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EP1141395A1 - Polymorphisme nucleotidique unique dans un pyruvate deshydrogenase kinase isoenzyme 2 (pdk2) chez l'homme - Google Patents

Polymorphisme nucleotidique unique dans un pyruvate deshydrogenase kinase isoenzyme 2 (pdk2) chez l'homme

Info

Publication number
EP1141395A1
EP1141395A1 EP99962355A EP99962355A EP1141395A1 EP 1141395 A1 EP1141395 A1 EP 1141395A1 EP 99962355 A EP99962355 A EP 99962355A EP 99962355 A EP99962355 A EP 99962355A EP 1141395 A1 EP1141395 A1 EP 1141395A1
Authority
EP
European Patent Office
Prior art keywords
pdk2
gene
polymoφhism
embl accession
single nucleotide
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.)
Withdrawn
Application number
EP99962355A
Other languages
German (de)
English (en)
Inventor
Rakesh Anand
John Edward Norris Morten
John Craig Smith
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.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1141395A1 publication Critical patent/EP1141395A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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

  • This invention relates to polymorphisms in the human pyruvate dehydrogenase kinase isoenzyme 2 (PDK2) gene.
  • the invention also relates to methods and materials for analysing allelic variation in the PDK2 gene, and to the use of PDK2 polymorphism in the diagnosis and treatment of diseases in which inhibition of PDK2 could be of therapeutic benefit, such as diabetes, obesity and sepsis.
  • ATP provides the energy for synthesis of complex molecules and, in muscle, for contraction. ATP is generated from the breakdown of energy-rich substrates, such as glucose or long chain free fatty acids. In oxidative tissues, such as muscle, the majority of the ATP is generated from acetyl CoA which enters the citric acid cycle: thus the supply of acetyl CoA is a critical determinant of ATP production in oxidative tissues. Acetyl CoA is produced either by ⁇ -oxidation of fatty acids or as a result of glucose metabolism by the glycolytic pathway.
  • PDH pyruvate dehydrogenase
  • PDH is an intramitochondrial multienzyme complex consisting of multiple copies of several subunits including three enzyme activities required for the completion of the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). El catalyses the non-reversible removal of CO 2 from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activities are associated with the complex: a specific kinase (PDK) which is capable of phosphorylating El at three serine residues. Phosphorylation of a single one of the three serine residues renders the El inactive.
  • PDK specific kinase
  • the complex contains a loosely-associated specific phosphatase which reverses the phosphorylation: the proportion of the PDH in its active (dephosphorylated) state is therefore determined by a balance between the activity of the kinase and phosphatase.
  • the activity of the kinase may be regulated in vivo by the relative concentrations of metabolic substrates such as NAD NADH, CoA/acetylCoA and ADP/ATP as well as by the availability of pyruvate itself, therefore providing intimate appropriate control of substrate availability.
  • metabolic substrates such as NAD NADH, CoA/acetylCoA and ADP/ATP
  • NIDDM non-insulin dependent
  • IDDM insulin-dependent diabetes
  • oxidation of lipids is increased with a concomitant reduction in utilisation of glucose, contributing to the hyperglycaemia.
  • the activity of PDH is reduced in both insulin-dependent and non insulin-dependent diabetes.
  • a further consequence of reduced PDH activity would be an increase in pyruvate concentration resulting in increased availability of lactate as a substrate for hepatic gluconeogenesis. Diabetes would be further exacerbated by impaired insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic ⁇ -cells. It is believed that increasing the activity of PDH would increase the rate of glucose oxidation and hence overall glucose utilisation, in addition to reducing hepatic glucose output.
  • Oxidation of glucose is capable of yielding more molecules of ATP per mole of oxygen than is oxidation of fatty acids, therefore in conditions where energy demand may exceed energy supply, such as myocardial ischaemia and reperfusion, intermittent claudication, cerebral ischaemia and reperfusion, shifting the balance of substrate utilisation in favour of glucose metabolism may be expected to improve the ability to maintain ATP levels and hence function.
  • Activation of PDH is predicted to have this effect.
  • An agent which is capable of activating PDH is expected to be of benefit in treating conditions where an excess of circulating lactic acid is manifest such as in certain cases of sepsis.
  • Pharmacogenetics can also be used in pharmaceutical research to assist the drug selection process. Polymorphisms are used in mapping the human genome and to elucidate the genetic component of diseases. The reader is directed to the following references for background details on pharmacogenetics and other uses of polymo ⁇ hism detection: Linder et al. (1997), Clinical Chemistry, 43, 254; Marshall (1997), Nature Biotechnology, 15, 1249; International Patent Application WO 97/40462, Spectra
  • the present invention is based on the discovery of a single nucleotide polymorphism
  • SNP single nucleotide polymorphisms in the 3 ' untranslated region (3 'UTR) of the human PDK2 gene.
  • a method for the diagnosis of a single nucleotide polymorphism in a PDK2 gene in a human comprises determining the sequence of the nucleic acid of the human at one or more of positions 288, 1281 and 1357 in the PDK2 gene as defined by the positions in EMBL
  • the term human includes both a human having or suspected of having a PDK2 -mediated disease and an asymptomatic human who may be tested for predisposition or susceptibility to such disease. At each position the human may be homozygous for an allele or the human may be a heterozygote.
  • 'PDK2 -mediated disease means any disease in which changing the level of
  • PDK2 or changing the activity of PDK2 would be of therapeutic benefit.
  • the term 'PDK2 drug' means any drug which changes the level of PDK-2 or changes the activity of PDK2.
  • a drug which inhibits the activity of PDK2 is preferred.
  • the method for diagnosis described herein is one in which the single nucleotide polymo ⁇ hism at position 288 is presence of C and/or T.
  • the method for diagnosis described herein is one in which the single nucleotide polymo ⁇ hism at position 1281 is presence of G and/or A.
  • the method for diagnosis described herein is one in which the single nucleotide polymo ⁇ hism at position 1357 is presence of G and/or C.
  • the method for diagnosis is preferably one in which the sequence is determined by a method selected from amplification refractory mutation system and restriction fragment length polymo ⁇ hism.
  • a method for the diagnosis of PDK2 -mediated disease comprises: i) obtaining sample nucleic acid from an individual, ii) detecting the presence or absence of a variant nucleotide at one or more of positions 288, 1281 and 1357 (as defined by the position in EMBL accession number L42451), in the PDK2-gene and iii) determining the status of the individual by reference to polymo ⁇ hism in the PDK2 gene.
  • Allelic variation at position 288 consists of a single base substitution from C (the published base), preferably to T.
  • Allelic variation at position 1281 consists of a single base substitution from G (the published base), preferably to A.
  • Allelic variation at position 1357 consists of a single base substitution from G (the published base), preferably to C.
  • the status of the individual may be determined by reference to allelic variation at any one, two, or all three positions optionally in combination with any other polymo ⁇ hism in the gene that is (or becomes) known.
  • test sample of nucleic acid is conveniently present in a sample of blood, bronchoalveolar lavage fluid, sputum, or other body fluid or tissue obtained from an individual. It will be appreciated that the test sample may equally comprise a nucleic acid sequence corresponding to the sequence in the test sample, that is to say that all or a part of the region in the sample nucleic acid may firstly be amplified using any convenient technique e.g. PCR, before analysis of allelic variation.
  • allelic variation requires a mutation discrimination technique, optionally an amplification reaction and optionally a signal generation system.
  • Table 1 lists a number of mutation detection techniques, some based on PCR. These may be used in combination with a number of signal generation systems, a selection of which is listed in Table 2. Further amplification techniques are listed in Table 3. Many current methods for the detection of allelic variation are reviewed by Nollau et al., Clin. Chem.
  • Fluorescence Fluorescence: FRET, Fluorescence quenching, Fluorescence polarisation - United Kingdom Patent No. 2228998 (Zeneca Limited)
  • Preferred mutation detection techniques include ARMSTM, ALEXTM, COPS, Taqman, Molecular Beacons, RFLP, and restriction site based PCR and FRET techniques.
  • Particularly preferred methods include ARMSTM and RFLP based methods.
  • ARMSTM is an especially preferred method.
  • the diagnostic methods of the invention are used to assess the efficacy of therapeutic compounds in the treatment of PDK2 -mediated diseases such as diabetes, obesity, sepsis, and peripheral vascular disease.
  • Assays for example reporter-based assays, may be devised to detect whether one or more of the above polymo ⁇ hisms affect transcription levels and/or message stability.
  • allelic variants of the PDK2 gene may therefore exhibit differences in their ability to regulate protein biosynthesis under different physiological conditions and may display altered abilities to react to different diseases.
  • differences in protein regulation arising as a result of allelic variation may have a direct effect on the response of an individual to drug therapy.
  • the diagnostic methods of the invention may be useful both to predict the clinical response to such agents and to determine therapeutic dose.
  • the diagnostic methods of the invention are used to assess the predisposition of an individual to diseases mediated by PDK2. This may be particularly relevant in the development of diabetes, obesity, sepsis, and peripheral vascular disease and other diseases which are mediated by PDK2.
  • the present invention may be used to recognise individuals who are particularly at risk from developing these conditions.
  • a haplotype is a set of alleles found at linked polymo ⁇ hic sites (such as within a gene) on a single (paternal or maternal) chromosome. If recombination within the gene is random, there may be as many as 2" haplotypes, where 2 is the number of alleles at each SNP and n is the number of SNPs.
  • One approach to identifying mutations or polymo ⁇ hisms which are correlated with clinical response is to carry out an association study using all the haplotypes that can be identified in the population of interest.
  • each haplotype is limited by the frequency of its rarest allele, so that SNPs with low frequency alleles are particularly useful as markers of low frequency haplotypes.
  • SNPs with low frequency alleles are particularly useful as markers of low frequency haplotypes.
  • mutations or polymo ⁇ hisms associated with certain clinical features, such as adverse or abnormal events are likely to be of low frequency within the population, low frequency SNPs may be particularly useful in identifying these mutations (for examples see: Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine.
  • CBS cystathionine beta synthase
  • the diagnostic methods of the invention are used in the development of new drug therapies which selectively target one or more allelic variants of the PDK2 gene. Identification of a link between a particular allelic variant and predisposition to disease development or response to drug therapy may have a significant impact on the design of new drugs. Drugs may be designed to regulate the biological activity of variants implicated in the disease process whilst minimising effects on other variants.
  • the presence or absence of variant nucleotides is detected by reference to the loss or gain of, optionally engineered, sites recognised by restriction enzymes.
  • restriction enzymes In the accompanying Example 2 we provide details of convenient engineered restriction enzyme sites that are lost or gained as a result of a polymo ⁇ hism of the invention.
  • nucleic acid comprising any one of the following polymo ⁇ hisms: the nucleic acid of EMBL ACCESSION No. L42451 with T at position 288 as defined by the position in EMBL ACCESSION No. L42451 ; the nucleic acid of EMBL ACCESSION No. L42451 with A at position 1281 as defined by the position in EMBL ACCESSION No. L42451 ; the nucleic acid of EMBL ACCESSION No. L42451 with C at position 1357 as defined by the position in EMBL ACCESSION No. L42451 ; or a complementary strand thereof or an antisense sequence thereto or a fragment thereof of at least 20 bases comprising at least one polymo ⁇ hism.
  • Fragments are at least 17 bases, more preferably at least 20 bases, more preferably at least 30 bases.
  • the scope of the invention does not extend to any nucleic acid as it is found in nature.
  • a nucleic acid of the invention is preferably in isolated form, for example through being at least partially purified from any substance with which it occurs naturally (if any).
  • Novel sequence disclosed herein may be used in another embodiment of the invention to regulate expression of the gene in cells by the use of antisense constructs.
  • an example antisense expression construct can be readily constructed for instance using the pREPIO vector (Invitrogen Co ⁇ oration).
  • Transcripts are expected to inhibit translation of the gene in cells transfected with this type construct.
  • Antisense transcripts are effective for inhibiting translation of the native gene transcript, and capable of inducing the effects (e.g., regulation of tissue physiology) herein described.
  • Oligonucleotides which are complementary to and hybridizable with any portion of novel gene mR A disclosed herein are contemplated for therapeutic use.
  • Identification may be accomplished by recovering the vector or by polymerase chain reaction (PCR) amplification and sequencing the region containing the inserted nucleic acid material.
  • nucleotide molecules can be synthesized for antisense therapy. These antisense molecules may be DNA, stable derivatives of DNA such as phosphorothioates or methylphosphonates, RNA, stable derivatives of RNA such as 2'-O-alkylRNA, or other oligonucleotide mimetics.
  • Antisense molecules may be introduced into cells by microinjection, liposome encapsulation or by expression from vectors harboring the antisense sequence.
  • the invention further provides nucleotide primers which can detect the polymo ⁇ hisms of the invention.
  • an allele specific primer capable of detecting a PDK2 gene polymo ⁇ hism at one or more of positions 288, 1281 and 1357 in the PDK2 gene as defined by the positions in EMBL ACCESSION NO. L42451.
  • An allele specific primer is used, generally together with a constant primer, in an amplification reaction such as a PCR reaction, which provides the discrimination between alleles through selective amplification of one allele at a particular sequence position e.g. as used for ARMSTM assays.
  • the allele specific primer is preferably 17- 50 nucleotides, more preferably about 17-35 nucleotides, more preferably about 17-30 nucleotides.
  • An allele specific primer preferably corresponds exactly with the allele to be detected but derivatives thereof are also contemplated wherein about 6-8 of the nucleotides at the 3' terminus correspond with the allele to be detected and wherein up to 10, such as up to 8, 6, 4, 2, or 1 of the remaining nucleotides may be varied without significantly affecting the properties of the primer.
  • Primers may be manufactured using any convenient method of synthesis. Examples of such methods may be found in standard textbooks, for example "Protocols for Oligonucleotides and Analogues; Synthesis and Properties," Methods in Molecular Biology Series; Nolume 20; Ed. Sudhir Agrawal, Humana ISBN: 0-89603-247-7; 1993; 1 st Edition. If required the primer(s) may be labelled to facilitate detection.
  • an allele-specific oligonucleotide probe capable of detecting a PDK2 gene polymo ⁇ hism at one or more of positions 288, 1281 and 1357 in the PDK2 gene as defined by the positions in EMBL ACCESSION NO. L42451.
  • the allele-specific oligonucleotide probe is preferably 17- 50 nucleotides, more preferably about 17-35 nucleotides, more preferably about 17-30 nucleotides.
  • probes will be apparent to the molecular biologist of ordinary skill.
  • Such probes are of any convenient length such as up to 50 bases, up to 40 bases, more conveniently up to 30 bases in length, such as for example 8-25 or 8-15 bases in length.
  • such probes will comprise base sequences entirely complementary to the corresponding wild type or variant locus in the gene.
  • the probes of the invention may carry one or more labels to facilitate detection.
  • a diagnostic kit comprising an allele specific oligonucleotide probe of the invention and/or an allele-specific primer of the invention.
  • kits may comprise appropriate packaging and instructions for use in the methods of the invention.
  • Such kits may further comprise appropriate buffer(s), nucleotides, and polymerase(s) such as thermostable polymerases, for example taq polymerase.
  • the single nucleotide polymo ⁇ hisms of this invention may be used as genetic markers in linkage studies. This particularly applies to the polymo ⁇ hisms at 288 (as defined by the position in EMBL ACCESSION NO. L42451) because of its relatively high frequency (see below).
  • a method of treating a human in need of treatment with a PDK2 drug comprises: i) diagnosis of a single nucleotide polymo ⁇ hism in the PDK2 gene in the human, which diagnosis comprises determining the sequence of the nucleic acid at one or more of positions 288, 1281 and 1357 of the PDK2 gene as defined by the position in EMBL accession number L42451, and determining the status of the human by reference to polymo ⁇ hism in the PDK2 5 gene; and ii) administering an effective amount of a PDK2 drug.
  • Preferably determination of the status of the human is clinically useful. Examples of clinical usefulness include deciding which drug or drugs to administer and/or establishing the effective amount of the drug or drugs.
  • PDK inhibitors are of value in a number of disease conditions, including disease states associated with disorders of glucose utilisation such as diabetes, obesity and associated with excessive production of lactate such as encountered in sepsis and other causes of lactic
  • PDK inhibitors may be expected to have utility in diseases where supply of energy-rich substrates to tissues is limiting such as peripheral vascular disease, coronary failure and certain cardiac myopathies muscle ataxia, weakness.
  • a PDK2 drug in the preparation of a medicament for treating a PDK2 -mediated disease in a human
  • a pharmaceutical pack comprising PDK2 drug and instructions for administration of the drug to humans diagnostically tested for a single nucleotide polymo ⁇ hism at one or more of positions
  • a computer readable medium comprising at least one novel polynucleotide sequence of the invention stored on the medium.
  • the computer readable medium may be used, for example, in
  • polynucleotide sequences of the invention or parts thereof, particularly those relating to and identifying the single nucleotide polymo ⁇ hisms identified herein represent a valuable information source, for example, to characterise individuals in terms of haplotype and other sub-groupings, such as investigation of susceptibility to treatment with particular drugs. These approaches are most easily facilitated by storing the sequence information in a computer readable medium and then using the information in standard bioinformatics programs or to search sequence databases using state of the art searching tools such as "GCC". Thus, the polynucleotide sequences of the invention are particularly useful as components in databases useful for sequence identity and other search analyses.
  • sequence information in a computer readable medium and use in sequence databases in relation to 'polynucleotide or polynucleotide sequence of the invention' covers any detectable chemical or physical characteristic of a polynucleotide of the invention that may be reduced to, converted into or stored in a tangible medium, such as a computer disk, preferably in a computer readable form.
  • a tangible medium such as a computer disk
  • chromatographic scan data or peak data photographic scan or peak data
  • mass spectrographic data sequence gel (or other) data.
  • the invention provides a computer readable medium having stored thereon one or more polynucleotide sequences of the invention.
  • a computer readable medium comprising and having stored thereon a member selected from the group consisting of: a polynucleotide comprising the sequence of a polynucleotide of the invention, a polynucleotide consisting of a polynucleotide of the invention, a polynucleotide which comprises part of a polynucleotide of the invention, which part includes at least one of the polymo ⁇ hisms of the invention, a set of polynucleotide sequences wherein the set includes at least one polynucleotide sequence of the invention, a data set comprising or consisting of a polynucleotide sequence of the invention or a part thereof comprising at least one of the polymo ⁇ hisms identified herein.
  • a computer based method for performing sequence identification, said method comprising the steps of providing a polynucleotide sequence comprising a polymo ⁇ hism of the invention in a computer readable medium; and comparing said polymo ⁇ hism containing polynucleotide sequence to at least one other polynucleotide or polypeptide sequence to identify identity (homology), i.e. screen for the presence of a polymo ⁇ hism.
  • AMPLITAQTM or AMPLITAQ GOLD TMavailable from Perkin-Elmer Cetus are used as the source of thermostable DNA polymerase.
  • Electrophero grams were obtained in a standard manner: data was collected by ABI377 data collection software and the wave form generated by ABI Prism sequencing analysis (2.1.2).
  • Templates were prepared by PCR using the oligonucleotide primers and annealing temperatures set out below.
  • the extension temperature was 72° and denaturation temperature 94°; each step was 1 minute.
  • 100 pg cDNA was used in each reaction and subjected to 40 cycles of PCR.
  • the forward primers were modified to include Ml 3 forward sequence (ABI protocol P/N 402114, Applied Biosystems) at the 5' end of the oligonucleotides.
  • Dye-primer sequencing using Ml 3 forward primer was as described in the ABI protocol P/N 402114 for the ABI PrismTM dye primer cycle sequencing core kit with "AmpliTaq FS”TM DNA polymerase, modified in that the annealing temperature was 45° and DMSO was added to the cycle sequencing mix to a final concentration of 5 %.
  • the extension reactions for each base were pooled, ethanol/sodium acetate precipitated, washed and resuspended in formamide loading buffer.
  • Standard methodology can be used to detect the polymo ⁇ hism at positions (288 and 1357 as defined by the position in EMBL ACCESSION NO. L42451) based on the materials set out below using a cDNA template.
  • T at position 288 creates a Bsr G I or a Fsp I site in the diagnostic fragment, 13-314, described above.
  • PDK2 SNPs were detected according to the "Sco ⁇ ions”TM method described in Whitcombe et al., Nature Biotech 17, 804-807, 1999; with the exception that amplification conditions were 45 cycles, 94°C 45secs, 55°C 45 sees.
  • SNP 1281 FAM was used for the A allele dye and Tet for the G allele.

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Abstract

L'invention porte sur des polymorphismes affectant le gène humain pyruvate déshydrogénase kinase isoenzyme 2 (PDK2), et notamment sur la découverte d'un polymorphisme nucléotidique unique dans la région codante du gène humain PDK2 et de deux polymorphismes nucléotidiques uniques dans la région 3' transduite du gène humain PDK2. Cette invention porte également sur des procédés et des matériaux permettant d'analyser le gène allélomorphe PDK2, et sur l'utilisation du polymorphisme de PDK2 dans le diagnostic et le traitement de pathologies telles que les diabètes, l'obésité et la septicémie dans lesquelles l'inhibition de PDK2 pourrait donner un résultat thérapeutique favorable.
EP99962355A 1998-12-23 1999-12-17 Polymorphisme nucleotidique unique dans un pyruvate deshydrogenase kinase isoenzyme 2 (pdk2) chez l'homme Withdrawn EP1141395A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9828256.9A GB9828256D0 (en) 1998-12-23 1998-12-23 Chemical compounds
GB9828256 1998-12-23
PCT/GB1999/004305 WO2000039331A1 (fr) 1998-12-23 1999-12-17 Polymorphisme nucleotidique unique dans un pyruvate deshydrogenase kinase isoenzyme 2 (pdk2) chez l'homme

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EP1141395A1 true EP1141395A1 (fr) 2001-10-10

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EP (1) EP1141395A1 (fr)
JP (1) JP2002533135A (fr)
AU (1) AU1872700A (fr)
GB (2) GB9828256D0 (fr)
WO (1) WO2000039331A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1247860A1 (fr) * 2001-04-06 2002-10-09 Pfizer Limited Structure cristalline de la pyruvate dehydrogenase kinase 2 (PDHK-2) et son utilisation dans des méthodes d'identification et de design de nouveaux ligands
WO2003018835A2 (fr) * 2001-08-23 2003-03-06 Hvidovre Hospital Procede de detection rapide d'haplotypes

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* Cited by examiner, † Cited by third party
Title
See references of WO0039331A1 *

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GB2361061A (en) 2001-10-10
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GB9828256D0 (en) 1999-02-17
JP2002533135A (ja) 2002-10-08
GB0111826D0 (en) 2001-07-04

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