AGTR2 Research Articles

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.

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.

Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer.

Tumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified. Correlation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models. A 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD. TiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.

Predictors of the Development of Associated Clinical Conditions in Working-Age Patients With Cardiovascular Risk Factors in Conditions of High Adherence to Treatment.

To determine predictors for the development of associated clinical conditions (ACC) in patients of working age with cardiovascular risk factors (CVRFs) in the conditions of high compliance with the treatment and healthy lifestyle (HLS). The study included 364 patients with CVRFs without target organ damage and a history of ACC. Mean age was 42.24±8.08 years. Patients were examined in consistency with the Russian Society of Cardiology (RSC) 2020 guidelines for arterial hypertension and chronic heart failure. The follow-up period was 6.45±0.42 years. 350 patients completed the study, 9 patients died during the follow-up period, and 5 were lost to follow-up. Patients were divided into two groups based on the development of ACC. The first group consisted of 56 (16%) patients with verified ACC, the second group included 294 (84%) patients without ACC. Regression logistic and correlation analyses confirmed the prognostic significance for the development of ACC by 12 indicators. The risk of ACC in smokers was increased more than 7 times (odds ratio (OR) 7.44, 95% confidence interval (CI): 3.42-16.21), and when type 2 diabetes mellitus (DM) developed, more than 9 times (OR 9.47, 95% CI: 4.36-20.59); with chronic kidney disease (CKD), more than 6 times (OR 6.75, 95% CI: 3.41-13, 37); with a history of COVID-19 (COronaVIrus Disease 2019) pneumonia, 7 times (OR 7.11, 95% CI: 3.04-16.58); with left ventricular hypertrophy (LVH), 6 times (OR 6, 35, 95% CI: 3.14-12.83); with CAVI index>7.2, almost 3 times (OR 2.69, 95% CI: 1.48-4.86); with PVWcf (carotid-femoral pulse wave velocity) >13 m/s, more than 5 times (OR 5.61, 95% CI: 2.79-11.28); with R-AI index (augmentation index) >1, more than 2 times (OR 2.26, 95% CI: 1.3-3.9); and with an increase in the indexed left atrial volume (ILAV) >27 ml/m2, more than 8 times (OR 8.80, 95% CI: 4.61-16.79). In the presence of polymorphisms in the form of homozygosity for the minor allele of the AGT gene (Thr174Met, rs4762), the risk of developing ACC increased 14 times (OR 14.13, 95% CI: 4.69-42.57), the APOE gene (Cys130Arg, rs429358), 11 times (OR 11.18, 95% CI: 4.18-29.93), and in the intron of the PRARα gene (rs4253778), 8 times (OR 8.11, 95% CI: 3.75-17.53). The development of ACC in patients with high compliance with treatment and a healthy lifestyle is associated with smoking, type 2 diabetes and CKD, a history of COVID-19 pneumonia, LVH, increased ILAV >27 g/m2, more pronounced arterial stiffness assessed by an increase in CAVI indices >7.2, R-AI >1, and PWVcf >13 m/s; and with the presence of polymorphism of the AGT, APOE and PPARα genes in the form of homozygosity for the minor allele.

1166A>C polymorphism of the <i>AGTR1</i> gene as a marker metabolic disorders in the North residents

BACKGROUND: dyslipidemia is currently considered to be one of cardiovascular risk factors. Angiotensin II receptor type I (AGTR1) genetic polymorphisms are known as candidate genes for hypertension, diabetes, as well as for diabetes and obesity complications. Until now, there are not much data on how 1166A>C (rs5186) polymorphism of the AGTR1 gene correlates with Northerners’ carbohydrate and lipid metabolism disorders. In addition, the data are contradictory. Following on from this, we see it is relevant to study the subject.AIM: this research assessed variants of 1166A>C (rs5186) polymorphism of the AGTR1 gene as a predictor of dyslipidemia, carbohydrate metabolism disorders, overweight, and hypertension.MATERIALS AND METHODS: the North residents from Magadan Region, Caucasian by ethnicity, aged from 24 to 56 (average age 43.7± 1.4 yrs) participated in the survey. By real-time polymerase chain reaction we determined the single nucleotide polymorphism of the AGTR1 (rs5186) gene. We also analyzed physical development and cardiovascular variables as well as the concentrations of glucose, insulin, glycosylated hemoglobin, C-reactive protein, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The insulin resistance index and the atherogenicity coefficient were calculated using standard methods.RESULTS: the examined subjects were one hundred and one volunteers. According to the results of genetic analysis, 55 people were assigned to the group of homozygotes for the wild type (AA) and 46 people were assigned to the group of the AGTR1*C allele variant carriers (heterozygotes and homozygotes AC+CC). Our findings contributed to the evidence on more unfavorable lipid pictures showed by the AGTR1*C allele variant carriers: significantly high values of total cholesterol (5,77±0,11, р=0.045), low-density lipoproteins (3,87±0,09, р=0.009), triglycerides (1,43±0,06, р=0.035), and atherogenicity coefficient (3,61±0,10, р=0.001), along with significantly low values of high-density lipoproteins (1,30±0,03, р=0,008). The above indicators were observed as opposed to significantly high fasting glycemia (5,74±0,14, р=0.006) and glycosylated hemoglobin (5,74±0,09, р=0.001) exhibited by the AA homozygotes subjects whose indices could be defined as the state of prediabetes. No intergroup differences were found in anthropometric or cardiovascular variables.CONCLUSION: thus, we could see impairments in the lipid pictures of the AGTR1*С polymorphic variant carriers along with the optimization of carbohydrate metabolism and no effect on the blood pressure or anthropometric characteristics.

Impact of the gene polymorphisms in the renin-angiotensin system on cardiomyopathy risk: A meta-analysis.

Due to the inconsistent findings from various studies, the role of gene polymorphisms in the renin-angiotensin system in influencing the development of cardiomyopathy remains unclear. In this study, we conducted a systematic review and meta-analysis to summarize the findings regarding the impact of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T, and angiotensin II Type 1 receptor (AGTR1) A1166C gene polymorphisms in patients with cardiomyopathy. We performed a comprehensive search of several electronic databases, including PubMed, Embase, the Cochrane Library, and Web of Science, covering articles published from the time of database creation to April 17, 2023. Studies on the assessment of genetic polymorphisms in genes related to the renin-angiotensin system in relation to cardiomyopathy were included. The primary outcome was cardiomyopathy. Risk of bias was assessed using the Newcastle-Ottawa Scale scale. The meta-analysis includes 19 studies with 4,052 cases and 5,592 controls. The ACE I/D polymorphisms were found to be associated with cardiomyopathy (allelic model D vs I: OR = 1.29, 95CI% = 1.08-1.52; dominant model DD+ID vs II: OR = 1.43, 95CI% = 1.01-2.02; recessive model DD vs ID+II: OR = 0.79, 95CI% = 0.64-0.98). AGT M235T polymorphism and cardiomyopathy were not significantly correlated (allelic model T vs M: OR = 1.26, 95CI% = 0.96-1.66; dominant model TT+MT vs MM: OR = 1.30, 95CI% = 0.98-1.73; recessive model TT vs MT+MM: OR = 0.63, 95CI% = 0.37-1.07). AGTR1 polymorphism and cardiomyopathy were not significantly associated under allelic model A vs C (OR = 0.69, 95CI% = 0.46-1.03) and recessive model AA vs CA+CC (OR = 0.89, 95CI% = 0.34-2.30), but under the dominant model AA+CA vs CC (OR = 0.51, 95CI% = 0.38-0.68). The current meta-analysis reveals that polymorphisms in ACE I/D may be a genetic risk factor for cardiomyopathy. There is an association between AGTR1 gene polymorphisms and risk of cardiomyopathy under the specific model.

Association of variants in AGTR1, ACE, MTHFR genes with microalbuminuria and risk factors for the onset of diabetic nephropathy in adolescents with type 1 diabetes in the population of Serbia.

Genetic studies may provide valuable information about patients who are at high risk of developing diabetes nephropathy. Before the appearance of albuminuria, there are genetic mutations that can predispose the development of kidney disease. The study included 130 adolescents with type 1 diabetes. Patients were divided into two groups according to the presence of microalbuminuria. This study was performed to examine clinical and laboratory differences between adolescents with type 1 diabetes with and without microalbuminuria and the distribution of the ACE, AGTR1, and MTHFR gene polymorphisms. The mean microalbuminuria in the first group 6.41±7.35 significantly differs from the second group 0.82±0.48 (p<0.001). HbA1c, 24-hour proteinuria, and day-time systolic blood pressure were significantly higher in the MA group (p<0.05). Smaller systolic blood pressure percentage nocturnal decline was observed in the microalbuminuric group (p 0.030). The frequencies of the ACE DD, ID, and II genotypes were 12.5%, 50.0%, and 37.5%, respectively, among T1D patients with MA, and 19.3%, 56.1%, 24.6%, in the control group without MA (P = .510). The frequencies of the AGTR1 AA, AC, and CC genotypes were 62.5%, 25.0%, and 12.5% among TID patients with MA, and 49.1%, 43.9%, 8.0%, in the group without MA (p 0.326). The frequencies of the MTHFR CC, CT and TT genotypes were 37.5%, 50.0%, 12.5% among TID patients with MA, and 37.7%, 45.6%, 16.7% in the group without MA (p 0.901). Our data suggest that common variants in the AGTR1, ACE, and MTHFR genes are not strongly associated with diabetic nephropathy in our patients with type 1 diabetes.