WO2005093096A1 - Methode et materiel de detection du risque de presenter une hypertension - Google Patents

Methode et materiel de detection du risque de presenter une hypertension Download PDF

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WO2005093096A1
WO2005093096A1 PCT/ES2005/000164 ES2005000164W WO2005093096A1 WO 2005093096 A1 WO2005093096 A1 WO 2005093096A1 ES 2005000164 W ES2005000164 W ES 2005000164W WO 2005093096 A1 WO2005093096 A1 WO 2005093096A1
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polymorphism
sequence
seq
polypeptide
nucleotide sequence
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English (en)
Spanish (es)
Inventor
José Manuel FERNÁNDEZ FERNÁNDEZ
Marta TOMÁS MESTRES
Esther Vázquez Gómez
Mariano SENTÍ CLAPÉS
Jaime Marrugat De La Iglesia
Miguel Ángel VALVERDE DE CASTRO
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Universitat Pompeu Fabra UPF
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Universitat Pompeu Fabra UPF
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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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • This invention is related in general to the field of medicine and specifically to diagnosis.
  • it refers to methods and kits based on polymorphisms in a gene. These methods and kits facilitate the determination of the risk of hypertension.
  • High blood pressure, or hypertension is not only a disease but also a risk factor for cardiac, cerebral and renal pathology. It is considered that 25-40% of the adult population has hypertension. In more than 90% of cases the hypertension is of unknown cause, that is, the so-called "essential hypertension”. Therefore, the provision of predictors of hypertension is of utmost importance both for public health management and for the development of antihypertensive treatments.
  • the pressure inside the arteries depends on the resistance of the vessels (that is, the diameter of the blood vessels), which in turn is controlled by the contraction of smooth muscle cells from their walls (arterial tone).
  • the control of arterial tone depends on a calcium signal in vascular smooth muscle, which comes mainly from an entry of Ca 2+ through voltage-dependent channels and its release from intracellular deposits.
  • a key element in the control of vascular tone is the K + channel dependent on Ca 2+ and voltage (also known as the BK channel or MaxiK channel), which associates local increases in intracellular Ca 2+ with an increase in activity of the canal and vascular relaxation (cf. JH Jaggar et al., "Calcium sparks in smooth muscle", Am. J. Phvsiol. Cell Physiol. 2000, vol. 278, pp. C235-6).
  • the BK channel of the vascular smooth muscle is formed by an ⁇ subunit that conducts ions and a regulatory ⁇ i subunit.
  • KCNMB1 ⁇ i gene disruption
  • the present invention provides the first evidence of a direct involvement of the BK channel in the control of blood pressure in humans.
  • the inventors have found a single nucleotide substitution (G352A) in the third exon of the KCNMB1 gene. which corresponds to a mutation of a glutamic acid to a lysine at position 65 (E65K) of the protein.
  • G352A single nucleotide substitution
  • E65K lysine at position 65
  • the inventors have found a strong association between the genotypic frequency of the ⁇ -
  • the invention provides methods, compounds and kits for the diagnosis and prognosis of essential hypertension in humans.
  • the invention also provides compounds for the prophylactic or curative treatment of essential hypertension.
  • a first aspect of the present invention relates to a method of prognosis or diagnosis of essential hypertension in a human being, which comprises the detection of the presence or absence of a polymorphism in the KCNMB1 gene. in a separate sample of said human being, said polymorphism causing an amino acid substitution of E (glutamic acid) with a K (lysine) at position 65 of the corresponding encoded polypeptide.
  • polymorphism is a substitution. of a single nucleotide of the G at position 352 of the sequence of the KCNMB1 gene and, in a preferred embodiment, the G is replaced by an A.
  • the positions in the KCNMB1 gene (eg position 352) and in the corresponding encoded polypeptide (eg position 65), are given with reference to the access number U25138 of the GenBank. This reference corresponds to the mRNA of the beta subunit of the human BK channel.
  • the one-letter amino acid codes are used to indicate glutamic acid (E) and lysine (K).
  • the method of prognosis or diagnosis of the invention involves the analysis of the polymorphisms mentioned above in the KCNMB1 gene. This analysis is carried out with technologies well known to a person skilled in the art.
  • the presence or absence of the polymorphism is detected using one or more oligonucleotides that hybridize a nucleotide sequence comprising the polymorphism in the KCNMB1 gene or its complementary sequence.
  • the nucleotide sequence comprising the polymorphism is included within SEQ ID NO: 7.
  • the nucleotide sequence comprising the polymorphism is included within the range from position 294 to position 465 of the gene. KCNMB1.
  • the nucleotide sequence comprising the polymorphism has a length of at least 15 nucleotides.
  • the oligonucleotides have sequences selected from the group consisting of SEQ ID NO: 1-6 and their complementary sequences.
  • the invention provides oligonucleotides that hybridize a nucleotide sequence comprising the polymorphisms defined above or their complementary sequence.
  • the nucleotide sequence comprising the polymorphism is included within SEQ ID NO: 7.
  • the nucleotide sequence comprising the polymorphism has a length of at least 15 nucleotides.
  • the oligonucleotides have sequences selected from the group consisting of SEQ ID NO: 1-6 and their complementary sequences. Any method can be used in which one or more oligonucleotides hybridize to a sample of nucleic acid taken from the individual and the result is analyzed to determine the presence or absence of polymorphism.
  • oligonucleotides examples include polymerase chain reaction (PCR), single strand conformational polymorphism (SSCP) and direct sequencing Digestion with restriction enzymes is also useful for the purpose of the present invention.
  • This technique is based on amplifying a nucleotide sequence that comprises the site of the alleged polymorphism and using, or creating, a restriction site on the amplified product that depends on the presence or absence of the polymorphism.
  • Mnll and BseRI are suitable restriction enzymes.
  • the oligonucleotides can be labeled fluorescent, chemiluminescent or radioactively to act as probes and detect the nucleotide sequence comprising the polymorphism. These probes can be used, for example, in glass-based microarrays or in bead-based microarrays.
  • the invention provides probes for use in real time polymerase chain reaction (PCR) that hybridize a nucleotide sequence comprising the polymorphisms defined above or their complementary sequence.
  • the nucleotide sequence comprising the polymorphism is included within SEQ ID NO: 7.
  • the nucleotide sequence comprising the polymorphism has a length of at least 15 nucleotides.
  • the probes have sequences selected from the group consisting of SEQ ID NO: 5-6 and their complementary sequences.
  • Real-time PCR is particularly useful in diagnostic laboratories for the analysis of a large number of samples.
  • the presence or absence of polymorphism is detected using the real-time polymerase chain reaction (PCR) with one or more primers and one or more probes, which both hybridize a sequence of nucleotides comprising polymorphism in the KCNMB1 gene or its complementary sequence.
  • the nucleotide sequence comprising the polymorphism is included within SEQ ID NO: 7.
  • the nucleotide sequence comprising the polymorphism is included within the range from position 294 to position 465 of the gene. KCNMB1. said sequence having the polymorphism of G to A at position 352.
  • the primers and probes for real-time PCR have been mentioned above.
  • the sample is a tissue or fluid, usually blood, taken from the individual. Depending on the technique selected, the sample will be processed to obtain isolated cells, the protein fraction or the nucleic acid fraction (eg genomic DNA or messenger RNA).
  • the protein fraction or the nucleic acid fraction eg genomic DNA or messenger RNA.
  • the invention provides a method of prognosis or diagnosis of essential hypertension in a human being, comprising the detection, in a separate sample of said human being, of the presence or absence of amino acid substitution of E (acid glutamic) at position 65 by a K (lysine) in the polypeptide encoded by the KCNMB1 gene or in a fragment of this polypeptide comprising position 65.
  • the polypeptide fragment comprises an amino acid sequence included within the range from position 40 to position 156.
  • the polypeptide fragment comprises SEQ ID NO: 9 or SEQ ID NO: 10.
  • the detection of the amino acid substitution E65K in the polypeptide encoded by KCNMBI can be done with appropriate reagents that are specifically bind the polypeptide, such as, for example, properly labeled peptides, antibodies or antibody fragments.
  • appropriate reagents that are specifically bind the polypeptide, such as, for example, properly labeled peptides, antibodies or antibody fragments.
  • direct sequencing is also useful.
  • mass spectrometry is also useful for the purpose of the invention, as is known to one skilled in the art.
  • the detection of the presence or absence of polymorphism or amino acid substitution is used as a prognosis of the risk of suffering from essential hypertension, the presence being associated with a relatively low risk, and the absence being associated with a relatively high risk.
  • Heterozygotes (EK) and homozygotes (KK) for the presence of the E65K amino acid substitution are associated with a risk relatively low of suffering from essential hypertension, while EE heterozygotes have a high risk of suffering from it. Therefore, the K allele has a protective effect against the severity of essential hypertension.
  • the detection of the presence or absence of polymorphism or amino acid substitution is used as a diagnosis of essential hypertension suffered by a human being, the absence being associated with a BK channel dysfunction, and the presence being associated with a BK channel function improvement.
  • the prognosis of the risk of suffering from essential hypertension allows preventive measures to be implemented before the onset of the disease.
  • the diagnosis of essential hypertension allows to evaluate the efficacy of the therapeutic treatment and to design a treatment tailored for the individual in particular.
  • the invention provides a kit for carrying out the method of prognosis or diagnosis of essential hypertension in a human being, said kit comprising appropriate reagents for detecting the presence or absence of polymorphisms and amino acid substitution.
  • the kit comprises one or more oligonucleotides as defined above.
  • the kit comprises one or more primers and one or more probes as defined above for use in real-time PCR.
  • the invention also provides a kit comprising a reagent that specifically binds to the polypeptide or the polypeptide fragments defined above.
  • the reagent is an antibody or an antibody fragment as defined above.
  • the invention also provides isolated nucleic acid molecules of at least 15 nucleotides, which comprise a sequence included in the range from position 277 to position 627 of the sequence of the KCNMB1 gene. said sequence having the polymorphism of G to A at position 352.
  • the nucleic acid molecule comprises SEQ ID NO: 7, and more particularly SEQ ID NO: 8.
  • the invention also provides a nucleic acid molecule that encodes a polypeptide comprising the amino acid sequence SEQ ID NO: 9 and, more particularly SEQ ID NO: 10. These nucleic acid molecules can be single or double stranded. Recombinant vectors comprising these nucleic acid molecules are also provided.
  • polypeptides comprising an amino acid sequence included in the range from position 40 to position 156 of the polypeptide encoded by the KCNMB1 gene. said sequence having an amino acid substitution of E (glutamic acid) with a K nail (lysine) at position 65.
  • the polypeptide comprises SEQ ID NO: 9, and more particularly SEQ ID NO: 10.
  • the invention also relates to the use of these nucleic acid molecules, recombinant vectors and polypeptides for the preparation of a therapeutic agent for the prophylactic or curative treatment of essential hypertension in a human being.
  • the invention relates to a method of prophylactic or curative treatment of essential hypertension in a human, comprising the administration of an effective amount of the vectors, nucleic acid molecules and / or polypeptides described above.
  • FIG. 1 shows the genotypic distribution of E65K by diastolic blood pressure and the "odds ratio" adjusted for age and sex at each level of diastolic hypertension for carriers of the K allele relative to the EE genotype.
  • FIG. 2 shows the graph of the V 1/2 (V) with respect to the concentration of Ca 2+ (in ⁇ M).
  • FIG. 3 shows the effect of ⁇ i E65 ⁇ n the activation and deactivation kinetics of the BK channel.
  • FIG. 4 shows a schematic of the amplified region in the analysis of KCNMB1.
  • FIG. 1 shows the genotypic frequency of E65K (GF, in%) by diastolic blood pressure (BPD, in mmHg).
  • BPD diastolic blood pressure
  • the "p" values for genotypic distributions in each degree of diastolic hypertension are shown.
  • KK + KE genotypes are represented with black squares and the EE genotype with gray squares.
  • the "odds ratios" ie, the relative opportunities or the ratio between two opportunities used to estimate risks, OR
  • adjusted for age and sex in each degree of diastolic hypertension (BPD, in mmHg) of carriers are presented K with respect to the EE genotype.
  • FIG. 2 shows the graph of the V 1 2 (V) with respect to the concentration of Ca 2+ (in ⁇ M).
  • V V 1 2
  • FIG. 3 shows the effect of ⁇ i E ⁇ s K on the activation and deactivation kinetics of the BK channel.
  • A shows the representative traces of currents obtained from cells transfected with different combinations of ⁇ and ⁇ i subunits and normalized to the peak of the current.
  • (C) shows the graph of the activation time constant (ATC, in ms) with respect to the Ca 2+ concentrations measured with a pulse at +200 mV.
  • (D) shows the families of tail currents registered at 1.6 ⁇ M Ca 2+ in the four conditions.
  • the deactivation time constants (DTC, in ms) were obtained by adjusting the tail currents with a single exponential function and represented with respect to the pulse potential (E) or with respect to the concentration of Ca 2+ at -80 mV ( F).
  • FIG. 4 shows a schematic of the amplified region in the analysis of KCNMB1. The sequence in the figure corresponds to the third exon of the gene
  • KCNMB1 KCNMB1. except the first two nucleotides at 5 '(AG) and the last two nucleotides at 3' (GT), which are part of the flanking introns.
  • the hybridization sites of the primers (primers with sequences SEQ ID NO: 3 and SEQ ID NO: 4) are indicated with two boxes.
  • the hybridization sites of the fluorescent probes are indicated with two lines (probes with sequences SEQ ID NO: 5 and SEQ ID NO: 6).
  • BPD diastolic blood pressure measurements
  • a precision balance was used to determine the weight.
  • the participants wore underwear.
  • the height was also measured.
  • the body mass index (BMI) was determined by dividing the weight by the squared height (kg / m 2 ).
  • the mean BMI of the participants in the study was 27.2 kg / m 2 .
  • Blood pressure measurements were obtained with a calibrated mercury sphygmomanometer.
  • a pad adapted to the perimeter of the upper arm (young, adult and obese) was chosen for each participant.
  • the first measurements were made after a five minute break and the second measurements at least 20 minutes later.
  • the value used was the arithmetic mean of the two determinations. Standardized questionnaires of hypertension and diabetes mellitus were used (cf. R.
  • KCNMB1 gene analysis exons coding for the ⁇ i modulator subunit (KCNMB1) of the BK channel were amplified from the genomic DNA of 11 severe hypertensive participants and 12 strict norrnotensive participants. PCR products were analyzed by direct sequencing. The E65K variant in the third exon of the KCNMB1 gene (GenBank Accession No.
  • DNA samples were analyzed with the Taqman assay (ABI Prism 7900HT, Applied Biosystems), using primers 5'-AGCGTGTGGACCCAGGAAT-3 '(SEQ ID NO: 3) and 5'-GGCAGCTGACACGTTGA-3' (SEQ ID NO: 4) and, FAM-CCTTCTTGCCCTTCAGCTTCTCCTC-TAMRA probes (SEQ ID NO: ) and VIC-CACCTTCTTGCCCTTCAGCTCCTC-TAMRA (SEQ ID NO: 6) for the K (base A) and E (base G) alleles, respectively.
  • Taqman assay ABSI Prism 7900HT, Applied Biosystems
  • Genotypic frequencies were 78.4% for EE homozygous individuals, 20.0% for EK heterozygotes and 1.6% for KK homozygotes. The observed genotypic frequencies were adjusted to the Hardy-Weinberg equilibrium. KK homozygous individuals and EK heterozygotes were analyzed together due to the low prevalence of the former. Statistical analyzes were performed separately for diastolic and systolic blood pressure values. The participants with a diastolic blood pressure (BPD) below 80 mmHg (10.66 kPa) who did not receive antihypertensive therapy constituted the normotensive group. The genotypic frequency of the E65K mutation (KK + KE) decreased as DBP values increased (cf. FIG. 1 A), from 21.6% in the normotensive group to 3.2% in the severe hypertensive group [ DBP> 11O mmHg (14.66 kPa)].
  • BPD diastolic blood pressure
  • the "odds ratios" (ie, the relative opportunities or the ratio between two opportunities used to estimate risks, OR) of the five levels of diastolic hypertension adjusted for age and sex for the allelic variant K compared to the genotype EE ( cf. FIG. 1B).
  • a decrease in the risk for the E65K variant was observed as the severity of diastolic hypertension increased (cf. FIG. 1 B).
  • PAR (%) 100 x (P ⁇ (OR - 1)) / (1 + P e (OR-1)); where P e is the proportion of non-hypertensive participants carrying K and OR is the "odds ratio" of diastolic hypertension adjusted for age and sex for K carriers.
  • the E65K mutant was expressed in HEK-293 cells and functionally analyzed (it is that is, the ionic currents generated by the movement of K + were measured through the wild-type and mutant BK channels). Because the frequency of the KK allele was very low, the functional significance of the co-expression of E65K in combination with wild ⁇ i was also evaluated.
  • HEK-293 cells that permanently express the pore-forming subunit ⁇ also known as hSlo, cf.
  • PK Ahring et al. "Stable expression of the human large-conductance Ca 2+ -activated K + channel alpha and beta subunits in HEK293 cells ", FEBS Letters 1997, vol. 415, pp. 67-70), were transiently transfected with the wild-type ⁇ i subunits (wild-type, ⁇ w ⁇ ), mutant ( ⁇ iE65 ⁇ ) or a combination of both ( ⁇ w ⁇ + ⁇ IE65K) -
  • the E65K mutation was introduced into the human ⁇ i subunit cloned into a pcDNA3 vector, using the QuikChange Mutagenesis kit (Stratagene), and verified by sequencing HEK-293 cells were transfected with the E65K BK ⁇ i construct using a linear derivative of polyethyleneimine (PEI), polycation ExGen ⁇ OO (Fermentas MBI) following the manufacturer's instructions (7 equivalent PEI / 3.3 ⁇ g DNA). 250,000 HEK-293 cells were seeded by 35 mm plate, 24 h before transfection.
  • PEI polyethyleneimine
  • Fermentas MBI Polycation ExGen ⁇ OO
  • the borosilicate glass pipettes for the patch had a resistance of 1.3-3 M ⁇ and were filled with a solution containing (in mM): 140 KCI, 1.2 MgCI 2) 0.2 CaCI 2 , 0.5 EDTA and 10 HEPES (300 mosmoles / l, pH 7.3).
  • the solutions that bathed the cytoplasmic face of the patch membrane contained (in mM): 140 KCI, 0.7 MgCI 2) 10 HEPES, pH 7.25, and 300 mosmoles / l.
  • the intracellular concentration of free Ca 2+ (calculated using EqCal from Biosoft, Cambridge, UK) was adjusted to the desired values by different combinations of CaCI 2 and EDTA added to the bath solution.
  • the currents were acquired at 10 kHz and filtered at 1 kHz.
  • the membrane patches were set at 0 mV, pulses of 150 ms were given from -100 mV to +200 mV in 10 mV steps and repolarized at -80 mV for 10-20 ms.
  • the tail currents were evoked by a step of 50 ms at +160 mV (for 10 ⁇ M of free cytosolic Ca 2+ ) or +200 mV (Ca 2+ ⁇ 1.6 ⁇ M) and then were repolarization measurements at different voltages (from -100 mV to +10 mV in 10 mV steps) for 50-90 ms.
  • the experiments were carried out at room temperature (22-26 ° C).
  • 3iFB ⁇ did not alter the kinetics of BK- ⁇ j_ channels: It was also evaluated whether the kinetics of BK currents in the presence of ⁇ i E65 ⁇ differed from those obtained by expressing only ⁇ w ⁇ . As FIG. 3, slower kinetics were observed in cells expressing the ⁇ i subunit than in those that did not express it, without differences between cells expressing different ⁇ i. Similar results were obtained when analyzing the deactivation kinetics (cf. FIG. 3E-F). The analysis of the time constants for different combinations of ⁇ i subunits at different concentrations of Ca 2+ or voltages also showed no differences in the kinetics of the currents of ⁇ w ⁇ and ⁇ 1E65K.

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Abstract

L'invention concerne une méthode de pronostic ou de diagnostic de l'hypertension essentielle chez un sujet humain consistant en la détection de la présence ou de l'absence d'un polymorphisme dans le gène <U>KCNMB1 </U>dans un échantillon prélevé sur ledit sujet humain, ledit polymorphisme provoquant une substitution d'acide aminé de E(acide glutamique) par une K(lysine) dans la position 65 du polypeptide codé correspondant. Notamment, le polymorphisme est une substitution d'un nucléotide unique de la G en position 352 de la séquence du gène <U>KCNMB1 </U>par une A. L'invention présente des méthodes, des composés et des matériels de diagnostic et de pronostic de l'hypertension essentielle chez des sujets humains. Elle concerne également des composés de traitement prophylactiques ou curatifs de l'hypertension essentielle.
PCT/ES2005/000164 2004-03-29 2005-03-29 Methode et materiel de detection du risque de presenter une hypertension Ceased WO2005093096A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2331883C1 (ru) * 2007-01-11 2008-08-20 Илья Николаевич Медведев Способ диагностики риска развития вазопатии у больных артериальной гипертонией с метаболическим синдромом

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051822A1 (fr) * 1997-05-14 1998-11-19 Musc Foundaton For Research Development Procedes et compositions permettant d'etablir une correlation entre des polymorphismes de promoteur du gene de kallikreine avec une hypertension essentielle
WO1999035279A1 (fr) * 1998-01-12 1999-07-15 Georgetown University Medical Center Mutant de kinases apparentees a la proteine g contre l'hypertension essentielle

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051822A1 (fr) * 1997-05-14 1998-11-19 Musc Foundaton For Research Development Procedes et compositions permettant d'etablir une correlation entre des polymorphismes de promoteur du gene de kallikreine avec une hypertension essentielle
WO1999035279A1 (fr) * 1998-01-12 1999-07-15 Georgetown University Medical Center Mutant de kinases apparentees a la proteine g contre l'hypertension essentielle

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FERMANDEZ-FERNANDEZ J.M. ET AL: "Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension.", J CLIN INVEST., vol. 113, no. 7, April 2004 (2004-04-01), pages 1032 - 1039 *
GOLLASCH M. ET AL: "The BK channel beta 1 subunit gene is associated with human baroreflex and blood pressure regulation.", J. HYPERTENS., vol. 20, no. 5, May 2002 (2002-05-01), pages 825 - 827 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2331883C1 (ru) * 2007-01-11 2008-08-20 Илья Николаевич Медведев Способ диагностики риска развития вазопатии у больных артериальной гипертонией с метаболическим синдромом

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