Genetic Aspects of Arterial Hypertension: How Gene Polymorphisms

Determine the Risk of Developing Hypertension

Abidova Dilorom Ergashevna

, Muhamedova Muyassar Gafurjanovna

and Mullabayeva Guzal Uchkunona

Republican Specialized Scientific Practical Medical Center of Cardiology, Tashkent, Uzbekistan

Research Institute of Military Medicine of the Military Medical Academy of the Armed Forces of the

Republic of Uzbekistan, Uzbekistan

Republican Specialized Scientific Practical Medical Center of Cardiology, Tashkent, Uzbekistan

Keywords: Arterial, Premature, Special, Genetic.

Abstract: Arterial hypertension (AH) is one of the leading causes of cardiovascular diseases and premature death.

Recently, special attention has been paid to genetic markers that may predispose to the development of AH

and its complications. The presented study, conducted with the participation of 392 people (100 without AH

and 292 with AH), was focused on the analysis of genetic factors influencing the development of

hypertension, myocardial hypertrophy and obesity. Genetic markers, such as polymorphisms of the AGTR1,

AGTR2, AGT, ADD1, CYP11B2, NOS3 and GNB3 genes, were studied using PCR and other molecular

methods. The results showed that the AGTR1 and AGTR2 genes did not have statistically significant

differences between the groups. However, the ADD1 gene was associated with a family history of

hypertension, and the CYP11B2 mutation was associated with obesity, as confirmed by the WC/HR indicator.

The GNB3 gene showed a direct relationship with the presence of left ventricular hypertrophy and the WC/HR

level. These data confirm the importance of genetic testing for assessing the risks of developing hypertension

and its complications, as well as the need for further research to develop personalized approaches to the

treatment and prevention of hypertension.

1 INTRODUCTION

Arterial hypertension (AH) remains one of the main

causes of cardiovascular diseases and premature

death worldwide. In particular, more than 1.1 billion

people suffer from hypertension, which is associated

with lifestyle changes, population aging and an

increase in risk factors such as obesity, stress and lack

of physical activity (Shabalov et al., 2019). Genetic

predisposition to hypertension has become an

important area of research in recent years, as it can

significantly affect the development of the disease

and its complications. The influence of genetic

factors on the development of hypertension,

myocardial hypertrophy and obesity has been

confirmed by a number of international and Russian

studies. For example, Sato et al. (2008) note the

association of gene polymorphisms, such as AGT and

CYP11B2, with the risk of hypertension and its

progression (Sato et al., 2008). In Russia, genetic

markers associated with predisposition to

hypertension are being studied. In the works of

Shabalov V.M. (2019) emphasizes the importance of

genetic testing for the early diagnosis of

hypertension. Also, as shown in the studies of

Kawarazaki et al. (2016), certain mutations in genes

regulating sodium balance may be associated with the

development of hypertension and obesity. An

important topic is also a genetic predisposition to left

ventricular hypertrophy (LVH), which is confirmed

by the works of Weiss et al. and Nazarov N.I. et al..

Thus, the study of genetic markers such as ADD1

G1378T, CYP11B2 C344T and GNB3 C825T

remains an urgent task for improving the methods of

prognosis, early diagnosis and creating individualized

approaches to the treatment of arterial hypertension

and its complications, which served as the goal of our

scientific work.

762

Ergashevna, A. D., Gafurjanovna, M. M. and Uchkunona, M. G.

Genetic Aspects of Arterial Hypertension: How Gene Polymorphisms Determine the Risk of Developing Hypertension.

DOI: 10.5220/0013424600004654

In Proceedings of the 4th International Conference on Humanities Education, Law, and Social Science (ICHELS 2024), pages 762-769

ISBN: 978-989-758-752-8

2 MATERIAL AND METHODS

The study included 392 people, of whom 100 were

individuals without hypertension (control group) and

292 had arterial hypertension (AH) of varying

severity (main group). The ratio of men to women

was 266/126, i.e. the number of men was 2.1 times

greater than the number of women. The gender ratio

in the groups was as follows: in the main group

198/94 (i.e. 2.1/1.0) and in the control group – 68/32

(i.e. 2.1/1.0). The average time from the diagnosis of

hypertension to inclusion in the study was 2.2 years.

The clinical parameters of the examined patients

included: measurement of systolic and diastolic blood

pressure (SBP and DBP, mmHg) of the maximum,

usual and at the time of examination, as well as

measurement of heart rate (HR, bpm).

From the anamnestic data, the presence of

concomitant pathologies was analyzed: chronic

obstructive pulmonary disease (COPD),

cerebrovascular pathology, anemic syndrome (with a

blood Hb level < 100 g / l), oncology, previous covid-

19, chronic kidney disease (CKD), visual impairment.

In addition to a general clinical examination, their

taste sensitivity to table salt was studied using a

modified method of R.J. Henkin. Salt sensitivity was

determined using the method of M.H. Weinberger.

Genetic studies were performed using peripheral

blood collected on ethylenediaminetetraacetic acid

(EDTA). Genomic DNA was isolated using the

QIAamp DNA Blood Mini Kit (QIAGEN,

Germantown, MD, USA). We investigated the

A1166C polymorphism of the AGTR1 gene and the

G1675A polymorphism of the AGTR2 gene using

real-time polymerase chain reaction (RT PCR)

performed using the ViiA 7 Real Time PCR System

(Life Technologies, USA). We used the TaqMan Pre-

Designed SNP Genotyping Assay. The following

candidate genes were analyzed:

angiotensin I receptor type 1 gene AGTR1

(A1166C),

angiotensin II receptor type 2 gene AGTR2

(G1675A),

angiotensinogen gene AGT (C521T and

T704C),

ADD1 gene G1378T was determined to

determine the genetic predisposition to salt-sensitive

hypertension,

aldosterone synthase gene CYP11B2

C344T,

GNB3 gene C825T,

as well as NOS3 genes G894T and NOS3

T786C.

Standard chi-square (x2) and Student's t-test

methods were used for statistical analysis;

calculations were performed using the Statistica 6.0

statistical program to determine the probability of

differences in the distribution of genotypes during the

development of hypertension. Differences were

considered reliable at p<0.05.

3 RESEARCH RESULTS

We studied in detail the frequency of certain

candidate genes and their genotypes in the analyzed

sample (Table 1). As can be seen from Table 1, the

studied genetic markers AGTR2 G1675A, AGTR1

A1166C, AGT C521T, AGT T704C, as well as NOS3

G894T and NOS3 T786C did not differ significantly

between the groups (all p>0.05).

Direct analysis of the isolated genotypes

established that the homozygous AA genotype of the

genetic marker AGTR1 A1166C, the CC genotype of

the marker AGT C521T and the TT genotype of the

marker AGT T704C were comparable in frequency of

occurrence and turned out to be the predominant

genotypes in general in all individuals of the studied

sample, regardless of the presence/absence of AH

(Table 1).

A similar situation was observed for the

homozygous GG genotype of the genetic marker

NOS3 G894T and the TT genotype of the marker

NOS3 T786C, which made up the majority of these

genes, both in patients with and without AH (Table

1).

In the cohort examined by us, the prevalence of

the homozygous GG genotype was revealed for the

ADD1 G1378T gene in both groups of patients, both

in the control group (87.0%) and in patients with AH

(56.5%). However, in the main group, this advantage

was not so pronounced and was 30.5% less in

comparison with the control group (p < 0.00001). In

the group of patients with AH, in comparison with the

control group, the heterozygous GT genotype

prevailed (32.9% versus 9.0%, respectively, in the

main and control groups; p < 0.00001). Also, among

patients with AH, the homozygous TT genotype was

noted 6.6% more often than in patients without AH.

That is, the last two genotypes are heterozygote GT

and homozygote TT, although they did not constitute

the majority of genotypes, nevertheless, their

frequency prevailed among individuals with AH

(about 43.5%), while in the control group these

genotypes constituted, in total, 13.0%.

Genetic Aspects of Arterial Hypertension: How Gene Polymorphisms Determine the Risk of Developing Hypertension

763

Table 1: Frequency of the candidate genes in question in the analyzed sample and depending on the presence/absence of AH.

Genes, genetic

markers and their

enot

The entire

sample (n=392)

Without AH

(n=100)

With AH

(n=292)

p χ2

AGTR2 G1675A

А 129

(

32,9%

)

(

32,0%

)

(

33,2%

)

0,920 0,010

G 137 (34,9%) 36 (36,0%) 101 (34,6%) 0,894 0,018

АА 38 (9,7%) 10 (10,0%) 28 (9,6%) 0,940 0,006

GA 40 (10,2%) 10 (10,0%) 30 (10,3%) 0,910 0,013

GG 48

(

12,2%

)

(

12,0%

)

(

12,3%

)

0,929 0,008

AGTR1 A1166C 392

АА 266

(

67,9%

)

(

69,0%

)

197

(

67,5%

)

0,874 0,025

АС 85 (21,7%) 20 (20,0%) 65 (22,3%) 0,740 0,111

СС 41 (10,5%) 11 (11,0%) 30 (10,3%) 0,988 0,000

AGT C521T

СС 309

(

78,8%

)

(

82,0%

)

227

(

77,7%

)

0,449 0,575

СТ 62

(

15,8%

)

(

14,0%

)

(

16,4%

)

0,676 0,175

ТТ 21 (5,4%) 4 (4,0%) 17 (5,8%) 0,660 0,195

AGT T704C

СС 40 (10,2%) 9 (9,0%) 31 (10,6%) 0,778 0,073

ТС 84

(

21,4%

)

(

22,0%

)

(

21,2%

)

0,984 0,000

ТТ 268

(

68,4%

)

(

69,0%

)

199

(

68,2%

)

0,974 0,001

ADD1 G1378T

GG 252 (64,3%) 87 (87,0%) 165 (56,5%) 0,000 28,854

GT 105 (26,8%) 9 (9,0%) 96 (32,9%) 0,000 20,454

TT 35

(

8,9%

)

(

4,0%

)

(

10,6%

)

0,072

3,238

CYP11B2 C344T

СС 269

(

68,6%

)

(

83,0%

)

186

(

63,7%

)

0,000 12,007

СТ 69 (17,6%) 12 (12,0%) 57 (19,5%) 0,121 2,409

ТТ 54 (13,8%) 5 (5,0%) 49 (16,8%) 0,006 7,740

GNB3 C825T

СС 241

(

61,5%

)

(

71,0%

)

170

(

58,2%

)

0,032 4,612

СТ 114

(

29,1%

)

(

20,0%

)

(

32,2%

)

0,029 4,794

ТТ 37

(

9,4%

)

(

9,0%

)

(

9,6%

)

0,981 0,001

NOS3 G894T

GG 259 (66,1%) 69 (69,0%) 190 (65,1%) 0,553 0,353

GT 92

(

23,5%

)

(

20,0%

)

(

24,7%

)

0,417 0,659

TT 41

(

10,5%

)

(

11,0%

)

(

10,3%

)

0,988 0,000

NOS3 T786C

CC 45 (11,5%) 11 (11,0%) 34 (11,6%) 0,995 0,000

TC 89 (22,7%) 24 (24,0%) 65 (22,3%) 0,826 0,048

TT 258 (65,8%) 65 (65,0%) 193 (66,1%) 0,939 0,006

Note: n – number of patients; AH – arterial hypertension; p – significance of differences between groups with/without

H at p<0.05; #

–

tendency to significance

Since the ADD1 gene encodes the alpha subunit

of the adducin protein, one of the regulators of

sodium-potassium adenosine triphosphatase (Na+,

K+-ATPase), the latter, in turn, is involved in the

transport of these ions through the membrane of the

renal epithelium, this gene is used in assessing the

genetic predisposition to salt-sensitive hypertension.

Based on this fact, we conducted a parallel

analysis with family history data. In this aspect, it was

found that in general, 201 (51.3%) people in the entire

sample of subjects indicated a burdened heredity for

AH, and in most cases (175 people) these were

patients from the main group, i.e. with the presence

of AH, the remaining 26 were from the control group.

In percentage terms of the number of groups, this

indicator also prevailed among people with AH,

amounting to 59.9% versus 26.0% in the control

group (p = 0.0000 and χ2 = 32.983). When

conducting a correlation analysis between the

frequency of the isolated genotypes of the ADD1

G1378T gene (GG, GT and TT) and family history,

the following dependencies were revealed (Fig. 1A

ICHELS 2024 - The International Conference on Humanities Education, Law, and Social Science

764

Note: On the X-axis, under the number “0” - the absence of an aggravated family history and under the number “1” - the

presence of an aggravated heredity for AH; on the Y-axis, under the number “0” - the absence of GT heterozygote and

under the number “1” - the presence of GT heterozygote of the ADD1 G1378T gene.

Figure 1A: Correlation graph between the heterozygous GT genotype of the ADD1 gene and the presence of a burdened

family history of AH. р=0,020; r=0,117 и t=2,328.

p=0.052#; r= -0.098 and t= -1.947

Note: On the X-axis, under the number “0” - the absence of an aggravated family history and under the number

“1” - the presence of an aggravated heredity for AH; on the Y-axis, under the number “0” - the absence of a GG homozygote

and under the number “1” - the presence of a GG homozygote of the ADD1 G1378T gene.

Figure 1B: Correlation graph between the homozygous GG genotype of the ADD1 gene and the presence of a burdened

family history of AH.

and 1B). Namely, the prevalence of the heterozygous

GT genotype was characterized by a direct

relationship with an aggravated family history of AH,

and the identified relationship reached the level of

reliability (Fig. 1A). No significant interdependence

was found between a family predisposition to AH and

the homozygous TT genotype (p=0.738; r= -0.016

and t= -0.334). On the contrary, an inverse correlation

with a tendency toward reliability was established

between the homozygous GG genotype and an

indication of an aggravated family history (Fig. 1B).

That is, a heredity burdened by AH, or a family

predisposition to the development of AH, had a clear

association with the heterozygous GT genotype of the

ADD1 gene, and given its connection with a

predisposition to salt-sensitive hypertension, we can

conclude that the patients we examined had, one way

or another, a nutritional disorder. On the contrary, the

homozygous GG genotype of the ADD1 gene,

according to the results of our analysis, was more

associated with healthy (free from AH) individuals.

Analysis of the genetic marker C344T of the

CYP11B2 gene also established the prevalence of the

homozygous CC genotype. Namely, in the sample as

a whole, its frequency of occurrence was 68.6%, and

in the compared groups 83.0% in the control group,

i.e. in individuals without AH and 63.7% in patients

with AH.

The heterozygous CT genotype accounted for

17.6% of cases in the entire sample (Table 1). In the

Genetic Aspects of Arterial Hypertension: How Gene Polymorphisms Determine the Risk of Developing Hypertension

765

group of patients with AH, this indicator was 7.5%

higher than in the control group (p=0.121 and

χ2=2.409).

A similar trend was observed for the homozygous

TT genotype. In particular, in the sample as a whole,

this genotype was recorded in 13.8% of cases, and in

the compared groups in 5.0% and 16.8% of cases

(p<0.05), respectively, in the control group and in the

main group of patients (Table 1).

It is widely known that the CYP11B2 gene

encodes aldosterone synthetase, which ensures the

synthesis of aldosterone from deoxycorticosterone.

Detection of the C344T mutation in the regulatory

region of the gene is associated with an increase in

aldosterone synthesis. The latter is known to be

responsible for the functioning of the renal sodium-

potassium pump and maintenance of water-

electrolyte balance. In this regard, we conducted a

correlation analysis between the isolated genotypes

(CC, CT and TT) of the CYP11B2 gene and the

presence of CKD in the examined patients. In this

aspect, no significant relationships were revealed.

Namely, the presence of renal pathology was

characterized by an inverse relationship with the

heterozygous CT genotype (p = 0.329; r = -0.057 and

t = -0.976) and a positive correlation with

homozygous CC (p = 0.900; r = 0.006 and t = 0.000)

and TT genotypes (p = 0.854; r = 0.010 and t = 0.183),

however, the identified trends did not reach the level

of reliability. The obtained results were probably due

to the small number of patients with CKD: 28.1% of

the total sample, and in the selected groups their

number was 12.0% in the control group and 33.6% in

the group of patients with AH (p=0.0000 and

χ2=16.104). According to the literature [3], some

variants of genes associated with sensitivity to salt

affect the risk of obesity, and together with salt

consumption, their combination may be associated

with the development of hypertension in obese

people. In this regard, we tried to study the

relationship of the isolated genetic marker CYP11B2

C344T with obesity, or rather its indirect indicator -

the waist-to-hip ratio (WHR). We found a positive

correlation (Fig. 2) between the studied genetic

marker and the WHR (p<0.05).

That is, this fragment of our work indicates a

relationship between the genetic marker CYP11B2

C344T and obesity (p<0.05), mediated by the

presence of a mutation in the regulatory region of the

gene responsible for the synthesis of aldosterone. At

the same time, its relationship with the potassium-

sodium renal pump and water-electrolyte balance did

not reach the level of reliability (all p>0.05), which

was probably due to the small number of diagnosed

renal pathology in the analyzed sample of patients. In

the sample of patients examined by us, another

genetic marker attracts attention - this is GNB3

C825T. Detection of the C825T mutation in the

GNB3 gene indicates changes in the differentiation of

lymphoblasts, fibroblasts and proliferative activity. In

scientific research, the study of this genetic marker is

carried out with the aim of identifying a genetic

predisposition to AH, as well as assessing the

relationship with LV myocardial hypertrophy (LVH),

the development of obesity and diabetes mellitus.

p=0.022; r=0.115 and t=2.290

Notes: on the X-axis – the selected genotypes of the CYP11B2 C344T marker and on the Y-axis – under the number “1” –

WC/HR < 1 and under the number “2” – WC/HR > 1.

Figure 2: Graph of the correlation between the genetic marker CYP11B2 C344T and the WC/HR ratio.

ICHELS 2024 - The International Conference on Humanities Education, Law, and Social Science

766

p=0.000; r=0.302 and t=6.260

Notes: X-axis – isolated genotypes of the marker GNB3 C825T and Y-axis – left ventricular hypertrophy (LVH) detected

by echocardiography.

Figure 3A: Correlation graph between the isolated genetic marker GNB3 C825T and the presence of LV myocardial

hypertrophy.

p=0.000; r=0.810 and t=27.292

Notes: on the X-axis – isolated genotypes of the marker GNB3 C825T and on the Y-axis – under the number “1” - WC/HR

< 1 and under the number “2” - WC/HR > 1.

Figure 3B: Correlation graph between the isolated genetic marker GNB3 C825T and the WC/HR ratio.

Based on the above, we conducted a correlation

analysis between the selected genotypes (CC, CT and

TT) of the genetic marker GNB3 C825T and the

presence of LVH according to echocardiography, an

indirect indicator of obesity - WC/OB and

postprandial blood glucose values. From this

position, a direct positive correlation was revealed

between the genetic marker GNB3 C825T and the

presence of LVH according to echocardiography - on

the one hand (Fig. 3A) and the level of WC/OB - on

the other hand (Fig. 3B), while both correlations were

highly reliable (both p < 0.0000). A direct

relationship was also established between the genetic

marker GNB3 C825T and the level of postprandial

blood glucose, although it did not reach the level of

reliability (p=0.082; r=0.087 and t=1.738).

A study of the frequency of occurrence of homo-

and heterozygous genotypes for the GNB3 C825T

gene revealed a picture that, in the sample as a whole,

regardless of the presence/absence of AH, the

homozygous CC genotype prevailed (61.5%), while

in patients with AH it was recorded in 58.2%, and in

individuals without AH - in 71.0% of cases. The

presence of the heterozygous CT genotype was

present in 114 (29.1%) patients, of which 94 (82.5%

of 114 people with this genotype or 32.2% of the main

group n=292) were people with AH and 20 people

(17.5% of 114 or 20.0% of the control group n=100)

were from the control group (p<0.05). The

homozygous TT genotype was found in the smallest

number of cases, amounting to 9.4% of the total

sample, and 9.0% and 9.6% in the analyzed control

groups and in people with AH, respectively (Table 1).

Thus, a detailed analysis of the genetic marker

CYP11B2 C344T established its relationship with the

presence of LVH (according to echocardiography)

Genetic Aspects of Arterial Hypertension: How Gene Polymorphisms Determine the Risk of Developing Hypertension

767

and obesity, or rather with its indirect indicator – the

WC/OB ratio, while both dependencies were highly

reliable (p<0.0001). There was also a positive

correlation with the level of postprandial blood

glucose, but this trend did not reach the level of

reliability. The genotypic picture of the GNB3 gene

revealed the prevalence of the homozygous CC

genotype, regardless of the presence/absence of AH,

but the heterozygous CT genotype was predominant

among patients with AH (82.5%), while the

homozygous TT genotype occurred with almost the

same frequency in the compared groups (9.0% and

9.6%).

4 DISCUSSION

The study found that among the genetic markers

studied (AGT, CYP11B2, GNB3, ADD1 and NOS3),

only some of them demonstrate a significant

association with the development of arterial

hypertension (AH) and its complications, such as

myocardial hypertrophy and obesity. This is

consistent with the results of many international

studies that emphasize the role of genetic

predisposition in the pathogenesis of AH.

The AGT gene (angiotensin I converting enzyme

gene) and its polymorphisms, such as AGT C521T,

AGT T704C, have long attracted the attention of

researchers as key markers of AH risk. The works of

Curb et al. (2007) and Gagliardi et al. (2009) show

that variations in genes encoding components of the

renin-angiotensin-aldosterone system (RAAS)

significantly affect the development of hypertension,

including the difficulty in its treatment [8,9]. Our

results, which did not show statistically significant

differences in these markers in the sample with AH

and the control group, are generally consistent with

similar studies, where polymorphisms in these genes

do not always have a clear effect on the severity of

the disease. The CYP11B2 gene, encoding

aldosterone synthetase, is also of interest as a factor

influencing the development of hypertension. The

works of Kawarazaki and Fujita (2016), as well as

Wang et al. (2018) demonstrated an association of

mutations in this gene with increased sensitivity to

salt and excessive secretion of aldosterone, which in

turn contributes to an increase in blood pressure. Our

findings of the prevalence of the homozygous CC

genotype in the control group and the prevalence of

the heterozygous CT genotype in the AH group

confirm the results of similar studies. However, as in

some studies, for example, Yang et al. (2015), we did

not observe a significant correlation with the

development of chronic kidney disease, which may

be due to differences in the sample or a lower

incidence of kidney disease in the study group. The

GNB3 C825T gene has been actively studied in

recent years in the context of hypertension and its

complications. Studies by Cohen et al. (2005) and

Weiss et al. (2003) show that a mutation in this gene

may be associated with myocardial hypertrophy,

obesity, and diabetes. Our findings on the high

prevalence of the heterozygous CT genotype among

patients with AH are also confirmed by international

data, which may indicate the importance of this

marker for predicting the risk of developing

hypertension and its cardiovascular complications.

The ADD1 gene, involved in the regulation of

sodium-potassium adenosine triphosphatase

(Na+,K+-ATPase), showed a significant association

with salt-sensitive hypertension, which is consistent

with the opinion of other researchers. According to

the work of Sowers et al. (2013), mutations in this

gene can increase the body's sensitivity to excess salt,

which leads to an increase in blood pressure. The

results of our study, where the heterozygous GT

genotype was more common among patients with AH

and was associated with a family predisposition, are

fully consistent with these findings. Overall, our

findings confirming the role of genetic markers such

as AGT, CYP11B2, ADD1 and GNB3 in the

development of AH are consistent with international

data and highlight the need for further research to

identify the exact mechanisms of their action. At the

same time, the lack of significant association with

chronic kidney disease in the case of CYP11B2 and

AGT requires additional studies aimed at clarifying

their role in the pathogenesis of AH.

5 CONCLUSION

The prevalence of certain genotypes in the group of

patients with AH (e.g., homozygous AGTR1

A1166C, AGT C521T, and NOS3 G894T genotypes)

suggests that these markers do not have a significant

difference in frequency between the groups with and

without AH. However, the ADD1 G1378T gene

demonstrated an association with a familial

predisposition to AH, especially in the case of the

heterozygous GT genotype, which is associated with

malnutrition and salt sensitivity.

The results of the CYP11B2 C344T marker

analysis showed a positive correlation with an

indirect indicator of obesity (WC/HC), which

confirms its possible role in the regulation of

metabolism and the development of obesity.

ICHELS 2024 - The International Conference on Humanities Education, Law, and Social Science

768

However, its association with renal pathology in this

sample was not statistically significant, which is

probably due to the small number of patients with

CKD. The GNB3 C825T marker showed a strong

positive correlation with left ventricular hypertrophy

(LVH) and obesity level, confirming its potential role

in the development of metabolic disorders and

hypertension. At the same time, the dependence on

the level of postprandial blood glucose was not

significant, which may indicate more complex

interactions between genes and metabolic processes

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