EP1392854A2 - Puce a adn utilisee dans le diagnostic causal de l'hypertension - Google Patents

Puce a adn utilisee dans le diagnostic causal de l'hypertension

Info

Publication number
EP1392854A2
EP1392854A2 EP01985807A EP01985807A EP1392854A2 EP 1392854 A2 EP1392854 A2 EP 1392854A2 EP 01985807 A EP01985807 A EP 01985807A EP 01985807 A EP01985807 A EP 01985807A EP 1392854 A2 EP1392854 A2 EP 1392854A2
Authority
EP
European Patent Office
Prior art keywords
blood pressure
receptor
growth factor
protein
nucleic acids
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Withdrawn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
EP01985807A
Other languages
German (de)
English (en)
Inventor
Rudolf Wiesner
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Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1392854A2 publication Critical patent/EP1392854A2/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Withdrawn legal-status Critical Current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
    • 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
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a DNA chip for the causal diagnosis of high blood pressure (hypertension), which enables an early diagnosis and a highly effective therapy which is tailored to the respective patient and as free of side effects as possible.
  • the present invention further relates to a DNA chip for the development of new blood pressure-lowering pharmaceuticals and for the stratification of patients in the early phases of clinical testing of such new pharmaceuticals.
  • Hypertension can currently only be diagnosed symptomatically, routinely by simple measurement according to Riva-Rocci (arm cuff, stethoscope) or in intensive care blood-invasive via arterial catheter. This means that when diagnosed, the disease and possibly negative side effects have already been manifested.
  • the diagnosis of limit hypertension is also not unproblematic, since physiologically large fluctuations in blood pressure can already be observed (e.g. daily rhythm) and many other factors can vary blood pressure (e.g.
  • D ⁇ A chip technology is a very efficient method, among other things for the detection of DNA polymorphisms.
  • This detection with the aid of DNA chip technology is used by an already existing method for the causal diagnosis of high blood pressure, ie differences in the DNA sequence of genes between different individuals are detected, which code for proteins that are responsible for mechanisms regulating blood pressure.
  • this procedure has the disadvantage that only in a few cases is essential hypertension monogenic, most cases will be due to a combination of mutations, each of which has little predictive value.
  • Another disadvantage is that, for ethical reasons, DNA analysis with regard to the predisposition to a serious illness such as high blood pressure will not be possible. Nevertheless, it is urgently desirable to clarify with each patient which of the many possible blood pressure regulating mechanisms is disturbed and is therefore responsible for their individual high pressure.
  • the present invention is therefore based on the object of providing means for causally diagnosing high blood pressure. Another object of the present invention is to provide a method for the early detection of hypertension. Another object of the present invention is to provide a method for dividing hypertension patients into subclasses, e.g. also for the stratification of patients in the early phases of the clinical trial of new pharmaceuticals.
  • subclass means a group of patients with high blood pressure, the causal cause of the high blood pressure being due to a disruption of the same blood pressure regulating system. The patients in a subclass therefore react immediately to a blood pressure lowering drug.
  • blood pressure regulating systems used here denotes central nervous mechanisms or hormonal systems which are involved in the regulation of the contraction state of the smooth muscles of the blood vessels (vessel width) or in the absorption capacity of the renal epithelium. Disrupted blood pressure regulating systems are those that are causally responsible for high blood pressure.
  • hypertension means any type of stage I, II, III and IN hypertension.
  • hypertension Depending on age, there is usually already hypertension with a systolic value above 140 mm Hg and a diastolic value from 90 to 94 mm Hg.
  • Hypertension is usually also present when there is only an increase in the diastolic value, whereby the following classifications can be made: mild hypertension at 95 to 104 mm Hg, moderate hypertension at 105 to 114 mm Hg, severe hypertension at over 115 mm Hg. Switching genes on and off is the basis of all biological processes and also an extremely sensitive response to changes in external conditions. DNA chips will therefore revolutionize biomedicine and molecular biology in the next few years.
  • RNA With the extraction of the RNA from a biological sample, the action of labeled cDNA or the RNA itself on a DNA chip (hybridization) and its analysis, a large amount of information about the gene expression profile and thus about the state of the cells in the cell is available within a very short time biological sample possible under changed conditions.
  • the technology based on the hybridization of nucleic acids has the advantage of extremely high specificity, sensitivity and relatively easy feasibility, in contrast to, for example, the analysis of protein patterns.
  • One aspect of the present invention therefore consists in the provision of a DNA chip for the causal diagnosis of hypertension, comprising at least two different nucleic acids, each coding for a polypeptide, the polypeptides being involved in different blood pressure regulating systems, and the nucleic acids as an indicator for at least two disturbed blood pressure regulating systems are used, and optionally also include one or more nucleic acids coding for polypeptides that are expressed in each cell and are part of the basic equipment of a cell (so-called housekeeping genes) for normalizing the signals obtained.
  • a DNA chip is preferred, wherein one, two, three, four, five, six or more nucleic acids of at least two blood pressure regulating systems are contained. Also preferred is a DNA chip with at least one each Nucleic acid, coding for one polypeptide each, of three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeen blood pressure regulating systems.
  • nucleic acids used on the DNA chip code for peptides that are involved in biochemical processes that are particularly involved in one or more of the following blood pressure regulating systems or also in other blood pressure regulating systems to be discovered in the future:
  • the pituitary adiuretin (vasopressin) system The atrial natriuretic peptide system • The renal kallikrein-kinin system The NO (nitric oxide) system
  • the EDHF system endothelial derived hyperpolarization factor
  • the prostaglandin system The endothelin system • The PTHrP system (parathormone-related peptide)
  • the histamine system The serotonin system «The purinergic system • Local growth factors and / or • The calcium Smooth vascular muscle cell or heart household
  • the nucleic acid used on the DNA chip can be any nucleic acid that is known to encode a peptide that is involved in blood pressure regulating systems or that is expressed or expressed at an increased rate in hypertension.
  • nucleic acids selected from the following nucleic acids are used for the DNA chip according to the invention (the GenBank accession number is given in each case in the brackets):
  • a DNA chip according to the invention with the nucleic acids listed below is particularly preferred, the nucleic acids encoding polypeptides which are involved in the respectively mentioned blood pressure regulating systems or which are differentially regulated in the event of disorders of these systems: cytochrome P 450 CYP11-B1 (aldosterone synthase) and cytochrome P 450 CYP11-B2, involved in the aldosterone system, angiotensin LT receptor type I (AT 1), angiotensin converting enzyme (ACE), intercellular adhesion molecule (ICAM-I), vascular cell adhesion molecule (VCAM-I), vascular endothelial growth factor / permeability factor (VEGF), monocyte chemoattractant protein I (MCP I), plasminogen activator inhibitor (PAI - I), transforming growth factor ß and fibroblast growth factor (FGF-II), involved in the renin-angiotensin system, adrenergic receptor ßl ,
  • proteins involved in blood pressure regulating systems on the one hand means that the polypeptides are involved in biochemical processes in blood vessels, in the heart muscle or in the renal tubular epithelium, which lead to hypertension in the event of a malfunction.
  • it also means those proteins whose expression is down-regulated or up-regulated due to high blood pressure (surrogate marker. Therefore, in tissue samples from hypertensive patients (e.g. white blood cells, blood-rich tissue, heart muscle tissue, kidney tissue), the expression of genes can also be changed in their products do not causally cause high blood pressure, such genes can also be indicative of the blood pressure regulating systems that are disturbed in the respective patient.
  • the nucleic acids which may be used to normalize the signals on the DNA chip according to the invention can be those which are known to be expressed in every cell and are part of the basic equipment of the cells.
  • the genes that code for these nucleic acids are usually also referred to as housekeeping genes.
  • housekeeping genes An exemplary selection for such nucleic acids is given below: cellular ⁇ -actin, cyclophilin, glyceraldehyde phosphate dehydrogenase (GAPDH), glycero-3-phosphate dehydrogenase (GPDH), histones, phospholipase, ribosomal proteins, tubulin, Ubiquitin. If a tissue rich in blood vessels is used for diagnosis, smooth muscular housekeeping genes such as the caldesmon or the calponin can be used to standardize the signals.
  • the nucleic acid sequences of the nucleic acids used on the DNA chip can be taken from the generally accessible databases (e.g. GeneBank, EMBL) and selected according to the usual criteria. Preference is given to sequences which are unique, have no GC-rich regions, do not allow intramolecular hybridization and do not form loops.
  • a single-stranded nucleic acid is preferably applied to the DNA chip according to the invention. Both the sense and the antisense strand can be used. However, a double-stranded nucleic acid can also be applied to the DNA chip according to the invention. There is no upper or lower limit on the length of the nucleic acids, as long as the length is sufficient for a specific hybridization.
  • the nucleic acids can also be DNA, RNA or hybrid molecules.
  • nucleic acids The production of such nucleic acids is state of the art and it is possible to apply and immobilize oligonucleotides, PCR products, cloned DNA or cDNA fragments or cRNAs after in vitro transcription (natural or modified) using standard techniques.
  • sequence complementary to the cDNA when using cDNA from the biological sample
  • sequence complementary to the RNA when using RNA from the biological sample
  • the carrier on which the nucleic acids are applied can be any carrier which is usually used for DNA arrays or DNA chips.
  • the methods for applying and immobilizing the nucleic acids are also prior art and known to the person skilled in the art.
  • the DNA chip according to the invention can be used, for example, for the sensitive early detection of developing hypertension, even before hypertension manifests itself clinically.
  • the DNA chip can also be used to divide the patients into sub-nipples.
  • the genes on the DNA chip can be used to detect the blood pressure regulatory systems that are disrupted in the respective hypertension patients.
  • the patient subgroups can then be treated with individually suitable active ingredients or combinations of active ingredients, which are not only the symptom of high blood pressure eliminated, but also counteracts the causal cause of high blood pressure.
  • the DNA chip according to the invention can be used for the development of new blood pressure-lowering pharmaceuticals or for the stratification of patients in the early phases of clinical testing of such new pharmaceuticals.
  • One aspect of the present invention therefore relates to the use of the DNA chip according to the invention for the diagnosis of high blood pressure, also for early diagnosis, for dividing high blood pressure patients into subnibs with different causes that trigger high blood pressure and for monitoring the therapy of high blood pressure.
  • RNA can be isolated from these patient samples using standard techniques and used either as total RNA or after fractionation as PolyA + RNA.
  • the RNA can be rewritten into cDNA with the aid of reverse transcriptase and thereby provided with a label, for example with a fluorescent group or an isotope etc.
  • PCR products can also first be produced and labeled, which are then hybridized with the DNA chip.
  • the RNA can also be used directly or unlabeled for hybridization on the DNA chip.
  • the binding of sample nucleic acids with the target nucleic acids on the support is analyzed. This can be done by optical methods in the case of fluorescence labeling, by autoradiography or by any other method that is able to recognize a successful hybridization of sample nucleic acids with target nucleic acids.
  • the tissue removed from the patient can be used as a biopsy, e.g. from the blood vessel-rich mouth-nose area or from any other blood vessel-rich but relatively low-risk tissue, or from the heart muscle, e.g. as part of cardiac catheterization to determine contractility and cardiac output. Lymphocytes (white blood cells) can also be taken from the patient's blood.
  • the patients can be divided into subgroups based on their gene expression profile (gene activity: ON-OFF; high-low), that is, in sub-nipples in which one or more of the hormonal or central nervous pathways described above (blood pressure regulating systems) are disturbed.
  • gene expression profile gene expression profile
  • the genes for cytochrome P 450 CYP11-B1 (aldosterone synthase) and for cytochrome P 450 CYP11-B2 are activated in white blood cells.
  • these patients should be treated with an aldosterone antagonist, such as spirolactone.
  • angiotensin II receptor type 1, ATI
  • the expression of the angiotensin converting enzyme of the intercellular adhesion molecule (ICAM-I), the nascular adhesion molecule (NCAM-I), the nascular endothelial growth factor / permeability factor (VEGF), the monocyte chemoattractant protein (MCP I), the PAI-1, the transforming growth factor ß and of fibroblast growth factor (FGF-IJ) in blood vessels or the expression of brain natriuretic peptide (BNP) in the heart muscle is increased.
  • an angiotensin II receptor antagonist e.g. with irbesartan
  • ACE angiotensin converting enzyme
  • a stimulated sympathetic-adrenergic system sympathetic-adrenergic nervous system and the adrenergic system of the adrenal medulla
  • the expression of the G protein-coupled receptor kinase II in white blood cells on the other hand the expression of the adrenergic receptors (ßl and ß2) and the ß-adrenergic receptor kinase in blood vessels or the expression of omithine decarboxylase (ODC) in the heart muscle is increased.
  • ßl and ß2 adrenergic receptors
  • ODC omithine decarboxylase
  • eNOS endothelial NO synthase
  • ACE angiotensin converting enzyme
  • type I collagen type I collagen
  • a submucosal biopsy is taken from the mouth or the lower turbinate (tissue rich in blood vessels), from the heart or from white blood cells
  • Both the lower lip and the lower turbinate are suitable for biopsy removal, as they are easily accessible, spraying with a local anesthetic is sufficient for anesthesia, the tissue is very rich in arterioles and nenoles, but does not have any large vessels or nerves and the removal defects are not visible and heal quickly.
  • a biopsy of approximately 500 mg was taken from the free chamber wall with a punch in three patients as part of a left-heart catheterization to diagnose left ventricular function.
  • the tissue was immediately snap frozen in liquid nitrogen.
  • lymphocyte fraction 100 ml of blood were drawn from 15 patients and subfractionated in a conventional manner into erythrocytes, thrombocytes and lymphocytes (Lymphoprep, Nycomed, Pharma AS or by density gradient centrifugation on a Ficoll / Metrizoat gradient). The lymphocyte fraction was immediately processed further.
  • the total RNA was obtained from the tissue samples or the white blood cells using various extraction methods with the aid of commercially available “kits”. The yield was about 0.5 mg RNA per g heart muscle, 0.1 mg RNA per g submucosal tissue and about 0.1 mg RNA per lymphocyte preparation.
  • the RNA was examined with conventional methods (blots, hybridization with radioactive or non-radioactive labeled probes) with regard to the expression of the genes involved.
  • the cDNA samples (subject or reference) were each mixed in the same ratio and hybridized with oligonucleotide arrays or cDNA arrays, these were washed after hybridization and the fluorescence signals were evaluated with a DNA array reader.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Analytical Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une puce à ADN utilisée dans le diagnostic causal de l'hypertension (hypertonus), qui permet d'effectuer des diagnostics précoces et de mettre en oeuvre une thérapie de haute efficacité, adaptée à chaque patient et induisant le moins d'effets secondaires possible. L'invention concerne en outre une puce à ADN utilisée dans la mise au point de nouveaux médicaments hypotenseurs et pour la stratification de patients à des phases précoces du test clinique de tels médicaments.
EP01985807A 2000-12-29 2001-12-28 Puce a adn utilisee dans le diagnostic causal de l'hypertension Withdrawn EP1392854A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10065666 2000-12-29
DE10065666A DE10065666B4 (de) 2000-12-29 2000-12-29 DNA-Chip zur kausalen Diagnose von Bluthochdruck
PCT/DE2001/004960 WO2002053769A2 (fr) 2000-12-29 2001-12-28 Puce a adn utilisee dans le diagnostic causal de l'hypertension

Publications (1)

Publication Number Publication Date
EP1392854A2 true EP1392854A2 (fr) 2004-03-03

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ID=7669391

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01985807A Withdrawn EP1392854A2 (fr) 2000-12-29 2001-12-28 Puce a adn utilisee dans le diagnostic causal de l'hypertension

Country Status (4)

Country Link
US (1) US20040053239A1 (fr)
EP (1) EP1392854A2 (fr)
DE (1) DE10065666B4 (fr)
WO (1) WO2002053769A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2527323A1 (fr) * 2003-06-09 2004-12-16 Decode Genetics Ehf. Methodes de prevision de la sensibilite a des medicaments chez des patients souffrant d'hypertension
US20060018519A1 (en) * 2004-07-16 2006-01-26 Cross Match Technologies, Inc. Hand-held personal identification device with distributed control system
DE102008063290A1 (de) * 2008-12-30 2010-07-08 Ernst-Moritz-Arndt-Universität Nutzung von Thrombozytenproteinen zur Überwachung der Therapie von Bluthochdruckerkrankungen

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987002709A1 (fr) * 1985-10-24 1987-05-07 Biotechnology Research Partners, Ltd. Teste sanguin pour diagnostiquer une hypertension
WO1988008457A1 (fr) * 1987-04-30 1988-11-03 Biotechnology Research Partners, Ltd. Tests sanguins relatifs a l'hypertension utiles a titre de marqueurs genetiques
WO1998053103A1 (fr) * 1997-05-21 1998-11-26 Clontech Laboratories, Inc. Ensembles d'acide nucleique
AU6116399A (en) * 1998-10-14 2000-05-01 Pyrosequencing Ab Genes for assessing cardiovascular status and compositions for use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02053769A2 *

Also Published As

Publication number Publication date
DE10065666A1 (de) 2002-07-11
DE10065666B4 (de) 2008-10-02
WO2002053769A2 (fr) 2002-07-11
US20040053239A1 (en) 2004-03-18
WO2002053769A3 (fr) 2003-12-04

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