Renin-angiotensin-aldosterone System Genes Research Articles

The Association between Genetic Variants and Gene Expression in RAAS Genes Using Captive-Bred Vervet Monkeys (Chlorocebus aethiops)

Mendelian genetics contribute largely to the development of hypertension; therefore, the identification of genetic variants related to blood pressure (BP) regulation remains crucial and may reveal new therapeutic drug targets. The purpose of the present study was to screen the captive-bred Vervet colony for salt-sensitive sequence variants or single nucleotide polymorphisms (SNPs) in the selected Renin-Angiotensin-Aldosterone System (RAAS) genes associated with salt sensitivity. Blood samples were collected from 16 captive-bred Vervet monkeys for genotyping and gene expression analysis. The impact of the identified sequence variants was determined using online prediction tools. Sanger sequencing analysis revealed 21 sequence variants in AGT, CYP3A5, GRK4, and SCL4A5, of which 19 were novel and two were previously reported in humans. All novel variants were either predicted to be polymorphic, disease-causing, or possibly damaging by prediction tools. Furthermore, the mRNA expression for AGT was significantly higher in the normal BP group ( p value = 0.02), and a similar trend was observed for CYP3A5 and GRK4, whereas SCL4A5 was higher in the hypertensive group. The identified salt-sensitive variants specifically in GRK4 may be suggestive to be the attributing factor of the elevated BP levels in these captive-bred Vervet monkeys. Therefore, RAAS variants could be considered as a biomarker to identify the potential risk of developing hypertension in both humans and nonhuman primates.

Renin-angiotensin-aldosterone system genotypes and cardiac remodeling response to essential hypertension

Abstract Background/Introduction Cardiac remodeling represent a response to uncontrolled essential hypertension (EHT). The morphological response is expressed by left ventricular (LV) mass index values and/or relative wall thickness (RWT) >0.42. Functionally response is expressed by isolated alteration of LV diastolic function (E/A<1). Purpose We aimed to establish the association between anatomical and functional adaptation to EHT, with two genetic variants of the renin-angiotensin-aldosterone system (RAAS): M235T-AGT and A3123C-R2 AngII. Methods In 139 hypertensive subjects cohort, we determined the M235T-AGT and A3123C-R2 AngII genotypes, using polymerase chain reaction-restriction fragment length polymorphism methods. The relationship between the studied RAAS gene polymorphisms and morphological and functional cardiac remodeling was assessed by multiple logistic regressions. Results We found that the C/C, A/C genotypes of the A3123C-R2 AngII polymorphism were statistically significantly associated with RWT<0.42 (p=0.033), so hypertensive patients carrying this genotype had a 2.7-fold increased risk to have a non-concentric type of cardiac response. The association was maintained even after adjustment for confounders - age, body mass index (BMI), systolic blood pressure (BP), and diastolic BP (p=0.008). We found statistically significant associations between LV diastolic dysfunction in hypertensive patients cohort carrying the T/T, M/T genotypes (M235T-AGT polymorphism) (p=0.037). Moreover, the association remained statistically significant even after adjustment for age, BMI, systolic BP, and diastolic BP (p=0.039). We could not identify any statistically significant associations between M235T-AGT, A3123C-R2 AngII polymorphisms, and LV mass index. Conclusion(s) Non-concentric type of cardiac response to essential hypertension was associated with A3123C-R2 AngII polymorphism. M235T-AGT polymorphism was found to be statistically significantly associated with alteration of LV diastolic function. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, as part of Doctoral Research Projects (DRP) 2016

SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45\u2212 Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome

Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin–angiotensin–aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1–7) (Ang [1–7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133+CD34+Lin−CD45− cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells.Graphical •Human VSELs and HSCs express ACE2 receptor for SARS-CoV2 entry.•Interaction of viral spike protein with ACE2 receptor may hyperactivate Nlrp3 inflammasome which induces cell death by pyroptosis.•SARS-CoV2 may also enter cells and eliminate them by cell lysis.•What is not shown since these cells express also Ang II receptor they may hyperactivate Nlrp3 inflammasome in response to Ang II which may induce pyroptosis. Our data indicates that Ang 1–7 may have a protective effect.

MO026TREATMENT WITH ACTIVE VITAMIN D DOES NOT IMPROVE LEFT VENTRICULAR HYPERTROPHY BUT FURTHER INCREASES FGF23 AND ACCELERATES CKD PROGRESSION IN CHILDREN

Abstract Background and Aims Elevated FGF23, activation of the renin-angiotensin-aldosterone system (RAAS), and vitamin D and Klotho deficiency promote left ventricular hypertrophy (LVH) and LV fibrosis in chronic kidney disease (CKD). Whether treatment with active vitamin D affects uremic cardiomyopathy and/or FGF23/Klotho system in CKD is unclear. Method 5/6 nephrectomized (5/6Nx) rats, as a well-established model of CKD, were dose-dependently treated with calcitriol for 10 weeks and the cardiac phenotype, including local RAAS activation, was investigated compared to untreated 5/6Nx and sham-operated rats. Additionally, 38 children with eGFR ≤ 30 ml/min/1.73 m2 selected from the Cardiovascular Comorbidity in Children with CKD (4C) study were enrolled in a case-control study. Nineteen children were started on active vitamin D treatment with either calcitriol or calcidiol (average dosage 0.4 μg/day), and 19 CKD children with non-active vitamin D treatment matched for age, eGFR, serum calcium, parathyroid hormone, and phosphate served as controls. LV mass index (LVMI), LVH prevalence (LVMI >95th percentile), intact (iFGF23) and C-terminal FGF23 (cFGF23), and soluble Klotho (sKlotho) were assessed at baseline and after nine months. Results In 5/6Nx rats, FGF23 synthesis in bone and heart was enhanced compared to sham-operated rats, and calcitriol further stimulated its expression in bone only. Renal Klotho expression was reduced in 5/6 rats and almost normalized after calcitriol treatment. 5/6Nx induced cardiomyocyte growth and LV fibrosis, and calcitriol treatment significantly ameliorated both. Cardiac RAAS genes, such as angiotensinogen, renin, angiotensin-converting-enzyme, and angiotensin II receptor type I, were significantly upregulated in 5/6Nx rats compared to sham-operated animals, and normalized by calcitriol treatment. In the 4C study cohort, median plasma cFGF23 and iFGF23 were significantly elevated in both groups, whereas sKlotho was not altered compared to healthy children. Forty-seven percent and 42% of active vitamin D-treated patients and controls, respectively, received blood pressure (BP) medications, however diastolic BP was slightly but significantly enhanced in both groups compared to healthy children. Mean LVMI and LVH prevalence of 47% in active vitamin D-treated patients and controls did not differ at baseline. After nine months, median cFGF23 and iFGF23 were significantly increased in active vitamin D-treated patients compared to controls. sKlotho levels were decreased in the active vitamin D-treated group compared to baseline but not in controls. A significant decline in median eGFR was observed in active vitamin D group but not in controls. Likewise, the median eGFR change during the observation period was higher in the active vitamin D group compared to controls. Median LVMI as well as frequency of LVH did not change significantly during vitamin D treatment, nor in controls. Consequently, final median LVMI as well as percentage of patients with LVH did not significantly differ between groups. Conclusion Calcitriol treatment in 5/6Nx rats improves cardiac hypertrophy and fibrosis, reduces uremia-induced cardiac RAAS gene expression, and improves renal Klotho expression. By contrast, treatment with active vitamin D does not decrease the prevalence of LVH in children with advanced CKD compared to matched controls. This may be due to further enhancement of FGF23 levels, faster progression of CKD associated with reduced Klotho in active vitamin D-treated patients and/or concomitant treatment with RAAS inhibitors. The latter may blunt the favorable effects of calcitriol on the activated RAAS.

The role of polymorphisms in genes that regulate neurohumoral systems in patients with atrial fibrillation

One of the important medical and social present-day problems is atrial fibrillation (AF) which prevalence in the adult population is 2 % for persons under 65 and 9 % for those over 65 years of age and it is a common cause of ischemic stroke. The embolic complications incidence is 2.1 % per year in patients with paroxysmal AF, and 3.0 % per year in patients with persistent AF. The aim of the study is to analyze the modern literary sources related to the role of gene polymorphisms regulating some neurohumoral systems in group of patients with atrial fibrillation. A combination of certain genes polymorphisms can contribute to AF risk. Especially important are gene studies of the renin-angiotensin-aldosterone system (RAAS) role in the pathogenesis of AF which are currently being studied with a particular intensity. Recent data show that activation of RAAS plays an important role in the development and recurrence of AF. These studies are of great practical interest as the associative effect of angiotensin converting enzyme (ACE) inhibitors in the prevention of AF has been identified. AGT gene encodes a plasma protein known as angiotensinogen. This protein is expressed in the liver and is cleaved by the enzymatic renin action in response to lower blood pressure. The resulting product, angiotensin I, is then cleaved by ACE to the physiologically active enzyme angiotensin II. Defects in this gene may also be associated with non-hereditary AF. More than 16 spot mutations in the AGT gene were discovered, most of which resulted in amino acid substitutions. Conclusions. The analysis of the literature allows to conclude that, first, genetic polymorphisms may influence both the severity of pathological changes in the body and the efficacy of pharmacotherapy, and second, the study of RAAS gene polymorphisms may allow early detection of persons with increased risk of persistent AF recurrence and its prevention.

Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis.

The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades. This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus. The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration. In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model). In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.

Hypertension in 2017: Novel mechanisms of hypertension and vascular dysfunction.

New findings in 2017 enhanced our understanding of the mechanisms that regulate blood pressure. Key studies provided insights into immune mechanisms, the role of the gut microbiota, the adverse effects of perivascular fat and inflammation on the vasculature, and the contribution of rare variants in renin–angiotensin–aldosterone system genes to salt sensitivity.

Association of renin–angiotensin–aldosterone system gene polymorphisms with left ventricular hypertrophy in patients with heart failure with preserved ejection fraction: A case–control study

ABSTRACTBackground: Heart failure with preserved ejection fraction (HFpEF) has close ties with hypertension, though risk factors to the development of HFpEF in hypertensive patients are not fully understood. Left ventricular hypertrophy (LVH) signifies the susceptibility toward diastolic heart dysfunction, and genetic determinants of LVH as a result may serve as risk predictors for HFpEF in hypertension. We investigated the role of three renin–angiotensin–aldosterone system (RAAS) gene polymorphisms in the development of LVH in hypertensive patients with a diagnosis of HFpEF. Methods: A total of 176 hypertensive patients with a diagnosis of HFpEF were divided to cases with LVH and controls without. rs4343 and rs4291 of angiotensin-converting enzyme (ACE) and rs5186 of angiotensin receptor type 1 were genotyped using PCR-RFLP method. Results: Genotypes and allele frequencies were significantly different between the case and control groups for rs4343 and rs4291, whereas no difference was observed for rs5186.Conclusion: Increased ACE activity explains the significant association of rs4343 and rs4291 polymorphisms with LVH in the carriers. Furthermore, findings support the pathophysiologic links between RAAS and increased LV mass in hypertension and suggest a genetic susceptibility to HFpEF. Such polymorphisms may serve as risk predictors of HFpEF in hypertensive patients.

Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis). We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1) were individually associated with lower systolic blood pressure with significant (P<0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at AGT and rs11658531 at ACE) and 1 SNP in women (rs12451328 at ACE). SNP-SNP interaction was suggested (P<0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for REN, 1 for AGT, and 1 for AGTR1). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.

Are genetic polymorphisms in the renin-angiotensin-aldosterone system associated with essential hypertension? Evidence from genome-wide association studies.

In candidate gene era, dozens of single-nucleotide polymorphisms (SNPs) within renin-angiotensin-aldosterone system (RAAS) have been reported to be significantly associated with hypertension. However, the unbiased genome-wide association studies (GWAS) rarely identified the SNPs within RAAS were associated with hypertension or blood pressure (BP) traits. In order to figure out whether genetic polymorphisms of RAAS are really associated with hypertension, we systemically searched the GWAS Catalogue and identified all the known RAAS genes and relevant diseases/traits. After data processing, we found that polymorphisms within REN, AGT, ACE2, CYP11B2, ATP6AP2 and HSD11B2 were not associated with any disease or trait. SNPs within ACE, AGTR1, AGTR2, MAS1, RENBP and NR3C2 were associated with other diseases or traits, but showed no direct connection with hypertension. The only SNP associated with a BP trait, systolic BP was rs17367504. However, it is located in the intronic region of MTHFR near many plausible candidate genes, including CLCN6, NPPA, NPPB and AGTRAP. Therefore, the effect of RAAS polymorphisms may have been overestimated during the 'candidate gene era'. In the time of 'precision medicine', the power of RAAS variants needs to be reconsidered when evaluating one's susceptibility of hypertension.

Resequencing Study Identifies Rare Renin-Angiotensin-Aldosterone System Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.

The role of rare variants in blood pressure (BP) salt-sensitivity is unknown. We conducted a resequencing study of the renin-angiotensin-aldosterone system (RAAS) to identify rare variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1,906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day). The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Seven RAAS genes were resequenced using capillary-based sequencing methods. Rare variants were tested for association with BP salt-sensitivity using traditional burden tests. Single-marker analyses were employed to test associations of low-frequency and common variants. Aggregate rare variant analysis revealed an association of the RAAS pathway with BP salt-sensitivity. Carriers of rare RAAS variants had a 1.55-fold [95% confidence interval (CI): 1.15, 2.10] higher odds of salt-sensitivity compared to noncarriers (P = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the APLN gene with salt-sensitivity was also identified, with rare APLN variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (P = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense RENBP variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (P = 0.03). This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity. Clinical Trial RegistryTrial Number: NCT00721721.

RAS Genetic Variants in Interaction with ACE Inhibitors Drugs Influences Essential Hypertension Control

Essential Hypertension (EH) is a common disorder associated with increased cardiovascular morbidity and mortality in Malaysia. To investigate how genetic polymorphisms of the renin-angiotensin-aldosterone system (RAS) influence EH control with angiotensin-converting enzyme inhibitor drugs (ACEI). A case-control, cross-sectional population-based nested study (n=142) included hypertensive subjects treated with ACEI drugs, either lisinopril or enalapril (20mg, once daily) as monotherapy for 24weeks. In total seven possible polymorphisms of RAS genes were genotyped. The association between those polymorphisms and the changes in blood pressure were observed in the 24week treatment. Statistically significant associations of I, G, T, M and G alleles of ACE (I/D, G2350A), AGT (M235T, T175M and G-6A) respectively were observed in essential hypertensive subjects. The decrease in systolic blood pressure and diastolic blood pressure after 24weeks of treatment of the patients carrying II, GG, and TT genotypes were greater than the groups carrying DD, AA, MM, MM and GG of I/D, G2350A, M235T, T174M and G-6A genotypes respectively. In contrast, No significant difference was observed between renin gene polymorphisms (Bg/I and MboI) and hypertensives. Although this study shows a possible association of polymorphisms of RAS genes with the risk of non-control of HT in ACEI-treated patients and indicates the importance of all this system's components in regulating HT, it needs to be replicated in other data sources.

Renin-angiotensin-aldosterone system gene polymorphisms in gestational hypertension and preeclampsia: A case-control gene-association study.

Pregnancy-induced hypertension (PIH, including preeclampsia [PE] and gestational hypertension [GH]) and cardiovascular diseases (CVDs) have some metabolic changes and risk factors in common. Many studies have reported associations between single nucleotide polymorphisms (SNPs) of renin–angiotensin–aldosterone system (RAAS) genes and CVDs (particularly hypertension), and their findings have provided candidate SNPs for research on genetic correlates of PIH. We explored the association between hypertension-related RAAS SNPs and PIH in a Chinese population. A total of 130 cases with PE, 67 cases with GH, and 316 controls were recruited. Six candidate SNPs of the RAAS system were selected. Multiple logistic regression analysis adjusting for maternal age, fetal sex, and gestational diabetes mellitus showed significant associations between angiotensinogen (AGT) rs3789678 T/C and GH (p = 0.0088) and between angiotensin II receptor type 1 (AGTR1) rs275645 G/A and PE (p = 0.0082). The study population was further stratified by maternal age (<30 and ≥30 years), and stratified and crossover analyses were conducted to determine genetic associations in different age groups. Our findings suggest that the impacts of different SNPs might be affected by maternal age; however, the effect of this potential gene–age interaction on PIH needs further exploration.

Abstract P263: Resequencing Study Identifies Renin-Angiotensin-Aldosterone System Genes and Novel Low Frequency Variants Associated with Blood Pressure Salt-sensitivity

Christopher E. Anderson, Changwei Li, Jiang He, Dabeeru C. Rao, James E. Hixson, Dongfeng Gu, Lawrence C. Shimmin, Jianfeng Huang, Treva K. Rice, Jichun Chen, Jianxin Li, Tanika N. Kelly Genetic association studies have identified significant associations between common variants from the renin-angiotensin-aldosterone system (RAAS) genes and blood pressure responses to dietary sodium interventions. The role of low-frequency and rare RAAS variants in salt-sensitivity remains largely unexplored. We hypothesized that low-frequency and rare RAAS variants are associated with BP salt-sensitivity. To test this hypothesis, we conducted a RAAS candidate gene resequencing study among participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1,906 participants from 633 families who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium (307.8 mmol sodium/day) feeding-study. We chose the 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of seven RAAS genes (ACE2, APLN, AGTR1, HSD11B1, HSD11B2, NR3C2 and RENBP) were resequenced using the VariantSEQr TM system (Applied Biosystems; Foster City, CA). For gene-based analyses, variants with MAF less than 5% were first collapsed within each RAAS gene. The collapsed indicator variable was then tested for association with BP salt-sensitivity using generalized estimating equations (GEE) to accommodate correlation of genotypes due to family structure. Single variant analyses were performed for all low-frequency variants with a minor allele frequency (MAF) greater than 1% and less than 5%, again using GEE to accommodate family structure. In gene-based, we identified significant associations between rare and low-frequency variants in APLN and AGTR1 , and a borderline significant association of HSD11B2 with BP salt-sensitivity, with respective p-values of 0.03, 0.05 and 0.06. Eight percent of GenSalt participants with high salt-sensitivity carried at least one of the rare or low-frequency APLN variants, while 4% of salt-resistant participants were carriers. Seventeen percent of participants with high salt-sensitivity were carriers of rare or low-frequency AGTR1 variants compared to 11% of salt-resistant subjects. Eight percent of those with high salt-sensitivity were carriers of a rare or low-frequency HSD11B2 variant, compared to 4% of salt-resistant subjects. In single variant analyses, only one low-frequency variant, AGTR1 variant rs75367686, was marginally associated with the BP salt-sensitivity phenotype, with a p-value of 0.06. In aggregate, these findings provide promising evidence for a role of low-frequency and rare RAAS variants in BP salt-sensitivity.

The angiotensin converting enzyme (ace) gene polymorphism: Insight study of the renal regulation of the arterial blood pressure

Since the renin-angiotensin-aldosterone system (RAAS) was originally described, it has become one of the best described hormonal systems, especially regarding the fact that it plays an important role in regulating blood volume and systemic vascular resistance, and thus indirectly influencing blood pressure (BP). On the other hand, arterial hypertension is one of the most pertinent disorders which plays an important role, not only in the progression of renal failure, but also represents a risk factor for the occurrence of end stage renal disease. Several epidemiological studies pointed out the fact that genetic predisposition accounts for about 30% of the BP variability. Up to date, there are several RAAS genes that may have effect in long-term BP control, but ACE is the most important and the most thoroughly examined. In this review, we present available data regarding the influence of gene polymorphisms of ACE on its function, within the RAAS related BP regulation. Therefore, by specially describing all its potential physiological roles, it will likely offer a new insight in the renal regulation of the BP, along with its other, not less important, roles.

The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

We conducted single-marker, gene- and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10(-6)). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10(-6)). No single-marker associations with CKD progression were observed. The current study provides strong evidence for a role of the RAAS in CKD progression.

Associations of Renin–Angiotensin–Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence

The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population. A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing. During an average of 7.2 years of follow-up, average systolic and diastolic BP increased, and 32.1% (512) of participants free from hypertension at baseline developed hypertension. NR3C2 SNPs rs7694064 and rs6856803 were significantly associated with longitudinal changes in systolic BP (P interaction = 6.9×10(-5) and 8.2×10(-4), respectively). Through gene-based analysis, NR3C2 was found to be significantly associated with longitudinal systolic BP change (P value of 1.00×10(-7)), even after removal of significant markers rs7694064 and rs6856803 from the analysis. The association between NR3C2 and longitudinal systolic BP change was replicated in Asian MESA participants (P value of 1.00×10(-4)). These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension.

Abstract 01: The Role of Renin-Angiotensin-Aldosterone System Genes in the Progression of Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

Background: We conducted single-marker, gene-based and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort (CRIC) study participants. Methods: A total of 1,523 white and 1,490 black subjects were genotyped for 490 SNPs in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results: Among white and black participants, eGFR declined an average of 1.2 and 2.3 ml/min/1.73m 2 per year, respectively, while renal events occurred in a respective 11.5% and 24.9% of participants. We identified strong gene and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (all P &lt;1.00х10 -6 ). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P &lt;1.00х10 -6 ). No single-marker associations with CKD progression were observed. Conclusions: The current study provides strong evidence for a role of the RAAS in CKD progression.

Genetic Variations in Renin-Angiotensin-Aldosterone System (RAAS) Genes Could Contribute to High Altitude Pulmonary Edema: Review

Background: At High Altitude (HA) (elevation >2500m), inevitable hypobaric hypoxia leads to development of symptoms associated with low oxygen pressure in many non acclimatized sojourners which includes severe forms of altitude mountain sickness (AMS) such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). These syndromes are reportedly less common in high altitude native population than in lowlanders which can be attributed to genetic adaptations that have taken place over generations. Methods: Numerous genetic studies have been associated with hypoxic adaptation and susceptibility to high altitude conditions. An increased pulmonary arterial pressure (PAP) and fluid loss has been observed in all forms of AMS with varied intensity. Since renin-angiotensin-aldosterone system (RAAS) has a critical function of maintaining homeostasis in closed circulatory system, the polymorphisms occurring in the genes of RAAS pathway could likely be contributing towards acclimatization/mal-adaptation to high altitude maladies. In view of above, this review has been compiled to associate the genetic variations in RAAS with adaptation/acclimatization to high altitude conditions. Results: Studies conducted so far relate allele frequencies of polymorphic loci in genes encoding components of RAAS pathway such as angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin receptors (AT1) and aldosterone synthase (CYP11B2) and associate them with hypertension, regulation of blood pressure and maintenance of osmotic balance in the body. Conclusions: In this review, various studies have been put together comprehensively indicating the involvement of genetic variants of RAAS genes in resistance or sensitivity of an individual towards development of HAPE.

Dietary salt restriction improves cardiac and adipose tissue pathology independently of obesity in a rat model of metabolic syndrome.

BackgroundMetabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear.Methods and ResultsWe investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS.Z‐Leprfa/Leprfa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal‐salt (0.36% NaCl in chow) or low‐salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS.Z‐Lepr+/Lepr+, or DS/lean rats). DS/obese rats fed the normal‐salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin–angiotensin–aldosterone system genes were increased in DS/obese rats fed the normal‐salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats.ConclusionsDietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome.