UA118412C2 - METHOD OF GENETIC STRATIFICATION OF CARDIOVASCULAR RISK IN PATIENTS WITH ARTERIAL HYPERTENSION - Google Patents

Abstract

The invention relates to a method for stratification of cardiovascular risk in patients with arterial hypertension with genetic factors by total evaluation of gene polymorphisms by generating a gene-modification index as a result of summing the scores assigned to each AG-genotypeT1, polymorphs1 : 521, AGTR1: 1166, AGTR2: 1675, CYP11B2: -344, GNB3: 825, NOS3: -786, NOS3: 894 and determine the percentage of modified genes that will allow a high degree of likelihood to predict cardiovascular events in patients with hypertension taking into account genetic factors.

Description

(54) METHOD OF GENETIC STRATIFICATION OF CARDIOVASCULAR RISK IN PATIENTS WITH

ARTERIAL HYPERTENSION

(57) Abstract:

The invention relates to a method of stratifying cardiovascular risk in patients with arterial hypertension taking into account genetic factors by summarizing gene polymorphisms by forming a gene modification index as a result of summing up the points assigned to each genotype of candidate gene polymorphisms AYUO1:1378, AST:704,

АссTB21, АСаТА1:1166, АСТА2:1675, СМРИ182:-344, С2МВ3:825, МО53:-786, МО53:894 and determination of the percentage of modified genes, which will allow predicting the occurrence of cardiovascular complications in patients with hypertension with a high degree of probability taking into account genetic factors.

The invention belongs to the field of medicine, namely cardiology, internal and preventive medicine, and can be used for cardiovascular risk stratification (CHD), primary and secondary prevention in patients with arterial hypertension (AH).

Arterial hypertension is one of the most important medico-social health problems worldwide. The prevalence of hypertension is more than 20 95 and with every decade there is a tendency to increase it. It is known that patients with hypertension have a 4-6 times increased risk of developing such complications as heart attack, stroke, heart failure, which subsequently leads to high rates of cardiovascular mortality and disability.

Stratification of SSR in patients with hypertension is an important component of their long-term therapeutic and preventive management. Currently, the method of stratification of SSR in patients with

AH, which is based on assessment of risk factors such as age, sex, blood pressure level, cholesterol level, smoking, target organ damage and presence of co-morbidities, does not take into account genetic factors, which, being fixed, can be identified before the development of AH as diseases and development of cardiovascular complications |11.

Until now, the traditional method of stratification of SSR in patients with

AH, which is proposed by the European Society of Cardiology and the International Society of Hypertension in the Recommendations for the treatment of arterial hypertension in 2013 PI, in which the stratification of SSR in patients with AH is carried out based on the assessment of systolic blood pressure (SBP), diastolic blood pressure (DBP), the presence of risk factors , asymptomatic damage to target organs, diabetes, CKD stage or clinically manifest cardiovascular diseases with definition of low, moderate, high and ultra-high risk categories. At the same time, the concept of low risk defines the probability of the occurrence of cardiovascular complications within 10 years of less than 10 95. Moderate risk - the probability of the occurrence of cardiovascular complications within 10 years from 10 95 to 20 95,

High risk - from 20 95 to 30 95 and ultra high risk - more than 30 95 probability of cardiovascular complications within 10 years.

The disadvantage of this method of stratification of SSR is that variable risk factors are used to a greater extent, among which age acquires the most significant importance. Therefore, most young patients fall into the low and medium risk category and do not receive enough

From curative and preventive measures. In addition, the traditional approach to the stratification of SSR does not take into account the influence of genetic factors, which is also a significant drawback, since many modern studies have proven their significant influence on the development, course and prognosis

AG.

The invention is based on the task of developing a method of cardiovascular risk stratification in patients with arterial hypertension based on the analysis of genetic factors, namely the presence or absence of gene polymorphisms, taking into account the patient's genetic factors, which will allow personalized prediction of the occurrence of cardiovascular complications with a high degree of probability in patients with hypertension, taking into account genetic factors.

The task is solved by the fact that, according to the invention, in the claimed method of cardiovascular risk stratification in patients with arterial hypertension, it is performed by forming a gene modification index by determining the percentage of "pathological" genotypes in the total population of candidate gene genotypes AYUOO1:1378 ,

AST:704, AST:521, АДИТА1:1166, АСТА2:1675, СУРИ182:-344, СМВЗ3:825, МО53:-786, МО53:894, while the specific weight of the "pathological" homozygous polymorphism of one gene is assigned 1.5 points , a "pathological" heterozygous polymorphism - 1 point, a "normal" homozygous polymorphism - 0 points, after which the sum of the assigned points of the available genetic polymorphisms M is added to the offspring ratio of modified genes according to the formula: 15.5 where: Mep1-p2zh-p3--p14- p5--p6b-p7pv by; 13.5 - the maximum possible number of points of available polymorphisms, which is a constant value, and with values of the gene modification index from 0 to 20 95, a low genetic cardiovascular risk is established, from 21 to 40 95 - a moderate risk, from 41 to 70 95 - high risk, from 71 to 100,925 - extremely high genetic cardiovascular risk.

Given that hypertension is a polygenic hereditary disease, the use of single genetic polymorphisms for prognostic purposes is not promising. To date, various data on the prevalence of candidate gene polymorphisms in hypertension have been accumulated in various population environments, but their use for prognostic purposes has not yet been resolved. According to recent meta-analyses, the use of single polymorphisms for the purpose of predicting hypertension has significant drawbacks and is recognized as ineffective. There was an urgent task to consider gene polymorphisms in their interaction and mutual reinforcement. Therefore, the formation of genetic scales taking into account multiple gene polymorphisms, which is a new innovative direction in predicting the course of cardiovascular diseases and their complications, is promising.

Accumulated data on polymorphisms of candidate genes in hypertension form a reasonable perspective for the use of genetic risk scales, which will allow use for both secondary and secondary prevention.

The technical result achieved by the implementation of the invention is that the application of the proposed model will allow predicting the occurrence of cardiovascular complications in patients with arterial hypertension based on the analysis of genetic factors, namely, the determination of candidate gene polymorphisms. Genetic polymorphisms were determined in the DNA material of venous blood cells by polymerase chain reaction using fluorescently labeled primers. The stated method of stratification is extremely effective, as it takes into account persistent unmodified risk factors and can be applied at any stage of the development of arterial hypertension, as well as in the pre-diagnosis period.

The method is carried out as follows.

A venous blood sample is taken from a patient with a diagnosis of arterial hypertension, and a vacutainer with the anticoagulant KZ-EDTA is used as a transport medium.

Next, polymorphisms of candidate genes are studied in the obtained material using the polymerase chain reaction method.

The traditional and generally accepted method of polymerase chain reaction is used, which is performed in the amplifier in real-time "teaI eat" mode with the use of fluorescently labeled primers.

PCR analysis consists of several stages: - processing of clinical material (venous blood); - amplification; - detection of amplification products.

Processing of clinical material includes the extraction of DNA from samples of the patient's venous blood.

Performed automatically by magnetic separation of cells in collected venous blood.

After DNA extraction from the patient's venous blood, amplification of the obtained DNA material and simultaneous detection of the amplification products using fluorescently labeled primers are carried out in real time "hea!te" according to standard methods. A specific primer is used for each studied gene polymorphism.

The following candidate gene polymorphisms are being studied: AYUOOI:1378, AST:704, AST:B21, datv1:1166, AITA2:1675, SMRI182:-344, CMV3:825, MO53;-786, MO53:894.

The A0OY gene encodes adducin, a heterodimeric protein of the cell cytoskeleton that regulates the activity of (Mazh, Kzh)-ATPase, which is involved in the transfer of sodium and potassium ions through the membrane of the kidney epithelium. Replacement of the Guanine nucleotide (C) in the coding region of the А0ОЙ1 gene at position 1378 by

Thymine (T) is designated as genetic marker 513787 (А0О1:1378). The altered protein activates (Mat, K)-ATPases in the renal tubules and thereby contributes to the retention of sodium in the body, which is the trigger for the development of arterial hypertension, i.e. high blood pressure (2.

The association with the development of hypertension is shown for the replacement of thymine (T) with cytosine (C) at position 704 of the DNA sequence of the AST gene - this area is called genetic marker 1704C (AST:704). As a result of this substitution in the angiotensinogen protein at position 235 of the amino acid sequence, the amino acid Methionine is replaced by Tryptophan (Mei235TPg), and the basal level of gene transcription also increases. As a result, the presence of the SS genotype leads to an increase in the plasma concentration of angiotensinogen by 10-20 95, compared to the TT genotype. The birth frequency of the C-allele in the European population is 41 95, it is most common in the African population (87 Os).

Another polymorphism in the AST gene associated with the risk of hypertension is the T174M polymorphism, when instead of Threonine in the peptide chain at position 174 Methionine stands. The reason for the replacement is a point mutation in position 521 - replacement of Cytosine with Thymine (AST:521). The T/T phenotype is considered a risk factor for hypertension. As a result of replacement, the level of angiotensinogen in the plasma also increases, which leads to the development of hypertension and left ventricular hypertrophy (LVH) |4).

The ASTKI1 gene is located on the long arm of the 3rd chromosome (3d21-25). The reason for increased expression of the ASTKI gene as a result of replacing Adenine (A) with Cytosine (C) at position 1166 in the regulatory region (АСТА1:1166) is a change in the nature of the regulation of gene translation by microRNA tik155. MicroRNA tik155 negatively regulates the expression of the ASTK1 gene, but because it can bind only to mRNA synthesized from the A allele, therefore, when A is replaced with C, the regulation of translation is disrupted, more protein is synthesized, and the sensitivity of the receptor to angiotensin II increases. This is the reason for the association of the C allele with hypertension.

Numerous studies have shown that the frequency of AS and SS genotypes on the A1166C marker of the ASTK!1 gene is significantly higher in groups of patients suffering from hypertension than in a control group of healthy people. The ASTKI gene and its allele 1166C are factors that lead to the development of HLSH

IB, 6, 71.

The ASTK gene (Khag3) is a section in the regulatory region of the DNA sequence of the ASTK2 gene, in which

Guanine (C) is replaced by Adenine (A) at position 1675, called genetic marker 51675А (АСТА2:1675). As a result of such substitution, the nature of gene expression regulation changes.

Allele b is associated with activation of transcription and an increase in the number of angiotensin II type 2 receptors on the cell surface. Allele A, on the other hand, is associated with a decrease in number

ASTKZ2 on the cell surface, as well as with relative hyperstimulation of ASTKI1 by angiotensin II. In this connection, the risk of hypertension, complications during pregnancy and coronary heart disease increases |81I.

The last stage of aldosterone hormone synthesis is catalyzed by aldosterone synthase enzyme (SUR1182). The polymorphism manifested in the replacement of Cytosine by

Thymine in the 344th position of the nucleotide sequence, in the regulatory region of the gene (SURI1182:- 344). This site is the binding site of the steroidogenic transcription factor 5E-1, a regulator of aldosterone synthase gene expression. The T allele leads to increased production of aldosterone, which in turn is associated with arterial hypertension, as well as with fibrosis and hypertrophy of the myocardium and with the risk of hypertensive complications of pregnancy. In addition, hyperproduction of aldosterone contributes to increased expression of plasminogen activator inhibitor-1, which entails the development of endothelial dysfunction, which is the cause of cardiovascular complications (91.

Recently, great importance has been attached to the study of the recently described C8257T polymorphism of the gene B-subunit of C-protein (2MV3). C-protein is a universal membrane transducer that transmits signals from more than 1000 receptors to many intracellular effectors, including enzymes and ion channels. With its participation, the signal transmission of most neurotransmitters and biological substances, such as insulin, platelet and epidermal growth factors, is carried out. As a result of a mutation in the 10th exon of the gene,

which consists in replacing Cytosine with Thymine at position 825 (С2МВ3:825), the synthesis of a functionally more active variant of C-protein occurs, which in turn leads to an increase in the concentration of calcium in the cytosol, an increase in intracellular signaling, and, as a result, to enhanced response of cells to hormonal stimulation. Genetically fixed increased activity of c-protein can lead to an increase in blood pressure, hypertrophic changes in the heart and blood vessels. In addition, studies show an association of the presence of the T allele with an increased risk of developing type 2 CC and obesity |101|.

The eMMoz gene is located in the 7th chromosome (7435-36) and consists of 26 exons. In the exons and introns of the eMmo5 gene, several polymorphic regions were found, among which the most significant are polymorphisms (38947 (СИн298А5р) of the 7th exon and T(-786)С of the eMmo5 gene promoter. The last polymorphism consists in replacing the nitrogenous base of thymine (T) with cytosine (C) in the 5'-end of the MO5Z gene leads to a significant inhibition of the promoter activity of the gene and, accordingly, to a decrease in the synthesis of endothelial MO (MO53:-786). In patients with acute coronary syndrome (ACS), three times more often than in healthy donors, found homozygotes with the pathological SS genotype of the MO53 gene promoter, which indicates the role of the T (-786) C polymorphism in the pathogenesis of ACS, especially in men with premature development of atherosclerosis (111.

The 5894T polymorphism of exon 7 of the emo5 gene is structural and consists of a substitution (3/7 in position 894 of the nucleotide sequence of the eMmo5 gene, which leads to the replacement of glutamine with asparagine in the 298th position (МО53:894). According to meta-analysis of the dependence of various polymorphisms of the eMmo5 gene with presence of hypertension and coronary artery disease, TT homozygotes were associated with an increased risk of developing these diseases (121.

On the basis of the obtained genotypes of the above candidate genes, a gene modification index (GMI) is formed by determining the percentage of changed ("pathological") genotypes in the total population of candidate genes under study: АЮО1:1378, АСТ:704, АСТ:521,

ASTK1:1166, ASTK2:1675, SUR1182:-344, СМВ3:825, MO53:-786, MO53:894. At the same time, the specific weight of the "pathological" homozygous polymorphism of one gene is assigned 1.5 points, the heterozygous polymorphism - 1 point, respectively, the "normal" genotype is assigned 0 points.

Table 1 provides a point assessment of polymorphisms of candidate genes for arterial hypertension in determining the gene modification index.

Table 1 in its 0

APO1:1378 (alpha-adductin) nn pi pi

AST:704 (angiotensinogen) CC 11171110

AST:521 (angiotensinogen)

AA 7 Y770

ASTE 1:1166 (type 1 receptor for angiotensin II) in Her 0

АСТЕ2:1675 (type 2 receptor for angiotensin II) CC 11711110

SURI182:-344 (cytochrome 11p2-aldosterone synthase) SS 11171110

СМВ3:825 (guanine-binding protein) nn pi pi

MO53:-786 (nitric oxide synthase) in Her 0

MO53:894 (nitric oxide synthase)

Sumabalv../////////77771111111111111111111111111111Ї1111111111111Ї1 (Gene modification index.о//////777777711Ї111111111111Ї111111111с1

Further, the gene modification index (GMI) is calculated according to the formula: 13.5 where: M is the sum of the points of the available genetic polymorphisms,

M-p1ya4-p2--p3--p4--p5--pb--p7 -p8--po; 13.5 is the maximum possible number of points available in the polymorphism, which is a constant value.

Next, genetic stratification of SSR is carried out on the basis of the obtained GMI. With values of the gene modification index from 0 to 20, low genetic cardiovascular risk is determined, from 21 to 40 95 - moderate risk, from 41 to 7095 - high risk, from 71 to 100 95 - extremely high genetic cardiovascular risk.

240 patients with arterial hypertension were examined in the study. The diagnosis of arterial hypertension was established on the basis of the 2012 protocol of the Ministry of Health of Ukraine and the 2013 recommendations of the European Society of Cardiology (ESC). All patients underwent traditional stratification of cardiovascular risk according to the 2013 ETC criteria.

Patients were divided into 4 groups: with low, moderate, high and ultrahigh SSR. After that, all patients were analyzed for polymorphisms of 9 candidate genes by the PCR method:

ABO1:1378, AST:704, AST:521, AaTA1T 1166, ASTA2:1675, SURI182:-344, 2MV3:825,. MO53:- 786, MO53:894. A point assessment of the genotype of each candidate gene was carried out: "pathological" homozygous polymorphism of one gene is 1.5 points, heterozygous polymorphism - 1 point, "normal" homozygous polymorphism - 0 points (Table 1). Subsequently, the gene modification index (GMI) was calculated according to the stated formula, and genetic stratification of cardiovascular risk was carried out on its basis. A statistical analysis of correlations (correlation coefficient r) between traditional and genetic stratification of SSR in patients with hypertension was performed.

As a result of the traditional stratification of SSR, the low-risk group consisted of 24 patients, while 75 95 patients had a similarly low cardiovascular genetic risk according to the calculated GMI (10.72, p«e0.01). The group with moderate SSR consisted of 96 patients, 75 of them had a moderate genetic cardiovascular risk (r-0.71, p«0.01), the group with high

SSR was 72 patients, of which 72,956 patients had a high genetic cardiovascular risk (1-0.71, p«0.05). The group with extremely high SSR consisted of 48 patients, of which 67 95 had an extremely high genetic cardiovascular risk (/-0.70, p«e0.05).

The relationship between traditional and genetic stratification of cardiovascular risk in patients with arterial hypertension is presented in Table 2.

Table 2

Genetic scale p-24 p-72 p-48 18 (75 Ov) 6 (6 95) 2 (Z Y)

Low "-0.72 "-0.09 "-0.07 reo.01 p»0.05 p»0.05 5 (21 Fo) 72 (75 U) 8(11 95) 6(12 95)

Moderate i-0.20 "-0.71 "-0.10 "-0.11 p»0.05 p-e0.01 p»0.05 p»0.05 1 (4 95) 16(17 95 ) 52 (72 9) 19(21 U) p»0.05 p»0.05 p0.05 p»0.05 2 (2 965) 10(14 9) Total (67 95)

Ultra high "-0.06 и-0.12 и-0.70 р»0.05 р»0.05 ре0.05

Thus, the proposed method of genetic stratification of cardiovascular risk, which is based on the application of the gene modification index by assessing the specific weight of "pathological" genotypes of candidate genes, has a reliably high correlation with the traditional clinical stratification of SSR and can be used for prognostic purpose in patients with arterial hypertension. Unlike clinical stratification, genetic stratification can be used to predict cardiovascular risk at an early prediagnosis stage and for both primary and secondary prevention purposes.

The stated technical solution is explained by a concrete example.

Patient 0., at the time of the examination, was 41 years old, weight - 90 kg, height - 1.70 m, BMI - 31 kg/m,

AT-166/106 mm Hg. Complaints about periodic headaches, dizziness, palpitations, sleep disturbances, pain in the heart area associated with a rise in blood pressure. The diagnosis of hypertension was made for the first time at the age of 33. The hereditary anamnesis is burdened by the mother (hypertension, stroke) and father (CHD). According to the results of ECG and echocardioscopy, concentric hypertrophy of the left ventricle was revealed.

When examining the fundus - signs of hypertensive angiopathy. Additional risk factors include hypercholesterolemia, smoking, obesity, metabolic syndrome.

On the basis of the conducted examinations, a diagnosis was established: Arterial hypertension 2

From stage, 2nd degree. Hypertensive heart. Very high cardiovascular risk.

A venous blood sample was taken from the patient, and polymorphisms of candidate genes were studied in the material obtained by the polymerase chain reaction method in real time "gea! ChShte" using fluorescently labeled primers: AOJU1:1378, AST:704, AST:521, datvIL1166, AaTA2 :1675, SU RI182:-344, 24M83:825, MO53:-786, MO5Z:894.

The following genotypes were obtained with further scoring:

АРО 1:1378 - S/I genotype ("pathological heterozygote") - 1 point;

ASTT:704 - C/C genotype ("pathological homozygous") - 1.5 points;

AaTB521 - SL genotype ("pathological heterozygote") - 1 point; datv1:1166 - A/A genotype ("normal homozygote") - 0 points;

ASsTV2:1675 - A/A genotype ("pathological homozygote") - 1.5 points;

SURI182:-344 - SL genotype ("pathological heterozygote") - 1 point; аМвВ3:525 - SL genotype ("pathological heterozygote") - 1 point;

MO53:-786 - C/C genotype ("pathological homozygote") - 1.5 points;

MO53:894- T/I genotype ("pathological homozygote") - 1.5 points.

In the future, the GMI was calculated according to the formula: 13.5 where: M is the sum of the points of the available genetic polymorphisms,

M-pich-p2a-pZ--p4--p5--pb--p7 4-p8--p9--1-4-1,54-1--04-1,5--1-4-1 --1.5--1.5-10;

IM is the maximally false number of points present in the polymorphism, which is constant. 13.5 zlotys, which creates an extremely high genetic risk of cardiovascular complications.

Conclusion: the given clinical example shows the coincidence of a high clinical risk of cardiovascular complications with a genetic risk, taking into account the burdened family history, it would be possible to conduct a genetic analysis at an early age in the examined patient with the determination of genetic risk, which would allow timely preventive measures to prevent development of the disease and damage to target organs.

Sources of information: 1. 2013 EZN/EBS Siiaeiiipev og te tapadetetpi oi apepa! purepepviop: Tne TavkK Rogse og She tapadetepi oi apegia! purepepvsiop oi She Etoreap Bosieiu oi Nurepepvsiop (EN) apa oi She

Eigtoreap 5osiviu oi Sagaioioau (E5C). Mapsia, S., Radaga V., Makiem/sya: K., Vedop u., 7apeNeyi, A.,

Vopt M, SpPgiznaeep5 T., SykKoma K., Oe VasKeg 0., Yuotipislak A., Saidegibi, M. ei aiYi. good luck

Nurepepziop: dshu 2013-Moishte 31-I55ye 7 - R. 1281-1357. 2. Topey G. AIrpa-adaysip tshiayop5 ipstease Ma/K ritr asiimpyu ip gtepa! seiii5 Bu apesiipd sopviishime epdosuiyuoviv: itriisaiop5 Tog Tbshiag Ma geabzogriip / G. Topep//At. U. RNuzio!i. Nepai

Rpuzio! - 2008. - R. 478-487.

Z. Dzyak G.V. Genotypic "ensembles" of polymorphic markers of renin-angiotensive system genes! in patients with hypertension / G.V. Dzyak, T.V. Chariot //

Ukrainian Journal of Cardiology. - 2008. - Volume 2. - P. 37-43. 4. Maikip5 MU.5. Sepoiure-rpepoiiure apaiuvov oi apdioiepzipodep roiutogrpizt5 apa ezzepiia! purepepviop: She itropapse oi parioiuresis / MU.5. UMaiKip5, 5.0. Nipi, s.N. UMPShatv This a!.| // 9.

Nurepepzv - 2010. - M. 28 (1). - R. 65-75. 5. ZeshShirashu, R. Nytap testVMA-155 op spPgotozote 21 aiyegepianyu ipiegasiv m/y yv

Zo roiutogrpis iagdei ip She ASTA1 Z-rgite ipigapvziaied hediop: a tespapibzt og Tipsiiopai! 5ipdie- pisieoiide roiutogrNivztv heiYaiieid o rpepoiurez / R. ZeipiraiNnu, S. Vogei, M. Ssadpebip, S.V. Szgapi,

Z. YuOeshivsy, Volume 5. Eop, A.S. Naigideogdiou, 5.E. Apiopagakov // At. U. Nit. С(епей. 81. - 2007.-Р. 405-413. 6. D.K. Miloslavsky Genetic markers in essential arterial hypertension associated with metabolic syndrome manifestations / D.K. Miloslavsky, I.A.

Snegurskaya, O.N. Litvynova, O.V. Mysnychenko, E.N. Shchenyavskaya // Medicine today and tomorrow. - 2010. - Me 2-3. - b. 99-106. 7. Tnapdariyu 59. Vezmegato! rgemepiv Te ayemeiortepi oi raipoiodisa! sagaias nureptornu apa sopigasiiye auvijpsiop ip She KNOWS m/yyposhi Iomegipud bioo4 rzhezvyge /5.U. Tpapaariyu, R.

Morsiespomukhki, U. Veprapapi |(ei a/.| / At. U. Nurepepzv. - 2010. - M. 23 (2). - R. 192-196. 8. Kygpeivoma T. bodisht ehsgeyop az a toashiayug oi depeiis avzzosiayope m/y sagaiomazstiag rpepoiurez ip She Eigoreap Rgo|esiop Sepez ip Nurepepviop / T. Kygpeivoma // In Nurepepv, 2006. - 24(2). - R. 235-42. 9. Vatige2-Zaiialag M. NeiaiiopzpPir oi aidoziegope zupipase depe (С-344Т) apa tipegaIosopisoia geseriog (58101) roiutogrpizt5 m/yyp devziaiopa! purepepvsiop Tehi. / M. Vatige2-Zaialag Gei a.) // u.

Thread Nurepepv 2011.- Mine. 25. - R. 320-326. 10. Kiapi US. Avvosiayop oi Si-rgoivip Beia-3 vybypii depe (CMV3) T825 aiIeie myy Ture I diaretev/ U.a. Kiapi, M. Zaeeed, 5.N. Ragueg, R.M. Egov5zaga// Meygo Epadostipo! Gay. - 2005. - 26(2). -

R. 87-88. 11. Sazav U.R. Epaoineiiia! pitis ohide zupinaze depoiure apa ivspetis Neap aibveaze: teia- apaiuvov oi 26 zshchaievz ipmoimipd 23028 zi!ibBiesiv / UR. Sazav, I.E. Vashivia, 5.E. NytrnNpev, A.O.

Nipdogapi// Sigsciaiop. - 2004. - Mine. 109. -R. 1359-1365. 12. My M.O. Wow! pis ohide zupipaze depeiis magiayop apa ezzepiia! purepepsviop givK ip

Nap Spipese: Te Rapdzpap 5ishau / MU. O. Mim, M. Oi, S. T. papa (hey a!) 1/5. Thread Nurepepv - 2009. (- M. 23 (2). - R. 136-139.

Claims (1)

FORMULA OF THE INVENTION The method of cardiovascular risk stratification in patients with arterial hypertension using the assessment of risk factors and clinical-instrumental signs, which differs in that it additionally forms a gene-modification index by summing up the scores, candidate gene polymorphisms assigned to each genotype AYUO1:1378, AST:704, AST:521, АСТВ1:1166, АДИТА2:1675, СУРИ1182:-344, СМВ3:825, МО53:-786, МО53:894, in which the specific weight of "pathological" homozygous polymorphism of one gene is 1.5 points, heterozygous polymorphism - 1 point, " "normal" homozygous polymorphism - 0 points, with further transfer to the percentage of modified genes according to the formula: EV--4x 135 where M-Apip2 Z np4 -claim 5 pbo-claim 7 -pv-pO which is the sum of the points of the available genetic polymorphisms, 13.5 is the maximum number of points available for the polymorphism, and with values of the gene modification index from 0 to 20 95 indicate a low genetic cardiovascular risk, from 21 to 40 95 - a moderate risk, from 41 to 70 95 - a high risk, from 71 to 100 925 - an extremely high genetic cardiovascular risk.