiovascular disease, FeM function or damage Genes are selected from Table 8, genes related to FeM function, damage or disease of the gastrointestinal tract are selected from Table 9, genes related to FeM function, damage or disease of the respiratory system are selected from Table 10, which are related to injury, Inflammation, infection, immunity and / or convalescence related genes are selected from Table 11, which are related to FeM function, damage or disease of the body as a result of a deviation in the development process related genes from Table 12, which are related to FeM function
  • a set of oligonucleotides is preferred in which oligonucleotides with up to 5% of the genes listed are not present.
  • oligonucleotides in which oligonucleotides with at least 95% of the genes listed are contained together with a limited number of additional oligonucleotides not listed.
  • a set of oligonucleotides is advantageous in which up to 5% of the corresponding oligonucleotides of the genes listed are replaced by a complete set of 25% of other oligonucleotides which are not listed.
  • oligonucleotides for a target group of genes in which the chemically pretreated DNA sequence of the genes to be detected matches at least 95% with the correspondingly pretreated DNA sequence of the genes from the above list.
  • a set of oligonucleotides is particularly advantageous, the chemical pretreatment being carried out by means of the solution of a bisulfite, bisulfite or disulfite.
  • a set of oligonucleotides consisting of a subset of the target group of genes is particularly advantageous.
  • oligonucleotides preference is given to a set of oligonucleotides in which the oligonucleotides are arranged at known locations in a rectangular or hexagonal grid on a support.
  • a set of oligonucleotides is also preferred, the oligonucleotides being arranged on a support which consists of silicon, glass, polystyrene, aluminum, StaM, iron, copper, nickel, silver or gold.
  • a set of is particularly preferred, the oligonucleotide probes being labeled via their mass, electrostatics, charge or fluorescence or with radionucleotides.
  • oligonucleotides in a biological examination to detect said gene variants with regard to DNA methylation.
  • a medical device which contains an oligonucleotide set according to the invention is advantageous for use in an examination for the detection of said gene variants, in particular as an indication for a higher risk of a patient or individual, to develop symptoms and sequelae of cancer or as an indication for a higher risk of development to learn about CNS FeMinkinkung, damage or disease or for the patient or the individual, symptoms and consequences of CNS FeM function, damage or disease.
  • a medical-technical device which contains an oligonucleotide set according to the invention, is particularly advantageous for use in an examination for the detection of different gene expression and / or for the prognosis and for the management of patients who suffer from the risk of developing symptoms and sequelae of cancer and / or Use in an investigation of whether a patient or individual may develop CNS FeM function, damage, or disease, or whether the patient or individual is likely to experience symptoms and consequences of CNS FeM function, damage, or disease.
  • a method for examining the DNA methylation profile of a patient or individual which detects the presence or absence of the relevant methylation variants from the target group of genes by hybridizing a chemically pretreated nucleic acid sample from said patient or individual to an oligonucleotide set according to the invention and the hybridization pattern is related to the variations. It is particularly preferred to use a set of oligonucleotides according to the invention or a device according to the invention for forecasting and / or treatment planning in patients who suffer from a health impairment. who have a risk of health impairment.
  • the use according to the invention is particularly advantageous for prognosis and / or treatment planning in patients who suffer from the consequences of undesirable drug effects or for whom there is a risk of occurrence of undesirable drug effects which suffer from the risk of developing symptoms and sequelae of cancer, who are at an increased risk of CNS FeM function, damage or illness, who suffer from the consequences of aggressive symptoms or behavioral disorders or who are at risk of developing aggressive symptoms or behavioral disorders, which are due to the consequences of clinical, psychological and social Suffer consequences of a menstrual injury or where there is a risk of the consequences of climatic, psychological and social consequences of a menstrual injury suffering from dementia and / or associated syndromes or where there is a risk of dementia and / or associated syndromes that suffer from symptoms and consequences of psychotic disorders and personality disorders, or that are at risk of occurrence of psychotic disorders and personality disorders that suffer from the symptoms or consequences of cardiovascular disease, FeMfunction or damage, or for which There is a risk of occurrence of symptoms or consequences of cardiovascular disease, FeM function or damage, which suffer from the symptoms and consequences
  • a set of oligonucleotides according to the invention or a device according to the invention for predicting realistic therapeutic risks or undesired drug effects due to the intake of specific medications.
  • a set of oligonucleotides according to the invention or a device according to the invention for predicting probable symptoms in the event of undesirable drug effects and the likelihood of the occurrence of secondary diseases or further symptoms and or for predicting probable patterns of disease symptoms and the likelihood of the occurrence of secondary diseases or others symptoms.
  • a set of oligonucleotides according to the invention or a device according to the invention for the development of new strategies in therapeutic intervention and in clinical studies and / or for the prognosis or management of patients who suffer from developing aggressive symptoms or behavioral disorders or for the said Disruptions belong to the risk group and / or to the modeling and evaluation of the impact of Diseases and health care measures on individuals, population groups, patient groups and populations and / or for generating a model, in order to assess the risk for individuals, population groups, patient groups and populations, to develop symptoms and after-effects of cancer and / or to generate a model for assessing the risk the development of symptoms and sequelae of CNS FeM function, damage or illness and / or to optimize the therapeutic intervention.
  • a method for creating a model for evaluating whether a patient, an individual or a population group will or will likely suffer health impairments which comprises the following steps: a) a DNA sample is taken from patients or individuals who have been diagnosed with a health impairment; b) a DNA sample is taken from a control group of individuals in whom the presence of this health impairment has been diagnosed; c) the samples obtained in a) and b) are analyzed for determining the DNA methylation variation within the target group of genes according to the invention; d) the frequency of the alleles with a different methylation pattern in the samples from a) and b) is calculated; e) the frequencies of the alleles in the samples from a) and b) are compared, f) a statistical analysis of the results obtained under e) is carried out in order to obtain a model for evaluating the risk of the occurrence of health impairments.
  • a method according to the invention is preferred, the health impairment being selected from: undesirable drug effects; Cancer; Symptoms and sequelae of CNS function, damage, or disease; developing aggressive symptoms or behavioral disorders; Consequences of clinical, psychological and social consequences of a male injury; Dementia and / or associated syndromes; psychotic disorders and personality disorders; Symptoms or consequences of cardiovascular disease, FeM function or damage; Symptoms and consequences of FeMfiintation, damage or disease of the gastrointestinal tract; FeM function, damage or disease of the respiratory system; Symptoms and consequences of injury, ignition, infection, immunity and / or convalescence; FeM function, damage or illness of the body as a result of a deviation in the development process; FeMfunction, damage or disease of the skin, the muscles, the connective tissue or the bones; endocrine and metabolic FeM function, damage or? A headache; sexual FeM functions.
  • a method for evaluating whether a particular individual bears the risk of health impairments occurring is advantageous, wherein the methylation profile is compared with the model created according to the invention.
  • a method according to which at least one of the steps is carried out by a computer is particularly advantageous.
  • kits comprising: a) test options for the presence or absence of encrypted relevant polymorphic DNA variations of the core group of genes according to the invention , in a sample of genomic DNA. b) reagents for use in the detection method. c) Script that describes the likelihood of a patient or individual experiencing adverse events and / or health impairments.
  • a specially designed assay is particularly advantageous for use in assessing the risk of a patient or individual of adverse events and / or health impairments, characterized in that the adverse event or health impairment is characterized by: undesirable drug effects; Cancer; Symptoms and sequelae of CNS function, damage, or disease; developing aggressive symptoms or behavioral disorders; Consequences of clinical, psychological and social consequences of brain injury; Dementia and / or associated syndromes; psychotic disorders and personality disorders; Symptoms or consequences of cardiovascular disease, FeM function or damage; Symptoms and consequences of FeM function, damage or disease of the gastrointestinal tract; FeM function, damage or disease of the respiratory system; Symptoms and consequences of injury, inflammation, infection, immunity and / or re- convalescence; FeM function, damage or illness of the body as a result of a deviation in the development process; FeM function, damage or disease of the skin, muscles, connective tissue or bones; endocrine and metabolic FeMfunction, damage or illness; A headache; sexual functions.
  • ADCY1 Adenylate cyclase.1 ADCY1
  • Adenylate kinase AK1 Adenylate transferase 1
  • Ndrenergic receptor alpha2 ADRA2 5
  • Ndrenergic receptor betal ADRB1 5
  • Ndrenergic receptor beta2 ADRB2 5
  • Ndrenergic receptor beta3 ADRB3 5
  • Adrenoleukodystrophy gene ALD 1 Adrenoleukodystrophy gene ALD 1
  • Ataxia teiangiectasia gene AT ATM 6
  • Bile acid coenzyme A amino acid N-BAAT 1 acyltransferase
  • GABA receptor gamma 1 GABRG1 5
  • GABA receptor gamma 2 GABRG2 5
  • GABA receptor gamma 3 GABRG3 5
  • Gadd45 growth arrest & D ⁇ A-damage-inducible protein
  • GAPDH Glyceraidehyde-3-phosphate dehydrogenase
  • GTPase-activating protein GAP RASAI 6
  • Guanine nucleotide binding protein alpha GNAI1 5 inMbiting activity polypeptide 1, GNAI1
  • GNAI2 Guanine nucleotide binding protein, alpha GNAI2 5 inMbiting activity polypeptide 2, GNAI2
  • GNAI3 Guanine nucleotide binding protein, alpha GNAI3 5 inMbiting activity polypeptide 3, GNAI3
  • Guanine nucleotide binding protein gamma GNG5 5 polypeptides 5
  • H3 5 Histamine receptors, H3 5 HLH transcription factor HAND1 HAND1 6
  • Interleukin (IL) 4 IL4 4
  • IL Mterleukin
  • IL6R Interleukin
  • IL 7 IL7 4
  • Interleukin (IL) 9 receptor IL9R 4 Interleukin (IL) receptor antagomst 1 IL1RN, IL1RA 4
  • Kinesin heavy chain KNSLI 6
  • Lipoxygenase 5 (leukocytes) 4
  • MAP Mitogen-activated protein
  • NADH dehydrogenase ubiquinone
  • Nuclear factor kappa beta NFKB 4 Nuclear factor of activated T cells (NFAT) NFATC 6 complex, cytosolic
  • NFAT Nuclear factor of activated T cells
  • Opioid receptor delta OPRDI 5
  • Opioid receptor kappa OPRK1 5
  • Opioid receptor mu OPRM1 5
  • PCNA proliferating cell nuclear antigen
  • Phospholipase A2 group 1B PLA2G 1B 4 Phospholipase A2, group 2A PLA2G2A 4
  • Phospholipase A2 group 5 PLA2G5 4
  • Retinoic acid receptor alpha RARA 6
  • Retinoic acid receptor beta RARB 6
  • Retinoic acid receptor gamma RARG 6
  • Retinoid X receptor alpha RXRA 6
  • Ribonucleotide reductase RRM 1 Ribosephosphate pyrophosphokinase 1
  • Serotome receptor 5HT1A HTR1A 5
  • Serotonin receptor 5HT1B HTR1B 5
  • Serotome receptor 5HT1C HTR1C 5
  • Serotonin receptor 5HT1D HTR1D 5
  • Serotome receptor 5HT1E HTR1E 5
  • Serotonin receptor 5HT1F HTR1F 5
  • Serotonin receptor 5HT2A HTR2A 5
  • Serotonin receptor 5HT2B HTR2B 5
  • Serotome receptor 5HT2C HTR2C 5
  • Serotome receptor 5HT3 HTR3 5
  • Serotonin receptor 5HT5 HTR5 5
  • Serotome receptor 5HT7 HTR7 5HT7
  • Solute carrier family 1 amino acid transporter
  • Solute carrier family 1 (glial Mgh affimty SLC1A3 2 glutamate transporter), member 3
  • Solute carrier family 1 (glutamate transporter), SLC1A1 2 member 1
  • Solute carrier family I (glutamate transporter), SLCIA2 2 member 2
  • Solute carrier family 1 neutral amino acid SLCIA4 2 transporter
  • Solute carrier family 10 sodium / bile acid SLCIOA1 cotransporter family
  • Solute carrier family IO sodium / bile acid SLC1OA2 cotransporter family
  • Solute carrier family 12 member 1 SLC12A1 2
  • Solute carrier family 12 member 2 SLC12A2 2
  • Solute carrier family 12 member 3 SLC12A3 2
  • Solute carrier family 14 member 2 SLC14A2 2
  • Solute carrier family 15 H + / peptide SLC15A1 2 transporter, intestinal
  • member 1 Solute carrier family 15 (H + / peptide SLC15A1 2 transporter, intestinal), member 1
  • Solute carrier family 15 H + / peptide SLC15A2 transporter, kidney
  • member 2 Solute carrier family 15 (H + / peptide SLC15A2 transporter, kidney), member 2
  • Solute carrier family 16 (monocarboxylate SLC16A1 transporter), member 1
  • Solute carrier family 16 (monocarboxylate SLC16A7 transporter), member 7
  • Solute carrier family 17 member 1 SLC17A1 2
  • Solute carrier family 17 member 2 SLC17A2 2
  • Solute carrier family 18 member 3 SLC18A3 2
  • Solute carrier family 19 (folate transporter), SLC19A1 2 member 1
  • Solute carrier family 2 (facilitated glucose SLC2A1 transporter), member 1
  • Solute carrier family 2 (facilitated glucose SLC2A2 transporter), member 2
  • Solute carrier family 2 (facilitated glucose SLC2A3 transporter), member 3
  • Solute carrier family 2 (facilitated glucose SLC2A4 transporter), member 4
  • Solute carrier family 2 (facilitated glucose SLC2A5 transporter), member 5
  • Solute carrier family 20 member 1 SLC2OA1 2
  • Solute carrier family 20 member 2 SLC2OA2 2
  • Solute carrier family 20 member 3 SLC2OA3 2
  • Solute carrier family 21 member 2 SLC21A2 2
  • Solute carrier family 21 member 3 SLC21A3 2
  • Solute carrier family 22 member 1 SLC22A1 2
  • Solute carrier family 22 member 2 SLC22A2 2
  • Solute carrier family 22 member 5 SLC22A5 2
  • Solute carrier family 25 member 12 SLC25A12 2
  • Solute carrier family 3 (facilitated glucose SLC3A1 2 transporter), member 1
  • Solute carrier family 4 anion exchanger
  • Solute carrier family 4 (amon exchanger), SLC4A2 2 member2 Solute carrier family 4 (anion exchanger), SLC4A3 2 member 3
  • Solute carrier family 5 sodium / glucose SLC5A1 2 transporter
  • Solute carrier family 5 sodium / glucose SLC5A2 2 transporter
  • Solute carrier family 5 sodium / glucose SLC5A5 2 transporter
  • Solute carrier family 5 member 3 SLC5A3 2
  • Solute carrier family 6 (neurotransmitter SLC6A3 2 transporter, dopamine), member 3
  • Solute carrier family 6 neurotransmitter SLC6A2 2 transporter, noradrenaline
  • member 2 neurotransmitter SLC6A2 2 transporter, noradrenaline
  • Solute carrier family 6 Neurotransmitter SLC6A4 2 transporter, serotome
  • member 4 Neurotransmitter SLC6A4 2 transporter, serotome
  • Solute carrier family 6 member 10 SLC6A10 2
  • Solute carrier family 6 member 6 SLC6A6 2
  • Solute carrier family 6 member 8 SLC6A8 2
  • Solute carrier family 7 amino acid transporter
  • SLC7A1 2 member 1 amino acid transporter
  • Solute carrier family 7 amino acid transporter
  • Solute carrier family 7 amino acid transporter
  • Solute carrier family 8 (sodium / calcium SLC8A1 2 exchanger), member 1
  • Tachykinin receptor NK1R TACR1 5
  • Tachykinin receptor Tachykinin receptor
  • NK2R TACR2 5 Tachylrinin receptor
  • Thyroid hormone receptor beta THRB 6
  • Thyroid-stimulating hormones alpha TSHA 6
  • Thyroid-stimulating hormones beta TSHB 6
  • RNA TTF1 6 polymerase 1
  • TNF Tumor necrosis factor
  • TRAF4 Tumor necrosis factor 4
  • TRAF6 Tumor necrosis factor receptor TRAF6 4 associated factor 6
  • Tumor necrosis factor beta receptor TNFBR 4 Tumor protein p53 TP53, P53 6
  • Adrenergic receptor alphal ADRA1 5
  • Adrenergic receptor alpha2 ADRA2 5
  • Adrenergic receptor betal ADRB1 5
  • Adrenergic receptor beta2 ADRB2 5
  • Adrenergic receptor beta3 ADRB3 5
  • AdrenocorticotropMc hormone ACTH
  • Bone morphogenetic protein BMP1 BMP1 6
  • Bone morphogenetic protein BMP2 BMP2 6
  • Bone morphogenetic protein BMP3 BMP3 6
  • Bone morphogenetic protein BMP4 BMP4 6
  • Bone morphogenetic protein BMP5 BMP5 6
  • Bone morphogenetic protein BMP6 BMP6 6
  • Bone morphogenetic protein BMP7 BMP7 6
  • Bone morphogenetic protein BMP8 BMP8 6
  • BDNF Brain derived neurotrophic factor
  • Calcitonin / Calcitonin gene-related peptides CALCA alpha Calcium Channel, voltage-dependent, alpha 1 F CACNA1F 5 subumt

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Abstract

L'invention concerne un jeu d'oligonucléotides servant de sondes pour la détection de variations importantes dans la méthylation de l'ADN dans un groupe cible de gènes, l'utilisation de ces oligonucléotides pour la mise en évidence de variantes génétiques concernant la méthylation de l'ADN, un dispositif médical utilisant un jeu d'oligonucléotides, un procédé pour l'analyse de l'état de méthylation d'un individu, ainsi qu'un procédé pour la création d'un modèle servant à évaluer la probabilité d'apparition d'un état maladif chez un individu. De telles maladies peuvent être : des effets secondaires indésirables de médicaments ; des maladies cancéreuses ; des dysfonctionnements, lésions ou maladies du système nerveux central ; des symptômes agressifs ou des troubles du comportement ; des conséquences cliniques, psychologiques et sociales de lésions du cerveau ; des troubles psychotiques et des troubles de la personnalité ; la démence ou des syndromes associés ; une maladie, un dysfonctionnement ou une lésion cardio-vasculaire ; un dysfonctionnement, une lésion ou une maladie du tractus gastro-intestinal ; un dysfonctionnement, une lésion ou une maladie du système respiratoire ; une blessure, une inflammation, une infection, une immunité ou une convalescence ; un dysfonctionnement, une lésion ou une maladie du corps sous forme d'anomalie dans le processus de développement ; un dysfonctionnement, une lésion ou une maladie de la peau, des muscles, du tissu conjonctif ou des os ; un dysfonctionnement, une lésion ou une maladie endocrinienne et métabolique ; des maux de tête ou un dysfonctionnement sexuel.
EP01940158A 2000-04-06 2001-04-06 Detection de variations dans le profil de methylation de l'adn Ceased EP1278892A1 (fr)

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DE10019058 2000-04-06
DE10019058A DE10019058A1 (de) 2000-04-06 2000-04-06 Detektion von Variationen des DNA-Methylierungsprofils
PCT/DE2001/001486 WO2001077373A2 (fr) 2000-04-06 2001-04-06 Detection de variations dans le profil de methylation de l'adn

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WO2001077373A2 (fr) 2001-10-18
US20070026393A1 (en) 2007-02-01
AU2001273840A1 (en) 2001-10-23

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