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WO1999066069A1 - Marqueur genetique permettant de determiner le risque de mortalite d'un sujet presentant des predispositions a l'hypertension ou aux maladies cardio-vasculaires - Google Patents

Marqueur genetique permettant de determiner le risque de mortalite d'un sujet presentant des predispositions a l'hypertension ou aux maladies cardio-vasculaires Download PDF

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Publication number
WO1999066069A1
WO1999066069A1 PCT/AU1999/000475 AU9900475W WO9966069A1 WO 1999066069 A1 WO1999066069 A1 WO 1999066069A1 AU 9900475 W AU9900475 W AU 9900475W WO 9966069 A1 WO9966069 A1 WO 9966069A1
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WO
WIPO (PCT)
Prior art keywords
seq
nos2a
polymorphism
allele
individual
Prior art date
Application number
PCT/AU1999/000475
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English (en)
Inventor
Brian James Morris
Original Assignee
The University Of Sydney
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 The University Of Sydney filed Critical The University Of Sydney
Priority to AU45893/99A priority Critical patent/AU4589399A/en
Publication of WO1999066069A1 publication Critical patent/WO1999066069A1/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
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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

  • the present invention is particularly suitable for potential hypertensive individuals. Analysis of subjects having or predisposed to angina, a manifestation of cardiovascular disease, also had a bearing on the results obtained for hypertensive individuals. From the results obtained by the present inventors, it will be appreciated that the method according to the present invention would be suitable for screening or testing for survival rates in individuals having, or predisposed to, cardiovascular disease including, for example, coronary artery disease, stroke, myocardial infarction, and complications stemming from cardiovascular disease including kidney related problems and disease.
  • the association study involved hypertensives with a strong genetic background (two hypertensive parents). These have a greater likelihood of showing an existing association than for only one affected first degree relative or an unselected hypertensive group.
  • This group has, moreover, been the subject of a number of previous molecular genetic studies of hypertension, wherein ascertainment details have been described. In all there were 112 unrelated, age- and sex-matched, non-diabetic, treated Caucasian essential hypertensive patients and a control group of 164 normotensive subjects who also had parents who both had the same blood pressure status. Hypertensives with two affected parents represent —10% of all hypertensive patients. Characteristics of the groups are shown in Table 1. These studies had human ethical approval and all subjects gave informed consent.
  • a "hot-start" protocol was employed in which after initial denaturation at 94°C for 5 min, there were 10 cycles of 94, 65 and 72°C for 1 min each, followed by 15 cycles of 94, 60 and 72°C for 1 min each, and finally 20 cycles of 94, 58 and 72°C for 1 min each, finishing with a step at 72°C for 30 min.
  • CMV-pGL2 which was constructed on a pGl-2 backbone, was used as a positive control.
  • Transfection efficiency control, CMV-SEAP was constructed by cutting pIRES-EGFP (Clontech, Palo Alto, CA, USA) with Notl/Bgl ⁇ l and cloned into Notl/Bglll linearized pSEAP2-Basic (Clontech). All constructs were verified by restriction enzyme analysis and DNA sequencing.
  • ⁇ " values are for comparison of data for HT, or each age-group of HTs, with data for NT group
  • Genotype frequency is fixed from conception and should remain constant throughout life. Any deviation with age could indicate an effect on longevity.
  • data in Table 2(a) were re-analyzed after subdivision into age groups of ⁇ 50 years, 50-59 and greater than or equal to 60, as done previously to reveal a deleterious effect of the deletion allele of an ACE gene variant in the same group.
  • A549 cells 10.2 ⁇ 0.4 1.1 ⁇ 0.2 ⁇ 0.0001 220 ⁇ 24 Calu-6 cells 3.4 ⁇ 0.7 0.2 ⁇ 0.03 0.005 20 ⁇ 1.2
  • the promoter variant tested could affect NOS2A expression or be in linkage disequilibrium with (an) other variant(s) that confers altered promoter activity, mRNA stability, or is a sequence variant of iNOS having different enzymatic activity.
  • alteration in iNOS-mediated NO formation could affect death rate in at- risk individuals.
  • cytotoxic effects of elevated iNOS activity might be either beneficial, e.g., in reducing tumour growth, or harmful, e.g., in ⁇ -cell destruction and onset of NIDDM, atherosclerosis and coronary disease. Infections result in an iNOS response, which may be beneficial or deleterious, depending on the pathogen.
  • iNOS vasodilatory actions
  • the effects of iNOS therefore appear dichotomous.
  • Atherosclerosis is an exacerbatory factor, for which iNOS has both pathogenic and protective functions.
  • Both iNOS and ACE are elevated markedly in human coronary plaque macrophages. Higher iNOS levels in -/- patients could thus have a survival disadvantage.
  • Subjects with the + allele by experiencing greater severity of angina (i.e., chest pain) will be more likely to seek medical attention, get treatment and have greater compliance with treatment. Thus they are not only more likely to be treated for cardiovascular disease (severe hypertension exacerbates CAD), but any treatment will have a more effective outcome. The memory of pain will be more likely to ensure diet and lifestyle modifications needed to improve prognosis. Thus the + allele patients will be more likely to survive. In contrast, the -/- patients will not be getting as strong a warning signal in the form of chest paid, so their frequency of seeking medical attention and subsequent compliance with advice and treatment may occur at a lower relative rate. As a result will be more likely to die from a terminal event such as a heart attack.
  • a terminal event such as a heart attack.
  • Tumor necrosis factor- ⁇ is a stimulatory cytokine for iNOS expression and may produce insulin resistance by phosphorylating insulin receptor substrate 1 that then inhibits insulin receptor tyrosine kinase to attenuate insulin receptor signalling, reduce GLUT-4 in muscle and raise plasma free fatty acids.
  • the association between NOS2A genotype and glucose could be an indirect effect of central obesity, as represented here by waist/hip ratio.
  • NOS2A 5 '-flanking DNA of Caucasians.
  • the NOS2A promoter is complex. An enormous number of actual or potential transcription factor binding sites have been demonstrated, with sequences of functional significance extending as far as 8.3 kb upstream. Within the region of promoter DNA tested, a NF-kB site at -115 is particularly important, with disruption reducing promoter activity by 67% in A549 cells.
  • a binding site for the cyclic AMP response element binding protein (CREB), and members of the C/EBP family of transcription factors, has been found just upstream of the NF-kB site.
  • CREB cyclic AMP response element binding protein
  • a heterodimer of a C/EBP family member and CREB exerts a synergistic effect on the NF-kB-mediated expression of iNOS in rat cardiac myocytes in response to cytokine stimulation.
  • a binding site for Jun/Fos (collectively referred to as AP-1) has also been noted, as well as one for STAT family members.
  • AP-1 Jun/Fos
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE cDNA
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 4:

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne une technique d'examen d'un sujet présentant des prédispositions à l'hypertension ou autres maladies cardio-vasculaires, laquelle technique permet établir le taux de survie général du sujet. Ladite technique consiste à déterminer, chez ledit sujet, le génotype d'un polymorphisme au niveau du gène (NOS2A) du monoxyde d'azote synthétase inductible (iNOS), la présence d'un allèle du polymorphisme étant significative d'un taux de survie amélioré par rapport à un sujet atteint d'hypertension porteur d'un allèle du polymorphisme différent.
PCT/AU1999/000475 1998-06-12 1999-06-15 Marqueur genetique permettant de determiner le risque de mortalite d'un sujet presentant des predispositions a l'hypertension ou aux maladies cardio-vasculaires WO1999066069A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45893/99A AU4589399A (en) 1998-06-12 1999-06-15 Genetic marker for mortality risk of an individual predisposed to hypertension or cardiovascular disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP4095A AUPP409598A0 (en) 1998-06-12 1998-06-12 Genetic marker for hypertension survival potential
AUPP4095 1998-06-12

Publications (1)

Publication Number Publication Date
WO1999066069A1 true WO1999066069A1 (fr) 1999-12-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1999/000475 WO1999066069A1 (fr) 1998-06-12 1999-06-15 Marqueur genetique permettant de determiner le risque de mortalite d'un sujet presentant des predispositions a l'hypertension ou aux maladies cardio-vasculaires

Country Status (2)

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AU (1) AUPP409598A0 (fr)
WO (1) WO1999066069A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038130A1 (fr) * 1996-04-10 1997-10-16 Medical Research Council Analyse de l'adn

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038130A1 (fr) * 1996-04-10 1997-10-16 Medical Research Council Analyse de l'adn

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, (1994), 21, R.Y.L. ZEE et al., "Frequencies of Variants of Candidate Genes in Different Age Groups of Hypertensives", pages 925-930. *
HYPERTENSION, (April 1999), Volume 33, No. 4, C.L. GLENN, W.Y.S. WANG and B.J. MORRIS, "Different Frequencies of Inducible Nitric Oxide Synthase Genotypes in Older Hypertensives", pages 927-932. *

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AUPP409598A0 (en) 1998-07-09

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