AGTR2 Research Articles

Assessing the influence of the angiotensinogen gene’s polymorphic marker <i>M235T</i> on the changes in daily blood pressure monitoring indicators in patients with stage I–II hypertension

BACKGROUND: The effectiveness of antihypertensive therapy may be associated with genetic factors that both influence the degree of increase in blood pressure and determine inter-subject variability of response to antihypertensive treatment. AIM: To study pharmacodynamic parameters of the effectiveness of therapy with angiotensin II receptor blockers as monotherapy and as part of combination drugs in patients with hypertension, depending on the genetic characteristics of patients, specifically the M235T polymorphism of the angiotensinogen gene. MATERIALS AND METHODS: The study involved 179 patients from the Moscow region with newly diagnosed stage I–II hypertension, including 141 (78.8%) women and 38 (21.2%) men aged 32 to 69 years, who were randomly assigned to groups receiving irbesartan and valsartan as monotherapy or in combination therapy with hydrochlorothiazide, using a simple randomization method. Genetic polymorphism rs699 (C4072T, M235T) of the AGT angiotensinogen gene was determined after 3 weeks of drug therapy. RESULTS: After three months of drug therapy, the maximum antihypertensive effect in the group of patients receiving valsartan was observed in CC homozygotes and heterozygotes by the level of decrease in mean daytime systolic blood pressure. In CC homozygotes, a trend was outlined by the level of decrease in mean daytime diastolic blood pressure; in CC homozygotes, by the level of decrease in mean nighttime systolic blood pressure; in CC and TT homozygotes, by the level of decrease in mean nighttime diastolic blood pressure. No statistically significant association of the angiotensinogen gene’s M235T polymorphism genotype with these parameters was found among patients receiving irbesartan. CONCLUSIONS: The obtained data may indicate a more rapid and stable antihypertensive effect in patients carrying the C allele of the M235T genetic polymorphism of the angiotensinogen gene. Therefore, personalized therapy of arterial hypertension using the detection of the M235T genetic polymorphism in the AGT gene may reasonably include the AT1-receptor blocker valsartan as a starting therapy for the C allele carriers in the Moscow region, as monotherapy or two-component therapy, depending on the stage of hypertension.

Polymorphism of genes involved in the regulation of blood pressure in elderly residents of the Arkhangelsk region

BACKGROUND: Living in the northern climate is associated with increased cardiovascular stress, which highlights the necessity for the study of candidate genes associated with the risk of cardiovascular diseases in both the native population and newcomers. Polymorphic loci of the renin-angiotensin system, NO-synthase, and endothelin-1 system genes have been identified as contributors to cardiovascular dysfunction and age-related blood pressure shifts. It is therefore crucial to assess the genetic polymorphism in the elderly population. AIM: To compare frequencies of gene alleles and genotypes involved in blood pressure regulation, including angiotensinogen AGT (rs699 and rs4762), angiotensin 2 type 1 receptor AGTR1 (rs5186), angiotensin converting enzyme ACE (rs4646994), endothelial NO synthase NOS3 and endothelin-1 EDN1 (rs5370) genes, in the native and non-native elderly population of the Arkhangelsk region. MATERIALS AND METHODS: A cross-sectional study was conducted in a random sample of Arkhangelsk residents between the ages of 60 and 74 years (N=604, with 36.4% of males). The molecular genetic analysis was conducted to determine the alleles and genotypes of six genes that are involved in blood pressure regulation. The Stata 18.0 software was used to assess the deviations of empirical genotype distributions from the predicted Hardy–Weinberg equilibrium and to compare the empirical distributions between the study groups. RESULTS: Alleles associated with the risk of cardiovascular diseases were minor in the study population. The genotype frequency distributions for the analyzed genetic variants were consistent with the Hardy–Weinberg principle, with the exception of the T704C variant of the AGT gene (rs699) in the native participants. The allele and genotype frequency distributions in the study sample were found to be similar to those reported worldwide and in European Russia. One exception was AGTR1 gene A1166C frequencies, with their 95% confidence intervals falling below the global level for both native and non-native elderly residents of the Arkhangelsk region. This may suggest that this allele is a selection variant associated with adaptation to the climate of the northern regions. CONCLUSION: The genetic polymorphism in blood pressure regulation was found to be similar between the native and non-native populations of the Arkhangelsk region. However, the AGTR1 gene A1166C frequency among the native population and newcomers was found to be lower than that observed globally.

Influence of angiotensin II type 1 receptors and angiotensin-converting enzyme I/D gene polymorphisms on the progression of Chagas' heart disease in a Brazilian cohort: Impact of therapy on clinical outcomes.

Chagas disease (CD), a neglected tropical disease, is caused by infection by the protozoan Trypanosoma cruzi. One-third of CD patients develop cardiac disease (CARD), an inflammatory and fibrotic process that may progress to heart failure associated with reduced left ventricular ejection fraction (LVEF). The determinants of CD progression are still uncertain. In non-infectious conditions, the angiotensin-converting enzyme (ACE) functional insertion (I)/deletion (D) and type 1 angiotensin II receptor (AT1R) +1166A>C gene polymorphisms have been linked to clinical outcomes. In a Brazilian cohort of 402 patients with positive serology for CD, in a case-control study we used PCR for genotyping the ACE rs4646994 I/D and AGTR1 rs5182C>T, rs275653 -119C>T, rs2131127A>G and rs5186 +1166A>C polymorphisms to evaluate association with CARD and progression to heart failure. Patients were classified as non-CARD (stage A; 109), and mild (stage B1; 161) or severe (stage C; 132) CARD. The groups were compared using unconditional logistic regression analysis and adjusted for non-genetic covariates (age, gender, and trypanocidal treatment). ACE II genotype appeared less frequent in C patients (15% in C vs 20% in B1 and 27% in A). After covariate adjustments, the ACE D allele showed a borderline association with susceptibility to severe CARD (C vs A: OR = 1.9; P = 0.08). AGTR1 +1166AC genotype showed a borderline association with protection against the progression and severity of CARD (C vs A: OR = 0.6; P = 0.09; C vs B1: OR = 0.6; P = 0.07; C vs A + B1: OR = 0.6; P = 0.05). However, adjustments for multiple comparisons showed no association of ACE I/D and AGTR1 polymorphisms with susceptibility and severity of CARD. The rs275653/rs2131127/rs5186/rs5182 T/A/C/T haplotype was protective against progression to the severe form of CARD (C vs B1: OR = 0.3; P = 0.03). Moreover, patients with ACE II and AGTR1 rs5186 +1166AC genotypes presented higher LVEF%. In C patients, TNF serum levels were higher in ACE D carriers than in II genotype. Although limited in number, a cross-sectional observation suggests that C-stage patients treated with benznidazole years prior to administration of ACE inhibitors/AT1R antagonists show reduced TNF serum levels and improved LVEF%. Therefore, variants of ACE and AGTR1 genes may influence the outcome of Chagas' heart disease and should be explored in precision medicine. Further, pharmacotherapies may improve immunological abnormality and clinical outcome in CD patients. Altogether, these data support prospective studies of this cohort and replication in other cohorts.

Clinical significance of post-COVID-19 in patients with hypertension, taking into account the polymorphism of genes encoding components of the renin-angiotensin system

To date, there has been no consensus on the impact of polymorphism of components of the renin-angiotensin-aldosterone system (RAAS) on the course of a new coronavirus infection or a possible role in post-COVID syndrome. The objective is to study the significance of COVID-19 and gene polymorphism encoding components of renin angiotensin system in patients with hypertension. Materials and methods: A clinical examination was conducted on 116 stage 2 hypertensive patients with uncontrolled hypertension. Of these, 96 underwent mild or moderate COVID-19, 51 before 12 weeks and 45 after 12. Results. Patients in the ongoing symptomatic phase of COVID- 19 had higher systolic blood pressure than those with post COVID syndrome (p1-2 = 0.03659, p1-3 ≤ 0,00001).The association of polymorphisms of genes AGT:704T>C, AGT521C>T, AGTR1:1166A>C, AGTR2:1675G>A, CYP1IB2:-344C>T with gender, BMI and COVID-19 transmission has not been identified. In the symptomatic phase of COVID-19, carriage of the TT genotype for the AGT704 gene was less frequent (p=0.005) compared to the control group. Conclusions. The effect of COVID on an increase in blood pressure in stage 2 hypertensive patients was determined. An association between blood pressure instability and BMI after COVID was established. During the symptomatic COVID phase, there was an association between increased blood pressure and the C allele of AGT gene polymorphisms (T704).

Genetic markers and traditional risk factors in predicting atrial fibrillation in patients with arterial hypertension, focus on the renin-angiotensin-aldosterone system genes

BACKGROUND: Genetic and environmental factors are involved in the development of atrial fibrillation in arterial hypertension. This determines the relevance of studying gene-environment interactions in the occurrence of arrhythmia. AIM: To evaluate the contribution of the renin-angiotensin-aldosterone system genes polymorphisms to the susceptibility to atrial fibrillation in patients with arterial hypertension, and also to study the combined influence of these polymorphisms and environmental factors on the risk of arrhythmia. MATERIALS AND METHODS: The study included 60 patients with arterial hypertension and paroxysmal atrial fibrillation (study group), 60 patients with arterial hypertension without atrial fibrillation (comparison group-1) and 20 healthy volunteers (comparison group-2). Angiotensin-converting enzyme (ACE (I/D)) and angiotensin II type 1 receptor gene (AGTR1 (A1166C)) polymorphisms were analyzed by real-time polymerase chain reaction. RESULTS: Genotype II and allele I of the ACE gene (I/D) in patients with arterial hypertension and atrial fibrillation were significantly more frequent compared to patients with arterial hypertension without arrhythmia (χ² = 4.547; p = 0.03 and χ² = 4.818; p = 0.03 respectively). Carriage of genotype II in patients with arterial hypertension increased the chance of developing atrial fibrillation by 2.8 times (95% CI 1.19–7.18). The odds ratio (OR) for arrythmia development in patients with arterial hypertension and allele I was 1.8 (95% CI 1.10–3.07). The presence of obesity in patients with arterial hypertension in the presence of genotype II of the ACE gene (I/D) was associated with an increased risk of developing atrial fibrillation, compared with the genotype alone (OR = 4.16, 95% CI 1.16–19.87). A study of the A1166C polymorphism of the AGTR1 gene did not reveal a reliable significant relationship between its inheritance and the development of atrial fibrillation. CONCLUSION: Genotype II and allele I of the ACE gene (I/D) were statistically significantly more frequent in patients with arterial hypertension and atrial fibrillation. Carriage of genotype II and allele I of the ACE gene (I/D) increased the chance of developing atrial fibrillation in patients with arterial hypertension. Obesity had a significant effect on the susceptibility to atrial fibrillation in the presence of genotype II of the ACE gene (I/D) in hypertensive patients.

ВЛИЯНИЕ ЭКСТРАКОРПОРАЛЬНОЙ АУТОГЕМОМАГНИТОТЕРАПИИ В ИНТРАОПЕРАЦИОННОМ ПЕРИОДЕ ПРИ ПРОВЕДЕНИИ РЕВАСКУЛЯРИЗАЦИИ МИОКАРДА В УСЛОВИЯХ ИСКУССТВЕННОГО КРОВООБРАЩЕНИЯ НА КИСЛОТНО-ЩЕЛОЧНОЕ СОСТОЯНИЕ АРТЕРИАЛЬНОЙ КРОВИ

Background. To evaluate changes in acid-base balance in patients with coronary heart disease in the intraoperative period during coronary artery bypass grafting under artificial circulation using extracorporeal autohemomagnetotherapy (EAHMT). To consider the presence of a negative effect of this technique on acid-base balance. To study the possible relationship between the polymorphism of the angiotensin-1 receptor gene (AGTR1 A1166C), endothelin-1 (EDN1 Lys 198 Asn), endothelial nitric oxide synthase (NOS3 C786T) and changes in the studied parameters of acid-base balance. Material and methods. Group 1 included standard anesthesia for coronary artery bypass grafting under cardiopulmonary bypass without the use of EAHMT (60 patients). Group 2 included standard anesthesia for coronary artery bypass grafting under cardiopulmonary bypass with the use of EAHMT (63 patients). The following parameters of the acid-base balance of arterial blood were assessed: hydrogen index (pH), lactate (Lac), base deficit (SBE), potassium (K), sodium (Na), hemoglobin (Hb), hematocrit (Hct). All patients of both groups underwent intraoperative venous blood sampling from the central venous catheter. Then, the polymerase chain reaction method was used to study the genotypes of the angiotensin-1 receptor gene polymorphism (AGTR1 A1166C), endothelin-1 (EDN1 Lys 198 Asn), endothelial nitric oxide synthase (NOS3 C786T). Results. At the second stage of the study, a decrease in the hydrogen index of arterial blood, hemoglobin, hematocrit, and base deficit was revealed in both groups. A statistically significant increase in lactate and potassium was obtained in both study groups. No associations were found between the polymorphism of the angiotensin-1 receptor gene (AGTR1 A1166C), endothelin-1 (EDN1 Lys 198 Asn), endothelial nitric oxide synthase (NOS3 C786T) and the arterial blood acid-base balance. Conclusion. The use of EAHMT does not have negative impact on the electrolyte balance and acid-base composition of the blood. The presence of polymorphism of the AGTR1 gene A1166C (rs 5186), EDN1 gene Lys 198 Asn (rs5370), NOS3 gene C786T (rs 2070744) does not affect the acid-base balance of arterial blood.

Differences in the DNA methylome of T cells in adults with asthma of varying severity

BackgroundDNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity are less well-defined.ObjectiveTo examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation.MethodsPeripheral blood T cells from 35 adults with asthma in Beijing, China, were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores.ResultsSignificant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included RUNX3, several members of the HLA family, AGT, PTPRC, PTPRJ, and several genes downstream of the JAK2 and TNF signaling pathway.ConclusionThese findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to differences in clinical indices of asthma.

Predictors of the development of abnormal patterns of circadian blood pressure rhythm in patients with hypertension after a new coronavirus infection

Objective. To determine the predictors of the development of abnormal patterns of circadian blood pressure (BP) rhythm in patients with arterial hypertension (AH) after a new coronavirus infection (NСVI). Materials and methods. The study is a comparative clinical research of the same patients with hypertension before and after NCVI with retrospective evaluation of the data. Within 2 years from 842 patients with cardiovascular risk factors, according to the inclusion and non-inclusion criteria 70 patients with target levels of office BP, home monitoring and 24-hour blood pressure monitoring (ABPM) on the background of a continuous antihypertensive therapy were included in the study. Abnormal patterns of circadian BP were recorded after NCVI during ABPM in all of them. All patients with hypertension underwent a complete examination before and after NCVI. Results. After NCVI in patients with AH who had achieved the target ranges of office BP before its development, at home measurement and ABPM against the background of continuous antihypertensive therapy with high adherence to treatment, in more than 50 % of patients BP readings were not in the target values, in more than 50 % of the examined patients, BP variability was higher than the permissible values, in 73 % of patients the average daily BP was above 53 mm Hg. Abnormal patterns of circadian BP rhythm in patients with hypertension after NCVI were detected in 61.5 %: "Non-dipper" in 28.6 %; "Night-dipper" – in 21.9 %, masked nocturnal hypertension – in 17.1 %. Conclusion. The indicative significance of the development of abnormal patterns of circadian BP rhythm in patients with hypertension after NCVI was demonstrated by 3 qualitative indicators: glomerular filtration rate with cystatin C 60 ml/min/1.73 m2, cardio-ankle vascular index (CAVI) ≥ 9, and a high frequency of AGT gene polymorphism – T/T genotype (in 54.3 % of patients).

AGTR1 variant rs2638355 is associated with increased salt sensitivity of blood pressure: a female-specific effect in individuals from the HyperPath cohort.

Salt-sensitive hypertension (SSH) affects approximately half of the hypertensive population, increasing the risk of vascular complications. The underlying pathophysiological mechanisms of SSH remain complex and need to be fully elucidated. Our prior research has identified genetic factors contributing to the salt sensitivity of blood pressure (SSBP), particularly involving genes regulating volume and blood pressure. We also observed enhanced peripheral vascular response to angiotensin II in humans with salt-sensitive hypertension. Given the pivotal role of the angiotensin II receptor type-1 (AT1R or AGTR1) in blood pressure and intravascular volume regulation, we hypothesized a genetic association between AGTR1 and SSBP. Our study involved 240 individuals of European ancestry from the HyperPATH cohort, examined under restricted and high dietary salt conditions. We employed a tagging single nucleotide variant approach to genotype participants at AGTR1 . Our regression model revealed a significant association between the rs2638355 (A/G) variant and salt-sensitive systolic blood pressure (SS-SBP), and rs2638355 increased AGTR1 gene expression. Notably, carriers of the risk-allele of the noncoding regulatory variant rs2638355 exhibited higher systolic blood pressure under high salt diet conditions than nonrisk allele individuals. A sex-stratified analysis showed this salt-driven effect on systolic blood pressure was significant only in females, underscoring the role of dietary salt in modulating genetic effects in this group. Furthermore, a restricted salt diet in these individuals diminished blood pressure and negated the blood pressure phenotype-genotype association. Overall, our findings could aid in pinpointing individuals with salt-sensitive blood pressure among hypertensive patients, especially considering dietary and sex-specific factors.

Abstract P431: Crosstalk Between Dopamine Receptors and AT1R in Hypertension Induced Cardiac Remodeling

Dopamine receptors are implicated in the regulation of cardiovascular function, yet their specific roles in the modulation of hypertension and cardiac remodeling are not fully understood. The angiotensin II type 1 receptor (AT1R) plays a critical role in the pathophysiology of hypertension by mediating vasoconstriction, sodium retention, and sympathetic nervous system activation. Previous studies from our lab have demonstrated that in Ang II-induced hypertension, there are alterations in D1R and D3R expression in the left ventricle (LV) compared to wild-type (WT) mice. Evidence indicates that AT1R and D1R form heterodimers and inhibition of AT1R has been shown to enhance D1R signaling in proximal tubules, suggesting a significant interaction between these receptor systems. However, the role of intracardiac dopamine receptors on AT1R expression during hypertension remains understudied. Therefore, this study aims to elucidate the crosstalk between intracardiac dopamine receptors and AT1R in the context of hypertension and cardiac remodeling by using in vitro and in vivo pharmacological and molecular methods combined with novel genetic models. Using global D3R deficient (D3KO) and WT mice, we observed that D3KO leads to alterations in AT1R gene expression in LV compared to WT hearts (p<0.001) and in isolated LV cardiac fibroblasts (p<0.0001). D3KO and WT mouse cardiac fibroblasts (mCFb) and human cardiac fibroblasts (hCFb) were stimulated with Ang II (300nM) ± D1R antagonist (SCH, 10µM) or D3R antagonist (SB, 10µM). D1R antagonism significantly increased AT1R (Agtr1 gene) levels in both WT and D3KO mCFb (p<0.01), whereas D3R antagonism reduced AT1R gene expression following Ang II stimulation (p<0.01). Furthermore, these data were confirmed in hCFb. To determine crosstalk between dopamine receptors and AT1R, we used proximity ligation assay (PLA) to examine the close proximity (<40nm) of receptor-receptor expression and interaction. Our results indicate that in mCFb and hCFb, there is an increase in D1R-AT1R interactions following Ang II both with and without D1R antagonism (p<0.05), however, AT1R-D3R interactions were reduced (p<0.05). These data suggest that dopamine receptor activity significantly influences AT1R gene expression, highlighting a potential modulatory role for dopamine receptors in the regulation of AT1R during hypertension.

O102 RELATIONSHIP BETWEEN AGTR1 (c.1166 A>C) POLYMORPHISMS AND KIDNEY INJURY IN HYPERTENSION

Background: High blood pressure is the main cause of cardiovascular diseases. Kidney damage is one of the most common organ secondary damage to hypertension. The study of hypertension gene polymorphisms is an important means of precision treatment of primary hypertension. Objectives: The objective of this study was to explore the relationship between AGTR1 (c.1166 A>C) gene polymorphisms and hypertension combined with kidney damage, while exploring the relationship between codominant, dominant and recessive gene model and hypertension with kidney injury and the susceptibility of different genotypes to hypertension with kidney injury. Methods: The distribution of AGTR1 polymorphism in the AGTR1 in hypertensive patients (hypertension group, 292 patients) and hypertension with kidney injury patients (44 patients) were detected and compared by PCR-melting curve method. Results: The genotype distribution of hypertension and combined groups met Hardy-Weinberg equilibrium (p > 0.05); the distribution difference between the three genotypes was statistically significant (p < 0.05), the codominant, dominant and recessive distribution frequency of genotypes (p < 0.05), and no difference between A allele and C allele (p > 0.05). Conclusions: Our study identified the relationship of AGTRA (c.1166 A>C) with hypertension combined with renal injury, and compared the susceptibility of different genetic models, which may provide novel targets for precision gene therapy of hypertension.

Integrated Management of Post-Myocardial Infarction Patients Using Genetic Analysis and Remote Control

Coronary heart disease (CHD) remains a leading cause of mortality and morbidity worldwide, particularly due to complications following myocardial infarction (MI). Despite advancements in therapeutic strategies, the prognosis for MI patients varies significantly, necessitating a comprehensive approach that integrates genetic and non-genetic factors. This study addresses the knowledge gap by evaluating the influence of genetic polymorphisms and non-genetic factors on the 12-month prognosis of MI patients. Using a cohort of 250 post-MI patients, we conducted genetic analysis on polymorphisms of the AGT, ADRB1, APOE, LPL, and CYP2C19 genes and assessed their correlation with clinical outcomes using modern statistical methods. Our findings indicate significant associations between specific gene polymorphisms and patient prognosis, highlighting the importance of personalized medicine. The results suggest that incorporating genetic analysis into the management of MI patients can improve survival rates and inform targeted therapeutic interventions, offering a novel approach to enhancing patient care in clinical settings.

Differences in the DNA Methylome of T cells in Adults With Asthma of Varying Severity.

DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes are less well-defined. To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. Peripheral blood T cells from 35 adults with asthma in Beijing, China were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included RUNX3, several members of the HLA family, AGT, PTPRC, PTPRJ, and several genes downstream of the JAK2 and TNF signaling pathway. These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to the phenotype and severity of their overall disease.

Genetic determinants of obesity in adolescent girls

Significant progress in understanding the genetic contribution in obesity and its prevalence at all ages has been achieved since existing methods of treatment and preventive measures aimed at combating obesity are not effective enough.Purpose. To study the prevalence of pathologic single nucleotide polymorphisms rs6265 of the brain neutrophic factor gene BDNF; rs1137101 of the leptin receptor gene LEPR; rs9939609 of the gene, associated with fat mass, FTO; rs4762 and rs699 of angiotensinogen AGT gene; rs1799883 of fatty acid transporter gene FABP2; rs1801282 of PPARG2 gene in obese adolescent girls.Material and methods. 72 teenage girls aged 12–17 years were examined. Group 1 consisted of 36 obese children (standard deviation coefficient SDS BMI ≥ 2.0), group 2 — 36 non-obese children (SDS BMI <1.0). Anthropometric, molecular genetic, and statistical methods were used.Results. In obese adolescent girls, an association was detected with only one gene — PPARG2, a polymorphic locus (Pro/Pro). The prevalence rate of the C allele in group 1 was 80%, in group 2 — 3% (p<0.05). No statistically significant differences in the frequencies of genotypes and alleles of other genes in children with obesity and normal body weight were established.Conclusion. Further large-scale studies, including biochemical and hormonal parameters, are needed to establish the influence of specific polymorphic loci of various genes contributing in obesity and metabolic processes.

BRAIN LOCAL ANGIOTENSIN II FORMATION DEPENDS ON RENIN ACTIVITY

Objective: The blood-brain-barrier limits the traffic of all components of the renin-angiotensin system. Brain-localized production of angiotensin II (Ang II) has been challenged because the rate-limiting enzyme, renin, is expressed at very low levels in the brain. Our group has developed a transgenic mouse line that selectively overexpresses rat angiotensinogen (Agt) in brain astrocytes (Agt-Tg) yielding detectable levels of Ang II. Design and method: To confirm that Ang II is locally produced in the brain, the endogenous mouse Agt gene was deleted from Agt-Tg (Agt-Tg/Agt-KO) by breeding Agt-Tg with Agt-deficient mice (Agt-KO). To determine if renin is involved in the local production of Ang II in the brain, the genes (Ren1d and Ren2) encoding for renin of Agt-Tg were genetically deleted by crossbreeding with renin-deficient mice (Ren-KO). The resulting mouse line overexpresses Agt specifically in the brain but globally lacks renin (Agt-Tg/Ren-KO). All lines were backcrossed to the FVB/N inbred background for at least 8 generations. Whole brains and blood were collected from males and females aging between 15-22 weeks. Angiotensin peptides (Ang I, Ang II, Ang III and Ang 1-7) were quantified using LC-MS/MS by Attoquant Diagnostics GmbH Results: Ang II was detected in the brain, but not in the blood of Agt-Tg/Agt-KO mice suggesting local synthesis. Interestingly, Ang II was not detectable in brain samples of Agt-Tg/Ren-KO in contrast to their littermates Agt-Tg indicating that renin is essential for brain Agt processing into Ang II. Moreover, Ang I, Ang II were not detected in the blood of Agt-Tg/Ren-KO as expected but detectable in Agt-Tg. Finally, FVB/N wildtype controls presented no detectable levels angiotensin peptides in brain samples but in the blood. Conclusions: Collectively, the results from mice with brain-specific Agt overexpression support the notion that the brain locally and renin-dependently produces Ang II. The specific involvement of central or peripheral renin remains to be determined.

Role of Genetic Variants AGT rs699 and ACE2 rs2106809 in Increasing the Risk and Severity of COVID-19 Infection in Iraqi Patients

The main aim of our study was to determine if the ACE2 rs2106809 and AGT rs699 polymorphisms increase the risk and severity of Covid-19 infection in Iraqi patients. This case-control study included 102 patients (mean age 52.66±18.82 years) and 92 healthy (mean age 37.88±14.19 years). The patients were grouped based on severity: hospitalized (n = 57) and non-hospitalized (n = 45). Demographic and comorbidity data was also collected. Genotype distribution of two selected SNPs ACE2 gene rs2106809 and AGT rs699 polymorphisms was performed by allele-specific PCR (AS-PCR) and sanger sequencing. The ACE2 rs2106809 C allele was associated to an increased risk of Covid-19 infection and the severity in males but not in the females (C vs. T OR = 3.04 p=0.01 and C vs. T OR = 4.9, p = 0.03, respectively). While AGT rs699 TC genotype was associated with 2.96 folds higher risk of Covid-19 infection (TC vs.TT, CC OR =2.96, 95%CI = 1.12–6.44; p = 0.02). The AGT rs699 was not associated with the severity of infection. Among outpatients, benign conditions were associated with a lower risk, however older age males and comorbidities increased the risk. We concluded that the genetic variant of rs2106809 ACE2 in males was significant with a risk of infection and severe clinical course because it could be located on the X-chromosome, and at the same time AGT rs699 polymorphism had an impact on the increased risk of Covid-19 but had no relation with the severity of Covid-19.

COMBINATION OF TWO DIFFERENT C174T AND C235T OF THE ANGIOTENSINOGEN GENE MUTATION AND C677T METHYLENETETRAHYDROFOLATE REDUCTASE GENE MUTATION IN PATIENTS WITH CVD IN THE POPULATION OF AZERBAIJAN

We studied two mutations of C174T (Met174Tre) and C235T (Met235Tre) of the angiotensinogen gene and mutation C677T (Ala677Val) of the methylenetetrahydrofolate reductase gene, as well as their combinations among patients with cardiovascular diseases: coronary heart disease, myocardial infarction and hypertension, using a complex of modern molecular genetic diagnostic methods. A high frequency of these mutations has been established in the group of patients with severe forms of cardiovascular disorders. Homozygous and compound conditions were found in people with severe diseases. In particular, the heterozygous state of the mutation was found in people with moderate hypertension. It was also found that the presence of close blood relationship between the parents of patients with cardiovascular diseases increases the homozygotization of mutations of the genes AGT and MTGFR in probands. Consequently, such persons are susceptible to the disease or in other words, have an increased risk of developing diseases of the cardiovascular system. For the first time, the frequencies of these mutations in the Azerbaijani population have been determined, which are mostly consistent with the frequencies described in other populations of the world. The studied genetic markers are of interest as genes presumably associated with a wide range of cardiovascular diseases and can be used in further population and epidemiological studies. Therefore, the results of molecular genetic studies obtained by us in people with diseases of the cardiovascular system are of great practical importance. Timely prevention by detecting mutations of C174T, C235T of the AGT gene and C677T of the MTGFR gene in patients will allow doctors to carry out qualified treatment of cardiovascular diseases

Prevalence of polymorphism of <i>АDRВ1, AGT, SOD2, CAT</i> genes and their combinations to assess the risk of developing cardiovascular disease

BACKGROUND: Cardiovascular disease remains a major public health problem associated with high mortality. The development of these diseases is associated with many genetic and cardiovascular risk factors, so the study of a person’s genetic predisposition to the development of cardiovascular disease based on gene polymorphism remains actual. The aim of research was to study the combination of polymorphisms of the ADRB1 rs1801253, AGT rs4762, SOD2 rs4880 and CAT rs1001179 genes in healthy young people to assess individual genetic predisposition to the development of cardiovascular disease.
 MATERIALS AND METHODS: The study involved 33 people aged 19 to 21 years who currently had no pathology of the cardiovascular system. DNA was isolated from oral epithelial cells. Genotyping of DNA samples was determined using real-time polymerase chain reaction.
 RESULTS: Among those examined, 39.4% had one or two unfavorable alleles for the ADRB1, AGT genes, suggesting a genetic predisposition to the development of cardiovascular disease. Unfavorable alleles of the ADRB1 gene were more common compared to the AGT gene. Each of those examined at risk of developing cardiovascular disease had one or two alleles associated with a decrease in the functioning of enzymes of the antioxidant system. Of the 33 people, only four (12.1%) do not have an unfavorable allele for the SOD2 and CAT genes.
 CONCLUSIONS: We believe that the determination of polymorphisms in genes for enzymes of the antioxidant system will be an important additional criterion for earlier and more active prevention of cardiovascular disease.

The Association of M235T Genetic Polymorphism in Angiotensinogen Gene and Other Non-Genetic Factors with Essential Hypertension among Jordanian Patients.

Hypertension, characterized by elevated pressure, poses a significant health risk. Recent studies in Jordan highlight high hypertension rates, emphasizing the need for genetic investigations to comprehend essential hypertension determinants. The AGT gene, part of the Renin Angiotensin System, is linked to blood pressure regulation. Limited information exists on the frequency of this polymorphism among Jordanian hypertensive patients. This study explores the association between the AGT M235T polymorphism and essential hypertension in Jordan. A cross-sectional study with 435 participants (199 hypertensive, 236 non-hypertensive) was conducted at the University of Jordan Hospital. Blood pressure was measured, and genetic analysis of the AGT M235T polymorphism was completed using the PCR-RFLP technique. Chi-square and t-tests were used for comparisons using SPSS software. Hypertensive patients exhibited significantly higher weight, BMI, and blood pressure. Genotyping results showed no significant difference (p > 0.05, Chi-square) in AGT M235T polymorphism distribution between control and patient groups. In addition, allele frequencies showed comparable patterns (p > 0.05, Chi-square). All genotype frequencies showed no deviation from the Hardy-Weinberg equation (p > 0.05, Chi-square). The AGT M235T genetic polymorphism is not more prevalent among hypertensive patients in Jordan, although the average weight and BMI among hypertensive patients is higher than the non-hypertensive participants. Obesity can be addressed as a potential risk factor for essential hypertension in Jordan. In addition, it is recommended to find out the influence of the AGT M235T genetic polymorphism on the response of antihypertensive drugs among hypertensive patients in Jordan.

Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis.

Systemic hypertension is one of the most common noncommunicable diseases globally, with over one billion people affected. Despite the widespread use of numerous antihypertensive drugs, it is estimated that only a fifth of diagnosed patients achieve adequate blood pressure control. For this reason, the pursuit for novel antihypertensive therapies is ongoing. Zilebesiran, an siRNA designed to target the liver, is the newest potential addition to the renin-angiotensin-aldosterone system-inhibiting drugs. This subcutaneous injection post-transcriptionally silences the AGT gene responsible for the synthesis of angiotensinogen. By preventing the progenitor protein of the renin-angiotensin-aldosterone system, zilebesiran blocks the downstream production of angiotensin II, which plays multiple roles in blood pressure elevation. Phase I clinical trials have demonstrated a dose-dependent negative relationship between zilebesiran and blood pressure/serum angiotensinogen levels-with sustained effects up to 6 months. Researchers also demonstrated a promising safety profile, as most of the adverse events were mild to moderate in nature. Phase II trials assessing efficacy and optimal dosing are currently underway, with a predicted completion by 2025.