WO2002020841A2 - Polymorphismes du gene du recepteur de la 5-hydroxytryptamine et reponse au traitement - Google Patents

Polymorphismes du gene du recepteur de la 5-hydroxytryptamine et reponse au traitement Download PDF

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WO2002020841A2
WO2002020841A2 PCT/US2001/027066 US0127066W WO0220841A2 WO 2002020841 A2 WO2002020841 A2 WO 2002020841A2 US 0127066 W US0127066 W US 0127066W WO 0220841 A2 WO0220841 A2 WO 0220841A2
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WO2002020841A3 (fr
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Kourtney J Davis
Mary Elizabeth Fling
Arlene R Hughes
Penelope Kupsinel Manasco
Michael James Stubbins
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Glaxo Group Limited
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Priority to JP2002525846A priority Critical patent/JP2004508056A/ja
Priority to AU2001288564A priority patent/AU2001288564A1/en
Priority to EP01968309A priority patent/EP1315837A2/fr
Publication of WO2002020841A2 publication Critical patent/WO2002020841A2/fr
Publication of WO2002020841A3 publication Critical patent/WO2002020841A3/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • IBS Irritable Bowel Syndrome
  • No. 5,360,800 is a 5-HT3 receptor antagonist. Both animal and human studies indicate that 5-HT3 receptor blockade has therapeutic value in the treatment of irritable bowel syndrome, particularly in diarrhea-predominant IBS. (The disclosures of all US patents cited herein are incorporated herein by reference in their entirety.) In double-blind, placebo controlled studies, alosetron hydrochloride has been shown to reduce pain and improve bowel function in female IBS patients whose predominant bowel symptom is diarrhea.
  • UDP-glucuronosyltransferases catalyze by glucuronidation various endogenous agents, including steroids, bile acids, and bilirubin. The products are rendered more polar, thereby facilitating excretion from the cell.
  • UGTs UDP-glucuronosyltransferases
  • a large family of UGTs exists, allowing for glucuronidation of numerous structurally diverse compounds (Tukey and Strassburg, Ann Rev Pharmacol Toxicol 40:581, 2000). Based upon overall structural similarities, the known UGTs are derived from either the UGT1 or UGT2 gene.
  • the present inventors have determined that polymorphisms in the 5- hydroxytryptamine-3 receptor (5HT3R) gene is correlated with the response of subjects with Irritable Bowel Syndrome (IBS) to pharmaceutical therapy. More particularly, they have found that the C178T polymorphism (as defined herein) in the 5HT3R gene is associated with the response of patients with IBS to treatment with a 5HT antagonist; and have identified a genetic subset of IBS patients that displays a higher incidence of adequate relief of IBS symptoms when treated with alosetron (compared to patients with an alternative polymorphism at the same site of the 5HT3R gene).
  • a first aspect of the present invention is a method of screening a patient population to identify those subjects with an increased likelihood of responding favorably to treatment with a 5HT ligand for a gastrointestinal disorder.
  • the subjects may have been previously diagnosed as having IBS, or the screening may be used in conjunction with IBS diagnostic efforts.
  • a further aspect of the present invention is a method of screening a 5- hydroxytryptamine (5HT) ligand for variations in a measurable phenotypic effects among genetic subpopulations of subjects with a gastrointestinal disorder.
  • the method comprises administering the 5HT ligand to a population of subjects suffering from the gastrointestinal disorder, and obtaining DNA samples from each of the subjects.
  • the DNA samples are genotyped for a polymorphic allele of the 5HT3R gene, and correlations between the polymorphic allele genotype and the occurrence of a phenotypic response in the population of subjects are determined.
  • Detection of a genotype that is correlated with an increased or decreased incidence of a desired therapeutic response or a side effect indicates that the effectiveness of the ligand in treating that gastrointestinal disorder varies among genetic subpopulations.
  • genotyping a subject (or DNA sample) for a polymorphic allele at a defined genomic locus or "determining the genotype at a polymorphic allelic site” means detecting which forms of the allele are present in a subject (or a sample).
  • an individual may be heterozygous or homozygous for a particular allele. More than two forms of an allele may exist, as is the case with microsatellite markers; thus there may be more than three possible genotypes.
  • a "genetic subset" of a population consists of those members of the population having a particular genotype. In the case of a biallelic polymorphism, a population can potentially be divided into three subsets: homozygous for allele 1 (1,1), heterozygous (1,2), and homozygous for allele 2 (2,2).
  • the term '5HT ligand' encompasses antagonists and agonists of 5HT receptors, including partial agonists, and drugs that interact with the 5-hydroxytryptamine transporter (5HTT) (e.g., selective serotonin re-uptake inhibitors, SSRIs).
  • 5HT ligands may bind to any subtype of the 5HT receptor, including 5HT3 and 5HT4 receptors; the ligands may be specific for a particular receptor subtype.
  • a compound with 5HT ligand activity may be screened for variation in its effects among genetic subpopulations of subjects with a gastrointestinal disorder.
  • Such methods involve administering the compound to a population of subjects suffering from a 5HT-mediated gastrointestinal disorder, obtaining DNA samples from the subjects (which may be done either prior to or after administration of the compound), genotyping polymorphic allelic sites in the 5HT3R gene and/or the UGT1A4 gene, and correlating the genotype of the subjects with their phenotypic responses (both favorable and unfavorable) to the treatment.
  • the methods of the present invention may be used to determine the correlation of a known 5HT3R polymorphic allele, and/or a known UGT1 A4 polymorphic allele, with the response of subjects with gastrointestinal disorders (such as IBS) to treatment with a 5HT ligand.
  • Subjects with the disease of interest are stratified according to genotype for the particular polymorphic allele, and their response to a therapeutic agent is assessed (either prospectively or retrospectively) and compared among the genotypes.
  • the response to the therapeutic agent may include either, or both, desired therapeutic responses (e.g., the alleviation of signs or symptoms) and undesirable side effects.
  • genotypes that are associated with an increased (or decreased) rate of therapeutic efficacy, or an increased (or decreased) incidence of a particular side effect may be identified.
  • the increase or decrease in response is in comparison to the other genotypes, or to a population as a whole.
  • Polymorphic alleles are typically detected by directly determining the presence of the polymorphic sequence in a polynucleotide or protein from the subject, using any suitable technique as is known in the art.
  • a polynucleotide is typically genomic DNA, or a polynucleotide fragment derived from this genomic polynucleotide, such as in a library made using genomic material from the individual (e.g. a cDNA library).
  • genomic DNA or a polynucleotide fragment derived from this genomic polynucleotide, such as in a library made using genomic material from the individual (e.g. a cDNA library).
  • the binding agent may be a polynucleotide (single or double stranded) typically with a length of at least 10 nucleotides, for example at least 15, 20, 30, or more nucleotides.
  • the agent may be a molecule that is structurally similar polynucleotides that comprises units (such as purines or pyrimidines) able to participate in Watson-Crick base pairing.
  • the agent may be a protein, typically with a length of at least 10 amino acids, such as at least 20, 30, 50, or 100 or more amino acids.
  • the agent may be an antibody (including a fragment of such an antibody that is capable of binding the polymorphism).
  • a polynucleotide agent which is used in the method will generally bind to the polymorphism of interest, and the flanking sequence, in a sequence specific manner (e.g. hybridize in accordance with Watson-Crick base pairing) and thus typically has a sequence which is fully or partially complementary to the sequence of the polymorphism and flanking region.
  • a binding agent is used as a probe.
  • the probe may be labeled or may be capable of being labeled indirectly.
  • the detection of the label may be used to detect the presence of the probe on (and hence bound to) the polynucleotide or protein of the individual.
  • the binding of the probe to the polynucleotide or protein may be used to immobilize either the probe or the polynucleotide or protein (and thus to separate it from one composition or solution).
  • the polynucleotide or protein of the individual is immobilized on a solid support and then contacted with the probe.
  • the presence of the probe immobilized to the solid support (via its binding to the polymorphism) is then detected, either directly by detecting a label on the probe or indirectly by contacting the probe with a moiety that binds the probe, hi the case of detecting a polynucleotide polymorphism the solid support is generally made of nitrocellulose or nylon.
  • the method may be based on an ELIS A system.
  • the present methods may be based on an oligonucleotide ligation assay in which two oligonucleotide probes are used.
  • probes bind to adjacent areas on the polynucleotide which contains the polymorphism, allowing (after binding) the two probes to be ligated together by an appropriate ligase enzyme.
  • the two probes will only bind (in a manner which allows ligation) to a polynucleotide that contains the polymorphism, and therefore the detection of the ligated product may be used to determine the presence of the polymorphism.
  • the probe is used in a heteroduplex analysis based system to detect polymorphisms, ha such a system when the probe is bound to a polynucleotide sequence containing the polymorphism, it forms a heteroduplex at the site where the polymorphism occurs (i.e. it does not form a double strand structure).
  • a heteroduplex structure can be detected by the use of an enzyme that is single or double strand specific.
  • the probe is an RNA probe and the enzyme used is RNAse H that cleaves the heteroduplex region, thus allowing the polymorphism to be detected by means of the detection of the cleavage products.
  • the polynucleotide agent is able to act as a primer for a PCR reaction only if it binds a polynucleotide containing the polymorphism (i.e. a sequence- or allele-specific PCR system).
  • a polynucleotide containing the polymorphism i.e. a sequence- or allele-specific PCR system.
  • a PCR product will only be produced if the polymorphism is present in the polynucleotide of the individual.
  • the presence of the polymorphism may be determined by the detection of the PCR product.
  • the region of the primer which is complementary to the polymorphism is at or near the 3' end the primer.
  • the polynucleotide the agent will bind to the wild-type sequence but will not act as a primer for a PCR reaction.
  • the method may be a Restriction Fragment Length Polymorphism (RFLP) based system.
  • RFLP Restriction Fragment Length Polymorphism
  • This can be used if the presence of the polymorphism in the polynucleotide creates or destroys a restriction site that is recognized by a restriction enzyme.
  • treatment of a polynucleotide that has such a polymorphism will lead to different products being produced compared to the corresponding wild-type sequence.
  • the detection of the presence of particular restriction digest products can be used to determine the presence of the polymorphism.
  • the presence of the polymorphism may be determined based on the change that the presence of the polymorphism makes to the mobility of the polynucleotide or protein during gel electrophoresis.
  • SSCP polynucleotide single-stranded conformation polymorphism
  • Denaturing gradient gel electrophoresis DGGE Denaturing gradient gel electrophoresis DGGE is a similar system where the polynucleotide is electrophoresed through a gel with a denaturing gradient, a difference in mobility compared to the corresponding wild-type polynucleotide indicating the presence of the polymorphism.
  • the presence of the polymorphism may be determined using a fluorescent dye and quenching agent-based PCR assay such as the TAQMANTM PCR detection system, hi brief, this assay uses an allele specific primer comprising the sequence around, and including, the polymorphism.
  • the specific primer is labeled with a fluorescent dye at its 5' end, a quenching agent at its 3' end and a 3' phosphate group preventing the addition of nucleotides to it. Normally the fluorescence of the dye is quenched by the quenching agent present in the same primer.
  • the allele specific primer is used in conjunction with a second primer capable of hybridizing to either allele 5' of the polymorphism.
  • Taq DNA polymerase adds nucleotides to the nonspecific primer until it reaches the specific primer. It then releases polynucleotides the fluorescent dye and the quenching agent from the specific primer through its endonuclease activity. The fluorescent dye is therefore no longer in proximity to the quenching agent and fluoresces.
  • the mismatch between the specific primer and template inhibits the endonuclease activity of Taq and the fluorescent dye in not released from the quenching agent. Therefore by measuring the fluorescence emitted the presence or absence of the polymorphism can be determined.
  • a polynucleotide comprising the polymorphic region is sequenced across the region which contains the polymorphism to determine the presence of the polymorphism. Accordingly, any of the following techniques may be utilized in the present methods for genotyping, as is known in the art.
  • Hybridization based solid phase hybridization (dot blots, MASDA, reverse dot blots, oligonucleotide arrays (chips)); solution phase hybridization (TAQMANTM, Molecular Beacons);
  • the present invention also provides for a predictive (patient care) test or test kit.
  • a predictive (patient care) test or test kit will aid in disease management of gastrointestinal disease based on predetermined associations between genotype and phenotypic response to 5HT ligands in treating gastrointestinal disease.
  • Such a test may take different formats, including:
  • test kit may include one or more of the following reagents or instruments: a means to detect the binding of the agent to the polymorphism, an enzyme able to act on a polynucleotide (typically a polymerase or restriction enzyme), suitable buffers for enzyme reagents, PCR primers which bind to regions flanking the polymorphism, a positive or negative control (or both), a gel electrophoresis apparatus, and a means to isolate DNA from a sample.
  • the product may utilise one of the chip technologies as described by the current state of the art.
  • the test kit would include printed or machine readable instructions setting forth the correlation between the presence of a specific polymorphism or genotype and the likelihood that a subject with a gastrointestinal disease such as IBS will respond favorably to therapy with a 5HT ligand;
  • test kit (b) a biochemical test which analyses materials derived from the subject's body, including proteins or metabolites, that indicate the presence of a pre-determined polymorphism.
  • An appropriate test kit would comprise a molecule, aptamer, peptide or antibody (including an antibody fragment) that specifically binds to a predetermined polymorphic region (or a specific region flanking the polymorphism), or a binding agent as defined herein.
  • the product may additionally comprise one or more additional reagents or instruments (as are known in the art).
  • the test kit would also include printed or machine-readable instructions setting forth the correlation between the presence of a specific polymorphism or genotype and the likelihood that a subject with IBS will respond favorably to therapy with a 5HT ligand.
  • the present invention provides a method for screening a subject diagnosed with
  • the method comprises screening the subject for a polymorphism in the 5HT3R gene, and/or the UGT1A4 gene, that have previously been associated with a high or low rate of a particular desirable therapeutic outcome (compared to the rate in subjects with other genotypes), or associated with a high or low incidence of an undesired side effect (compared to the incidence in subjects with other genotypes).
  • Subjects are mammalian, and preferably humans.
  • Treatment of a subject with a 5HT ligand comprises administration of an effective amount of the pharmaceutical agent to a subject in need thereof.
  • the dose of agent is determined according to methods known and accepted in the pharmaceutical arts, and can be determined by those skilled in the art.
  • a suitable dosage range and plasma concentration for alosetron are provided in the disclosure of US Patent Number 5,360,800, the entire disclosure of which is hereby incorporated herein by reference.
  • Linkage disequilibrium refers to refers to the tendency of specific alleles at different genomic locations to occur together more frequently than would be expected by chance.
  • Linkage disequilibrium may be quantitated by methods as are known in the art (see, e.g., Devlin and Risch, Genomics 29:311 (1995); BS Weir, Genetic Data Analysis II, Sinauer Associates, Sunderland, MD (1996)). For example, alleles at given loci may be defined as in complete equilibrium if the frequency of any particular set of alleles (or haplotype) is the product of their individual population frequencies A commonly used measure of linkage disequilibrium is r:
  • genotyping methods as are well known in the art, genetic data were obtained from 237 subjects enrolled in clinical trials of alosetron for the treatment of non- constipation predominant IBS. Samples of subjects' DNA were genotyped, including typing for the presence of the C178T polymorphism in the 5HT3R gene, and for the - presence of the C70A polymorphism in the UGT1 A4 gene (as described above).
  • alosetron In the double-blind, placebo controlled clinical trials, female subjects received up to 12 weeks of treatment with either alosetron or a placebo. A favorable response to alosetron was defined as when a subject reported adequate relief of her IBS symptoms of pain and discomfort; the duration of symptom relief was recorded. Each subject's response to alosetron in the clinical trial setting was then analysed in conjunction with genotyping data, to identify genotypes associated with an increased (or decreased) rate of therapeutic efficacy.
  • 'adequate relief from pain and discomfort' (referred to herein as 'adequate relief).
  • Analyses were conducted using three different coding schemes: continuous (ranging from 0 weeks of adequate relief to 12 weeks of adequate relief, 3 levels (relief occurring for 0 weeks, for 1-4 weeks, or for 5-12 weeks and dichotomous (0-4 weeks of adequate relief, versus 5-12 weeks of adequate relief).
  • the recursive partitioning analyses (see Tables 1 & 2) identified polymorphisms in two genes that were associated with an increased rate of response to alosetron in the clinical trials. These were the C178T polymorphism in the 5HT3R gene (as defined herem , and the C70A polymorphism in the UGT1 A4 gene (as defined). Subjects' DNA was coded according to the presence of various polymorphisms, including polymorphisms in the 5HT3R and UGT1A4 genes.
  • a subject homozygous for "C” at the C178T polymorphic site in the 5HT3R gene was coded 1,1; a subject homozygous for "T” at the C178T polymorphic site was coded 2,2; and the heterozygous condition was coded 1,2.
  • a subject homozygous for "C” at the C70A polymorphic site in the UGT1A4 gene was coded 1,1; a subject homozygous for "A" at the C70A polymorphic site was coded 2,2; and the heterozygous condition was coded 1,2.
  • the model for alosetron treated subjects only suggested the same gene-gene interaction as the decision tree, where subjects having a 1,1 UGT1A4 genotype and a
  • 5HT3R genotype of either 1,1 or 2,2, were more likely to have good response when compared to other genotypes (p 0.057).
  • DNA samples are obtained from a population of subjects with gastrointestinal disease, and genomic DNA is extracted using standard procedures (automated extraction or using kit formats). The genotypes of the subjects, and any control individuals utilized, are determined for polymorphisms within the 5HT3R and UGT1A4 gene sequences, using either PCR, PCR-RFLP, TAQMANTM allelic discrimination assays, or any other suitable technique as is known in the art.
  • a simple size discrimination assay can be employed to determine the genotype of an individual, hi this case, two primers are employed to specifically amplify the gene of interest in a region surrounding the site of the polymorphism. PCR amplification is carried out, generating products that differ in length, dependent on the genotype (insertion or deletion) they possess. When subjected to gel electrophoresis, the differently sized products are separated, visualized, and the specific genotypes interpreted directly.
  • PCR-RFLP polymerase chain reaction - restriction fragment length polymorphism
  • a PCR-RFLP assay employs two gene- specific primers to anneal to, and specifically amplify a segment of genomic DNA surrounding the polymorphic site of interest.
  • specific restriction endonuclease enzymes are employed to digest the PCR products produced.
  • the enzyme utilized for an assay is selected due to its specific recognition sequence which it requires to bind to, and cleave the PCR product in the presence/absence of the polymorphism, yielding fragments diagnostic of the specific base present at the polymorphic site.
  • gel electrophoresis is employed to separate and visualize the fragments produced.
  • TAQMANTM PE Applied Biosystems, Foster City, CA assays, as are known in the art, may also be utilized to identify polymorphisms.
  • the allelic discrimination assay uses two allele specific probes labeled with a different fluorescent dye at their 5' ends but with a common quenching agent at their 3' ends. Both probes have a 3' phosphate group so that Taq polymerase cannot add nucleotides to them.
  • the allele specific probes comprise the sequence encompassing the polymorphic site and differ in the sequence at this site. The allele specific probes are capable of hybridizing without mismatches to the appropriate site.
  • the allele specific probes are used in conjunction with two primers, one of which hybridizes to the template 5' of the two specific probes, while the other hybridizes to the template 3' of the two probes. If the allele corresponding to one of the specific probes is present, the specific probe will hybridize perfectly to the template.
  • the Taq polymerase extending the 5' primer, will then remove the nucleotides from the specific probe, releasing both the fluorescent dye and the quenching agent. This will result in an increase in the fluorescence from the dye no longer in close proximity to the quenching agent.
  • the mismatch at the polymorphic site will inhibit the 5' to 3' endonuclease activity of Taq and hence prevent release of the fluorescent dye.
  • the ABI7700 sequence detection system is used to measure the increase in the fluorescence from each specific dye at the end of the thermal cycling PCR directly in PCR reaction tubes. The information from the reactions is then analyzed. If an individual is homozygous for a particular allele only fluorescence corresponding to the dye from that specific probe will be released, but if the individual is heterozygous, then both dyes will fluoresce. The genotypes of the individuals are then correlated with their phenotypic response to treatment with a 5HT ligand. Responses that vary among the genetic subpopulations are identified.

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Abstract

L'invention concerne des corrélations entre polymorphismes dans le gène du récepteur de la 5-hydroxytryptamine 3, et/ou de polymorphismes dans le gène UGT1A4, et une réponse phénotypique du sujet au traitement au moyen de ligands de la 5-hydroxytryptamine. Cette invention concerne également des méthodes de dépistage chez des sujets pour l'aide au traitement, des méthodes de criblage de ligands 5HT et des méthodes de traitement.
PCT/US2001/027066 2000-09-06 2001-08-31 Polymorphismes du gene du recepteur de la 5-hydroxytryptamine et reponse au traitement WO2002020841A2 (fr)

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JP2002525846A JP2004508056A (ja) 2000-09-06 2001-08-31 ５−ヒドロキシトリプタミン受容体遺伝子多型、および治療に対する応答
AU2001288564A AU2001288564A1 (en) 2000-09-06 2001-08-31 5-hydroxytryptamine receptor gene polymorphisms and response to treatment
EP01968309A EP1315837A2 (fr) 2000-09-06 2001-08-31 Polymorphismes du gene du recepteur de la 5-hydroxytryptamine et reponse au traitement

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WO2009060089A1 (fr) * 2007-11-09 2009-05-14 Universitätsklinikum Heidelberg Procédé de diagnostic et d'analyse de sous-groupe dans des sujets ayant ou étant suspectés d'avoir le syndrome du côlon irritable, acides nucléiques et kits, et leur utilisation
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MX2008012392A (es) * 2006-03-27 2008-12-17 Globeimmune Inc Mutacion de ras, y composiciones y metodos relacionados con la misma.
US20080085524A1 (en) * 2006-08-15 2008-04-10 Prometheus Laboratories Inc. Methods for diagnosing irritable bowel syndrome

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WO2009060089A1 (fr) * 2007-11-09 2009-05-14 Universitätsklinikum Heidelberg Procédé de diagnostic et d'analyse de sous-groupe dans des sujets ayant ou étant suspectés d'avoir le syndrome du côlon irritable, acides nucléiques et kits, et leur utilisation
WO2011053831A1 (fr) * 2009-10-30 2011-05-05 Prometheus Laboratories Inc. Procédés pour le diagnostic du syndrome du côlon irritable
CN102712956A (zh) * 2009-10-30 2012-10-03 普罗米修斯实验室股份有限公司 肠易激综合征的诊断方法

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