EP1135534A1 - Utilisation du polymorphisme du facteur x dans le diagnostic et le traitement d'affections induites par le facteur x et/ou xa - Google Patents

Utilisation du polymorphisme du facteur x dans le diagnostic et le traitement d'affections induites par le facteur x et/ou xa

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Publication number
EP1135534A1
EP1135534A1 EP99973308A EP99973308A EP1135534A1 EP 1135534 A1 EP1135534 A1 EP 1135534A1 EP 99973308 A EP99973308 A EP 99973308A EP 99973308 A EP99973308 A EP 99973308A EP 1135534 A1 EP1135534 A1 EP 1135534A1
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EP
European Patent Office
Prior art keywords
factor
gene
ofthe
exon
embl accession
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Withdrawn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
EP99973308A
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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 UK Ltd
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AstraZeneca UK Ltd
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Filing date
Publication date
Application filed by AstraZeneca UK Ltd filed Critical AstraZeneca UK Ltd
Publication of EP1135534A1 publication Critical patent/EP1135534A1/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Withdrawn legal-status Critical Current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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 Factor X gene.
  • the invention also relates to methods and materials for analysing allelic variation in the Factor X gene, and to the use of Factor X polymorphism in the diagnosis and treatment of Factor X and/or Factor Xa-mediated diseases, such as thrombotic diseases.
  • Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation.
  • the protease known as thrombin is the final protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin.
  • Factor Xa is produced by cleavage ofthe zymogen precursor Factor X, by activated factor VII.
  • DNN sequence may not lead to Factor X deficiency but may increase the probability of pathological conditions or affect drug response or may be genetically linked to other polymo ⁇ hisms which do so.
  • the present invention is based on the discovery of two single nucleotide polymo ⁇ hisms (SNPs) in the coding sequence ofthe human Factor X gene.
  • a method for the diagnosis of a single nucleotide polymo ⁇ hism in a Factor X gene in a human comprises determining the sequence ofthe nucleic acid ofthe human at position 41 in exon 5 ofthe Factor X gene as defined by the position in EMBL ACCESSION NO. L00394, and/or at position 57 in exon 7 ofthe Factor X gene as defined by the position in EMBL ACCESSION NO. L00396 and determining the status ofthe human by reference to polymo ⁇ hism in the Factor X gene.
  • a method for the diagnosis of a single nucleotide polymo ⁇ hism in a Factor X gene in a human comprises determining the sequence ofthe nucleic acid ofthe human at position 41 in exon 5 ofthe Factor X gene as defined by the position in EMBL
  • the term human includes both a human having or suspected of having a Factor X- 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.
  • the method for diagnosis described herein is one in which the single nucleotide polymo ⁇ hism at exon 5 position 41 is presence of C and or T.
  • the method for diagnosis described herein is one in which the single nucleotide polymo ⁇ hism at exon 7 position 57 is presence of C and/or T.
  • Cargill et al have confirmed the presence of a single nucleotide polymo ⁇ hism in human Factor X at exon 5 position 41 and/or at exon 7 position 57 (Cargill et al., Nature Genetics, 22, 231-239, 1999).
  • 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 Factor X- and/or Factor Xa-mediated disease comprises: i) obtaining sample nucleic acid from an individual, ii) detecting the presence or absence of a variant nucleotide at position 41 in exon 5 ofthe
  • Allelic variation at exon 5 position 41 consists of a single base substitution from C (the published base), preferably to T.
  • Allelic variation at exon 7 position 57 consists of a single base substitution from C (the published base), preferably to T.
  • the status ofthe individual may be determined by reference to allelic variation at any one or both positions optionally in combination with any other polymo ⁇ hism that is or becomes known.
  • test sample of nucleic acid is conveniently 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 be a nucleic acid sequence corresponding to the sequence in the test sample, that is to say that all or a part ofthe 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 the 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 ofthe invention are used to assess the efficacy of therapeutic compounds in the treatment of Factor X and/or Factor Xa-mediated diseases, such as thrombotic diseases.
  • Assays for example reporter-based assays, may be devised to detect whether one or more ofthe above polymo ⁇ hisms affect transcription levels and/or message stability.
  • allelic variants ofthe Factor X gene may therefore exhibit differences in their ability to regulate protein biosynthesis under different physiological conditions and will 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 ofthe invention may be useful both to predict the clinical response to such agents and to determine therapeutic dose.
  • the diagnostic methods ofthe invention are used to assess the predisposition of an individual to diseases mediated by Factor X and/or Factor Xa. This may be particularly relevant in the development of thrombotic disease and other diseases which are modulated by Factor X and/or Factor Xa.
  • 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 ofthe invention are used in the development of new drug therapies which selectively target one or more allelic variants ofthe Factor X gene. Identification of a link between a particular allelic variant and predisposition to disease development or response to drag 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.
  • nucleic acid comprising any one ofthe following polymo ⁇ hisms: the nucleic acid of EMBL ACCESSION No. L00394 with T at position 41 as defined by the position in EMBL ACCESSION No. L00394; 5 the nucleic acid of EMBL ACCESSION No.
  • Fragments are at least 17 bases, more preferably at least 20 bases, more preferably at least
  • Novel sequence disclosed herein may be used in another embodiment ofthe invention to regulate expression ofthe gene in cells by the use of antisense constructs.
  • an example antisense expression construct can be readily constructed for instance using the
  • Transcripts are expected to inhibit translation of the gene in cells transfected with this type construct.
  • Antisense transcripts are effective for inhibiting translation ofthe 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 mRNA disclosed herein
  • the sequence ofthe ohgonucleotide having the desired activity can be identified. 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 may be DNA, stable derivatives of DNA such as phosphorothioates or methylphosphonates, RNA, stable derivatives of RNA such as 2'-O- alkylRNA, or other ohgonucleotide 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 Factor X gene polymo ⁇ hism at position 41 in exon 5 ofthe Factor X gene as defined by the positions in EMBL ACCESSION NO. L00394, and/or at position 57 in exon 7 in the Factor X gene as defined by the positions in EMBL ACCESSION NO. L00396.
  • 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 ofthe 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 ofthe remaining nucleotides may be varied without significantly affecting the properties ofthe 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
  • primer(s) may be labelled to facilitate detection.
  • an allele-specific ohgonucleotide probe capable of detecting a Factor X gene polymo ⁇ hism at position 41 in exon 5 ofthe Factor X gene as defined by the positions in EMBL ACCESSION NO. L00394, and/or at position 57 in exon 7 in the Factor X gene as defined by the positions in EMBL
  • the allele-specific ohgonucleotide probe is preferably 17- 50 nucleotides, more preferably about 17-35 nucleotides, more preferably about 17-30 nucleotides.
  • the design of such 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.
  • probes will comprise base sequences entirely complementary to the corresponding wild type or variant locus in the gene.
  • one or more mismatches may be introduced, provided that the discriminatory power ofthe ohgonucleotide probe is not unduly affected.
  • the probes ofthe invention may carry one or more labels to facilitate detection.
  • a diagnostic kit comprising an allele specific ohgonucleotide probe ofthe invention and/or an allele-specific primer of the invention.
  • kits may comprise appropriate packaging and instructions for use in the methods ofthe invention.
  • Such kits may further comprise appropriate buffer(s) 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 ⁇ hism at exon 7 position 57 because of its informative frequency (see below).
  • a method of treating a human in need of treatment with a Factor Xa ligand antagonist drag comprises: i) diagnosis of a single nucleotide polymo ⁇ hism in Factor X gene in the human, which diagnosis comprises determining the sequence ofthe nucleic acid at position 41 in exon 5 ofthe Factor X gene as defined by the positions in EMBL ACCESSION NO. L00394, and/or at position 57 in exon 7 in the Factor X gene as defined by the positions in EMBL
  • Factor Xa ligand antagonist drag includes drags acting at Factor Xa and/or Factor X but the former is preferred.
  • Factor Xa ligand antagonist drags possess activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro-vascular disease.
  • medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or on the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina).
  • myocardial infarction the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes
  • Preferably determination ofthe status ofthe human is clinically useful.
  • clinical usefulness include deciding which antagonist drug or drags to administer and/or in deciding on the effective amount ofthe drag or drags.
  • Inhibitors of Factor Xa have been disclosed in the following publications: European patent application EP 540051 A, Daiichi; WO98/21188, Zeneca Ltd and WO96/10022, Zeneca Ltd.
  • According to another aspect ofthe present invention there is provided use of a Factor Xa ligand antagonist drug in preparation of a medicament for treating a Factor Xa and/or Factor
  • a pharmaceutical pack comprising a Factor Xa- ligand antagonist drag and instructions for administration ofthe drag to humans diagnostically tested for a single nucleotide polymo ⁇ hism at position 41 in exon 5 ofthe Factor X gene as defined by the positions in EMBL ACCESSION NO. L00394, and/or at position 57 in exon 7 in the Factor X gene as defined by the positions in EMBL ACCESSION NO. L00396.
  • a computer readable medium comprising at least one novel polynucleotide sequence ofthe invention stored on the medium.
  • the computer readable medium may be used, for example, in homology searching, mapping, haplotyping, genotyping or pharmacogenetic analysis or any other bioinformatic analysis.
  • the reader is referred to Bioinformatics, A practical guide to the analysis of genes and proteins, Edited by A D Baxevanis & B F F Ouellette, John Wiley & Sons, 1988.
  • Any computer readable medium may be used, for example, compact disk, tape, floppy disk, hard drive or computer chips.
  • the polynucleotide sequences ofthe 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 drags. 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 ofthe art searching tools such as "GCC". Thus, the polynucleotide sequences ofthe 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 ofthe invention' covers any detectable chemical or physical characteristic of a polynucleotide ofthe 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 a more polynucleotide sequences ofthe 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 ofthe invention, a polynucleotide consisting of a polynucleotide ofthe invention, a polynucleotide which comprises part of a polynucleotide ofthe invention, which part includes at least one ofthe polymo ⁇ hisms ofthe invention, a set of polynucleotide sequences wherein the set includes at least one polynucleotide sequence ofthe invention, a data set comprising or consisting of a polynucleotide sequence ofthe invention or a part thereof comprising at least one ofthe 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 ofthe 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 available from Perkin-Elmer Cetus, is used as the source of thermostable
  • Electropherograms were obtained in a standard manner: data was collected by ABI377 data collection software and the wave form generated by ABI Prism sequencing analysis
  • DNA Preparation DNA was prepared from frozen blood samples collected in EDTA following protocol I
  • the thawed blood was diluted in an equal volume of standard saline citrate instead of phosphate buffered saline to remove lysed red blood cells. Samples were extracted with phenol, then phenol/chloroform and then chloroform rather than with three phenol extractions. The DNA was dissolved in deionised water.
  • Exons 5 and 7 were amplified from genomic DNA by PCR. Templates were prepared using the ohgonucleotide primers described below.
  • Exon 5 was amplified in a two step PCR reaction with an annealing temperature of 68° and denaturation temperature of 94°.
  • Exon 7 was amplified in a three step PCR reaction with an annealing temperature of 64°, extension temperature of 72° and denaturation temperature of 94°. Each step was 1 minute. Both reactions were carried out in l.OmM MgCl 2 buffer.
  • genomic DNA For analysis generally 50 ng of genomic DNA was used in each reaction and subjected to 35 cycles of PCR.
  • Forward oligos were modified by the addition of Ml 3 forward sequence to the 5' end for use in dye-primer sequencing.
  • 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. 4.25 % Acrylamide gels were run on an automated sequencer (ABI 377, Applied Bio systems).
  • Standard methodology can be used to detect the polymo ⁇ hism at position 41 (as defined by the position in EMBL ACCESSION NO L00394) and the polymo ⁇ hism at position 57 (as defined by the position in EMBL ACCESSION NO. L00396) based on the materials set out 15 below using a cDNA template.
  • T at position 41 generates an engineered Nco I site in the diagnostic fragment 17-156 described above.
  • T at 57 generates an engineered Spe I site in the diagnostic fragment 1-81 as described above.

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Abstract

L'invention se rapporte à des polymorphismes dans le gène du facteur X humain. Elle concerne en particulier la découverte de deux polymorphismes nucléotidiques simples dans la séquence de codage du gène du facteur X humain. Elle concerne également des techniques et des matériaux permettant d'analyser la variation allélique dans ledit gène, ainsi que l'utilisation dudit polymorphisme dans le diagnostic et le traitement de maladies induites par le facteur X et/ou le facteur XA, telles que des affections thrombotiques.
EP99973308A 1998-12-05 1999-11-30 Utilisation du polymorphisme du facteur x dans le diagnostic et le traitement d'affections induites par le facteur x et/ou xa Withdrawn EP1135534A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9826747.9A GB9826747D0 (en) 1998-12-05 1998-12-05 Chemical compounds
GB9826747 1998-12-05
PCT/GB1999/003973 WO2000034515A1 (fr) 1998-12-05 1999-11-30 Utilisation du polymorphisme du facteur x dans le diagnostic et le traitement d'affections induites par le facteur x et/ou xa

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EP1135534A1 true EP1135534A1 (fr) 2001-09-26

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EP (1) EP1135534A1 (fr)
JP (1) JP2002531144A (fr)
AU (1) AU1396700A (fr)
GB (1) GB9826747D0 (fr)
WO (1) WO2000034515A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT405517B (de) * 1997-02-27 1999-09-27 Immuno Ag Faktor x-deletionsmutanten und analoge davon

Non-Patent Citations (1)

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Title
See references of WO0034515A1 *

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GB9826747D0 (en) 1999-01-27
AU1396700A (en) 2000-06-26
WO2000034515A1 (fr) 2000-06-15

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