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WO1988008457A1 - Tests sanguins relatifs a l'hypertension utiles a titre de marqueurs genetiques - Google Patents

Tests sanguins relatifs a l'hypertension utiles a titre de marqueurs genetiques Download PDF

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Publication number
WO1988008457A1
WO1988008457A1 PCT/US1988/001402 US8801402W WO8808457A1 WO 1988008457 A1 WO1988008457 A1 WO 1988008457A1 US 8801402 W US8801402 W US 8801402W WO 8808457 A1 WO8808457 A1 WO 8808457A1
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Prior art keywords
polymorphism
renin
probe
gene
polymorphisms
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Philippe M. Frossard
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Biotechnology Research Partners Ltd
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Biotechnology Research Partners Ltd
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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
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • 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 invention relates to the use of genetic polymorphism detection to diagnose presence or probabil ⁇ ity of disease. More particularly, it relates to the use of these techniques to assess the risk of, and to follow familial patterns of, the incidence of high renin hypertension, hypertension of other types, and variable, plasma renin activity. Other correlations are also dis ⁇ closed, and the pattern of genetic polymorphisms is also a tool for genetic identification.
  • Hypertension is one of the most important pub- lie health problems in developed countries. It affects more than 60 million people in the United States alone. The disease, which is defined as an elevation of arte ⁇ rial blood pressure, results in secondary organ damage and a reduced..1ifespan. A significant form of hypertension is associ ⁇ ated with; art array-of symptomology indicating the involvement of the aldosterone/renin/angiotensin system. There is a series of metabolic interactions that are believed to characterize this form of hypertension. The measured hypertension itself, the increased blood pres ⁇ sure measured in the arterial system, has, as its imme ⁇ diate cause, vasoconstriction effected by angiotensin II.
  • Angiotensin II is the product of metabolically inactive precursors which are activated by renin. Renin is secreted by the kidneys, and also causes the release of aldosterone from the renal cortex. The levels of excretion of various ions and compounds are also affected. Whatever their precise interrelationship, indicators related to this mechanism are known to be associated with the condition designated high renin hypertension. These indicators include, in addition to high blood pressure itself, elevated levels of plasma renin activity (PRA) , elevated levels of urinary aldosterone (UA) , diminished levels of urinary sodium ion (U(Na)V), and increased levels of urinary potassium (U(K)V). Elevated PRA is always associated with the disease; the remaining parameters appear more secondary. There are, of course, other types of hyperten ⁇ sion which do- not follow this pattern. Also, some of these indicators, when correlated independently, are diagnostic of other conditions.
  • PRA plasma renin activity
  • UUA urinary aldosterone
  • a technique that inherently offers the advan ⁇ tages of early detection, if its results can be effec ⁇ tively correlated with the disorder to be assessed, is genetic analysis. Since the genomic characteristics of an individual are basically determined, it is assumed, at conception, genetic aberrations which are indicia of later metabolic disorders are an ideal early diagnosis tool. Genetic testing can be routinely conducted using present methodology, as early as the seventh week of fetal life. In adults and children, it can be accom ⁇ plished using a small blood sample. Over the last ten years, the availability of restriction enzymes and DNA probing techniques has made possible the use of "restriction fragment length polymorphisms" (RFLPs) in such diagnosis.
  • RFLPs restriction fragment length polymorphisms
  • The-present * invention uses the L/M/U insertion upstream of the insulin gene as a test site for the occurrence of polymorphisms associated with high renin hypertension.
  • Canadian patent 1,186,991 discloses correlations with atherosclerosis for the presence of the U insertion and with non-insulin-dependent diabetes for the absence of the two insertions.
  • the gene encoding renin also shows useful polymorphisms. Appropriate DNAs encoding human renin ' are also available. Human renin cDNA and genomic DNA have been described by Hardmann, J.A., et al, DNA (1984) 2:457; Imai, T. , et al, Proc Natl Acad Sci (USA) (1983) ___: 7405; Hobart, P.M., et al, Proc Natl Acad Sci (USA) (1984) 8_1: 5026; Miyazaki, H. , et al, Proc Natl Acad Sci (USA) (1984) 8_1: 5999. Means for detection of the L/M/U insertion in the insulin region are known in the art.
  • the present invention provides a number of polymorphic sites,.in the above-mentioned gene regions which are useful both alone and in combination in pre ⁇ dicting the incidence of high renin hypertension and of other forms of hypertension of variable PRA and of other metabolic parameters by means of a simple blood test.
  • the pattern of the polymorphisms in an individual also provides a tool for characterizing the subject and for establishing familial relationships.
  • the invention provides identification of a polymorphism which is predictive of the subsequent development of high renin hypertension, and of additional polymorphisms which are predictive for hyper-tension per se, variable PRA, and other metabolic indications, and which contribute to the genetic iden ⁇ tity of individuals and families.
  • the invention is directed to a method of predicting the likelihood of development of high renin hypertension in an individual, which method comprises detecting the presence or absence of the U-allele insertion of the insulin gene.
  • the -invention to a location in the DNA of the genome which is different in various individuals.
  • a majority of alleles present in a population of individuals will be of one form, and a minority of the alleles present in the population will be of another.
  • the form found in the minority of alleles will be referred to as "the polymorphism", using the form pre- sent in the majority as a reference. This is in analogy to the manner in which, for example, the term “isotope” is often used.vto.refer to the less common nuclides of an element. )
  • Some forms of hypertension per se, associated with high systolic or diastolic blood pressure or both, - are correlated with the presence of one or more of the Bglll polymorphism of the renin gene, the TaqI polymorphism of the renin gene, the HindiII polymorphism of the renin gene (which has a negative correlation with high diastolic blood pressure), the Bgll polymorphism of the ANP gene (which correlates with high systolic blood pressure), and the Bglll polymorphism of the ANP gene (which correlates with both) .
  • Ah apoAI deletion and a PvuII polymorphism in the apoCIII gene also show correlations.
  • Estrogen receptor gene polymorphisms may show correlations as well.
  • correlations include correlation with variable PRA and urinary aldosterone levels for the Bglll and TaqI renin polymorphisms, with urinary aldosterone levels for the Bgll ANP polymorphism, and with urinary sodium and potassium levels for the Bgll ANP and HindiII renin polymorphisms, as well as U(Cr)V for several of the above.
  • the polymorphisms of the estrogen receptor gene are expected to correlate with the development of osteoporosis.
  • the invention relates to identification of individuals or familial patterns using polymorphisms.
  • the invention relates to identification of individuals or familial patterns, and/or establishing the risk of hypertension in subjects using polymorphisms of the renin, ANP, apoAI/CIII gene complex, estrogen receptor gene or the Na,K-ATPase genes.
  • Figure 1 shows the DNA sequence of the renin 5' and renin 3' probes.
  • Figure 2 shows typical results in assessing the presence or absence of the Bgll polymorphism of the renin gene.
  • DNA is extracted from the somatic cells of the individual to be tested, for example from leukocytes, placental cells, cultured fibroblasts, or, in the case of fetal individuals, from cells of the amniotic fluid.
  • the test material comprises leukocytes-from a.-blood sample -25-50 ml blood yields 200-400 ⁇ g DNA.
  • the high molecular weight DNA fraction is separated, and-subjected to treatment with a particu- lar, selected restriction enzyme, such as, for example, EcoRI, Ba HI, MstI, XmnI, and the like.
  • Transfer to nitrocellulose or other support and probing by prehybridization with nonspecific DNA followed by hybridization with labeled probe are also standard procedures disclosed, for example, in the fore- going references and by Southern, E., (supra).
  • the sec ⁇ tion of the genome which is fingerprinted or otherwise subject to study using the results is, of course, depen ⁇ dent on the nature of the probe.
  • the fragment pattern obtained is diagnostic for a particular polymorphism if the probe selected is complementary to a DNA sequence sufficiently proximal to the polymorphism on the genome that it is not severed from the polymorphism by the restriction cleavage, and has a low probability of being segregated from the polymorphism by crossing over. Acceptable distance lim ⁇ its between the region of probe complementarity and the polymorphism are therefore arbitrary. Generally, probes which hybridize to DNA sequences within 10 kb upstream or downstream of the polymorphism give acceptable results. Occasionally, the pattern of restriction enzyme cleavage may place a distal probe hybridization site on a fragment irrelevant to the polymorphism. The closer the probe to the polymorphism, the greater the range of usable restriction enzymes.
  • a probe which is a "substantial equivalent" to a specified probe is one which hybridizes to the same fragment length in digests of DNA from individuals with a particular polymorphism when the same restriction enzyme is used.
  • the renin 5' and renin 3' probes are equivalent. For Hindlll digestion, they are not.
  • cDNA probes can be labeled by nick translation using [ 32 P] dCTP and ⁇ [ 32 P] dGTP. Oligomer probes are labeled by kinasing. cDNA probes which are comple- mentary only to the exon regions of the gene and which span over intron regions are workable in the method of the invention. Other labeling methods can also be used so as to utilize a variety of detection techniques. For example, the cDNA can be extended with a polyA tail and hybridized for detection to a fluorescent material or an enzyme conjugated to polyT.
  • kits are commer ⁇ cially available- hich employ this general principle.
  • fluorescence or enzyme activity may be used as the ultimate means for sensing the hybridization.
  • antibod ⁇ ies which bind selectively to double-stranded DNA, as opposed to singlestranded forms.
  • the hybridization can also be detected by use of these anti ⁇ bodies and any desired labeling method.
  • Renin is a critical protein in the angiotensin system, which controls vasoconstriction/dilation and is, of course, central to high renin hypertension. (Unex ⁇ pectedly, while correlation to hypertension is shown for some renin gene modifications, and with variable PRA, there seems to be no correlation with high renin hyper ⁇ tension.
  • angiotensin-II an octapeptide which acts directly to cons.trict vascular smooth muscle and to induce the release aldosterone from the adrenal cortex.
  • the level of angiotensin-II is determined by the balance between its rate of inactivation by angiotensinases and its rate of formation in a two step process from angiotensinogen.
  • the rate-limiting step in the conversion of angiotensinogen to angiotensin-II is the step catalyzed by renin—the conversion of angiotensinogen to angiotensin-I.
  • the second step is mediated by a "con ⁇ verting enzyme''.
  • -Renin is secreted in vivo by the juxtaglomerular cells of the kidney, and is synthesized as a prorenin precursor, which is then processed to give the active renin form.
  • the involvement of renin in the regulation of *' -blood,pressure has been established by the utility of inhibitors of renin secretion or direct renin inhibitors.
  • Correlations have also been found, as further described below, between hypertension in general, and certain polymorphisms of the ANP, apoAI and apoCIII genes.
  • polymorphisms of the estrogen receptor gene are expected to show correlations and Na,K-ATPase genes are expected to show correlations.
  • Steroid metabolism is known to influence blood pressure, Na,K-ATPase is a known Na + pump; abnormal Na + excretion is often associated with hypertension.
  • the insulin gene has no apparent relationship to high renin levels or to hypertension, but recent results, reported by Christlich, A.R. , et al in Diabetes and Hypertension (1985) 2(Suppl 2):II-54 to 11-57, sug ⁇ gest that there is a causal relationship between the level of circulating insulin and diastolic blood pres- sure. These authors further suggest that because insu ⁇ lin increases the renal tubular reabsorption of sodium, it contributes to the hypertension. This result is also consistent with the finding of reduced levels of excre ⁇ tion for sodium in high renin hypertension. On the other hand, the L/M/U insertion upstream of the insulin gene, seems to have no effect on insulin production, and thus the correlation found herein would not have been predicted from any relationship of insulin levels to hypertension.
  • the findings are interpreted in terms of the relative risk of persons having the polymorphism to show the disease, compared to those hav ⁇ ing an absence of the polymorphism.
  • These "relative incidence” values are calculated according to Wolf, B., Ann Hum Genet (1955) ⁇ 9:251.
  • the rela ⁇ tive incidence is calculated as equal to: PP x CN PN x CP
  • PP is the number of hypertensive patients hav ⁇ ing the polymorphism
  • PN is the number of hypertensive patients not having the polymorphism
  • CP is the number of controls having the polymorphism
  • CN is the number of controls not having the polymorphism.
  • a “p” value is also calculated to show the degree of confidence in the Rp correlation coeffi ⁇ cient, according to the standard student "t” test; val ⁇ ues of "p" less than 0.05 indicate a 95% confidence level.
  • High renin hypertension is characterized by a pattern of parameters, including high renin concentra ⁇ tion in the plasma and the high blood pressure per se. Therefore, in exploring correlations with regard to high renin hypertension, not only blood pressure, but other parameters associated with high renin hypertension, were measured and correlated statistically as above described with the polymorphism in question. Of particular impor ⁇ tance, of course, is correlation with blood pressure per se and with high levels of plasma renin activity (PRA).
  • the renin 3' probe contains the remaining mature protein codons. It will be recalled that the nick translation method of labeling fragments the probe, and thus the presence of intron regions in the target gene does not undermine the effectiveness of the probes if this labeling method is used.
  • the essential fea ⁇ tures of the invention as it relates to detection of .a particular polymorphism are (1) the selection of enzyme, and (2) the selection of probe.
  • restriction enzyme a number of substantially equivalent probes which are not segregated from the identified fragment by this restriction cleavage are usable.
  • other restriction enzymes may be used in conjunction with a probe which hybridizes in particu ⁇ larly close proximity to the polymorphism.
  • Leukocytes were obtained from freshly drawn blood collected from each of the human subjects, and high molecular weight genomic DNA was isolated by the procedure of Law, D. J., et al, Gene (1984) 28:153-158.
  • the filters were rinsed in 2 x SSC (Ix SSC is 0.15 M NaCl, 0.015 M sodium citrate pH, 7.4) and baked for 2 hr at 80°C .in vacuo and then were prehybridized for 5 hr in plastic bags using 0.3 ml/cirr' of a solution containing 5x SSPE (Ix SSPE is 10 mM Na phosphate pH 7.4, 0.18 M NaCl and 1 mM EDTA) containing 5x Denhardt's solution (1 x Denhardt's contains 0.2 mg/ml each of
  • the probes were labeled to a specific activity of 2.0-5.0 x 10 8 cpm/ ⁇ g by nick-translation, using the BRL nicktranslation kit (Bethesda Research Laboratories) under recommended conditions with ⁇ [ 32 P] dCTP (800 Ci/mM; Amersham Corporation) in the presence of unla- beled dATP and dTTP.
  • the probes were denatured just before the hybridization step by incubation for 5 min in a boiling water bath, followed by rapid cooling in ice water.
  • a cDNA library was. prepared from oligo-dT-primed polyA + RNA, purified from the kidney of- a human accident victim.
  • the cDNA library was constructed in the bacteriophage vector ⁇ gtlO and probed with appropriate fragments of Charon-4 human renin genomic clones which had been obtained from a human genomic library by probing with mouse submaxillary gland renin cDNA fragments.
  • the ⁇ gtlO library was prepared by standard procedures which include obtaining double-stranded cDNA from the mRNA, blunt-ending the cDNA with DNA polymerasel (Klenow) , adding commercially available EcoRI linkers, cleaving with EcoRI, and ligating the fragments into EcoRI-digested ⁇ gtlO vectors.
  • Two positively responding cDNA clones together, when sequenced using the dideoxy method of Sanger (supra) were shown to contain the entire renin-encoding sequence and 3' untranslated region except for a missing 7 base pairs at the 5' end of the signal sequence.
  • the two clones include 1211 bp of coding region, followed by the entire 3' 198 bp untranslated region, followed, in turn, by a polyA tail.
  • the assignment of the sequence to the appropriate preprorenin codons and reading frame was made by compar ⁇ ison to the published Imai et al (supra) sequence. Two cloned fragments result because of the EcoRI site shown in position 692 in Figure 1.
  • Frequency in this case as in all others is determined as follows: Each individual has two copies' of each chromosome; therefore, at any locus or position on the chromosome each person has two "alleles". If these two alleles are identical,- the individual is "homozygous" at this locus; if the two alleles are dif ⁇ ferent, he is heterozygous at this locus. Genetic vari ⁇ ation between populations can be quantified using the concept, of allele.. frequency, the proportion of .all. alleles in a population at the locus that are a particu ⁇ lar allele. The frequency of any particular allele in a sample is therefore equal to twice the number of homozygotes for that allele plus the number of heterozygotes for that allele divided by two times the number of individuals in the sample.
  • Typical results are shown for the Bgll polymorphism in Figure 2.
  • Each lane of the autoradiogram shows the results for one individual probed with renin 5' probe.
  • Lanes 4, 7, 11 and 13 show individuals homozygous for 5 kb fragment
  • lanes 5, 6, 10, 12, 14, and 15 show individuals homozygous for the 9 kb fragment
  • lanes 1-3, 8 and 9 show the results for heterozygous .individuals.
  • Table 2 sets forth the correlation coeffi ⁇ cients, Rp, calculated as described above, with increases in the measured quantities, for the renin polymorphisms.
  • Polymorphisms in the ANP gene and in the apoAI/apoCIII complex were also shown to correlate with hypertension as measured by blood pressure, although not with the symptomology associated with high renin hyper- tension. Indeed, for these polymorphisms, there was no correlation with high renin levels in plasma. However, because blood pressure itself showed a positive correla ⁇ tion with these genetic characteristics, they have pre ⁇ dictive value with respect to hypertension in general.
  • the pat ⁇ tern of genetic polymorphisms for and individual can be useful in identification and in tracing familial rela ⁇ tionships, as well as providing a basis for ascertaining genetic patterns associated with other diseases.
  • the invention * also relates to methods to obtain a genetic pattern for a particular individual or for a family by assessment " of the presence or absence of one or more of these polymorp isms.

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Abstract

Des polymorphismes dans les régions de gènes d'insuline sont indicateurs d'hypertension rénine élevée chez l'homme; d'autres polymorphismes dans les régions rénines, ANP (peptide natriurétique atrial), réceptrices d'oestrogène, et apoAI/apoCIII sont indicateurs d'autres formes d'hypertension. Des sites polymorphiques récemment découverts dans ces gènes et dans des gènes de sous-unités d'beta ATPase sont utiles pour l'identification génétique.
PCT/US1988/001402 1987-04-30 1988-04-28 Tests sanguins relatifs a l'hypertension utiles a titre de marqueurs genetiques Ceased WO1988008457A1 (fr)

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US4443787A 1987-04-30 1987-04-30
US044,437 1987-04-30
US9334787A 1987-09-04 1987-09-04
US093,347 1987-09-04

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0580767A4 (fr) * 1991-04-19 1995-07-12 Univ Iowa State Res Found Inc Marqueurs genetiques de la taille de portees de porcs.
US5593833A (en) * 1992-07-31 1997-01-14 Garvan Institute Of Medical Research Assessment of allelic variation in vitamin D receptor correlated to bone density or turnover
WO1997027321A1 (fr) * 1996-01-25 1997-07-31 Universite Laval Marqueur du gene recepteur des oestrogenes pour la determination des predispositions a l'osteoporose
EP0955382A3 (fr) * 1998-05-07 2000-07-05 Affymetrix, Inc. (a California Corporation) Des polymorphismes associés à l'hypertension
WO2000022166A3 (fr) * 1998-10-14 2000-09-14 Pyrosequencing Ab Genes d'evaluation d'etat cardio-vasculaire et compositions d'utilisations associees
US6197505B1 (en) 1997-04-04 2001-03-06 Pyrosequencing Ab Methods for assessing cardiovascular status and compositions for use thereof
WO2002053769A3 (fr) * 2000-12-29 2003-12-04 Rudolf Wiesner Puce a adn utilisee dans le diagnostic causal de l'hypertension
WO2006082570A1 (fr) * 2005-02-02 2006-08-10 Royal College Of Surgeons In Ireland Pharmacogenomique d’agents de reduction de la pression arterielle
WO2006102177A3 (fr) * 2005-03-22 2007-05-10 Novartis Ag Bio-marqueurs pour l'evaluation de l'efficacite de l'aliskirene en tant qu'agent hypertensif
WO2008049953A1 (fr) 2006-10-23 2008-05-02 Neocodex, S.L. Méthode de pronostic et/ou de diagnostic in vitro de l'hypersensibilité aux oestrogènes ou à des substances ayant une activité oestrogénique

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AUPN058895A0 (en) * 1995-01-16 1995-02-09 Garvan Institute Of Medical Research Diagnostic method

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US4623619A (en) * 1982-03-03 1986-11-18 Nordisk Insulinlaboratorium Method for the determination of liability in human individuals to develop atherosclerosis

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Title
NATURE, Vol. 301, issued 1983, (Neptune, N.J. 07753), (S.K. KARATHANASIS et al.), "An Inherited Polymorphism in the Human Apolipoprotein A-1 Gene Locus...", pages 718-720, see pages 718, column 2, lines 1-26 of article. *
NUCLEIC ACIDS RESEARCH, Vol. 14, Number 7, issued 11 April 1986, (IRL Press LTD. Eynsham Oxford, England), (K. KAWAKAMI et al.), "Molecular Cloning and Sequence Analysis of Human Na, K-ATPase Beta Subunit", pages 2833-2844, see page 2835, last 4 lines-page 2837, first 4 lines. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Vol. 81, issued August 1984, (Washington D.C. 20418), (P.M. HOBART et al.), "Human Renin Gene: Structure and Sequence Analysis", pages 5026-5030, see abstract; page 5028, column 2, last 18 lines. *
THE LANCET, issued 26 February 1983, (London, WC2N GAD England). (A. REES et al.), "DNA Polymorphism Adjacent to Human Apolipoprotein A-1 Gene..", pages 444-446, see Summary; page 445, last line-page 446, column 1, line 21. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0580767A4 (fr) * 1991-04-19 1995-07-12 Univ Iowa State Res Found Inc Marqueurs genetiques de la taille de portees de porcs.
US5593833A (en) * 1992-07-31 1997-01-14 Garvan Institute Of Medical Research Assessment of allelic variation in vitamin D receptor correlated to bone density or turnover
WO1997027321A1 (fr) * 1996-01-25 1997-07-31 Universite Laval Marqueur du gene recepteur des oestrogenes pour la determination des predispositions a l'osteoporose
US5834200A (en) * 1996-01-25 1998-11-10 Universite Laval, Cite Universitaire Marker at the estrogen receptor gene for determination of osteoporosis predisposition
US6197505B1 (en) 1997-04-04 2001-03-06 Pyrosequencing Ab Methods for assessing cardiovascular status and compositions for use thereof
EP0955382A3 (fr) * 1998-05-07 2000-07-05 Affymetrix, Inc. (a California Corporation) Des polymorphismes associés à l'hypertension
US6525185B1 (en) 1998-05-07 2003-02-25 Affymetrix, Inc. Polymorphisms associated with hypertension
WO2000022166A3 (fr) * 1998-10-14 2000-09-14 Pyrosequencing Ab Genes d'evaluation d'etat cardio-vasculaire et compositions d'utilisations associees
WO2002053769A3 (fr) * 2000-12-29 2003-12-04 Rudolf Wiesner Puce a adn utilisee dans le diagnostic causal de l'hypertension
WO2006082570A1 (fr) * 2005-02-02 2006-08-10 Royal College Of Surgeons In Ireland Pharmacogenomique d’agents de reduction de la pression arterielle
US8304190B2 (en) 2005-02-02 2012-11-06 Royal College Of Surgeons In Ireland Pharmacogenomics of blood pressure lowering agents
WO2006102177A3 (fr) * 2005-03-22 2007-05-10 Novartis Ag Bio-marqueurs pour l'evaluation de l'efficacite de l'aliskirene en tant qu'agent hypertensif
WO2008049953A1 (fr) 2006-10-23 2008-05-02 Neocodex, S.L. Méthode de pronostic et/ou de diagnostic in vitro de l'hypersensibilité aux oestrogènes ou à des substances ayant une activité oestrogénique

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