Tagging SNPs in REN, AGTR1 and AGTR2 genes and response of renin activity, angiotensin II and aldosterone concentrations to antihypertensive treatment in Kazakans

Hypothesis: Polymorphisms of REN, AGTR1 and AGTR2 may be associated with responses of renin–angiotensin–aldosterone system (RAAS) activity phenotypes to angiotensin-converting enzyme inhibitor (ACEI) antihypertensive treatment. Materials and methods: A total of 400 first diagnosed Kazak hypertensives were randomly allocated to two groups and received a 3-week course of either captopril and atenolol as monotherapy under double blinding. Genotype–phenotype association analyses were performed by covariance analyses between baseline level and responses of blood pressure, renin, angiotensin II and aldosterone concentrations with tagging single nucleotide polymorphisms (SNPs) in REN, AGTR1 and AGTR2 genes. A false discovery rate method was used to adjust multiple testing. Results: After adjustment for multiple testing, we found that the G allele of rs6676670 (T/G) in intron 1 of REN was significantly associated with higher baseline aldosterone concentrations ( p < 0.0001, explained variance (EV) = 2.3%). Significant associations after adjustments were also found between the A allele of rs2887284, with higher baseline renin activity ( p = 0.022, EV = 1.0%), higher responses of renin ( p = 0.018 EV = 5.4%), and higher responses of angiotensin II ( p = 0.0255, EV = 3.13%) to the treatment of ACEI. The carriers of the A allele of rs2887284 appeared to be more sensitive to the ACEI treatment. Conclusion: rs2887284 in intron 9 of REN is associated with the response of renin and angiotensin II levels to ACEI treatment.

Download Full-text

Dopaminergic Control of Aldosterone Secretion is Independent of the Renin—Angiotensin System in Rats

Clinical Science ◽

10.1042/cs059101s ◽

1980 ◽

Vol 59 (s6) ◽

pp. 101s-103s ◽

Cited By ~ 5

Author(s):

J. R. Sowers ◽

M. L. Tuck ◽

J. Barrett ◽

M. P. Sambhi ◽

M. S. Golub

Keyword(s):

Plasma Renin Activity ◽

Enzyme Inhibitor ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Plasma Aldosterone ◽

Renin Activity ◽

Dopamine Antagonist ◽

Aldosterone Secretion ◽

Angiotensin System ◽

Renin Angiotensin

1. In rats, intra-arterial metoclopramide, a dopamine antagonist, resulted in an elevation of plasma aldosterone at 5 min and plasma renin activity at 10 min and peak aldosterone and renin responses at 10 and 30 min respectively. 2. Pre-administration of l-dopa blunted and delayed aldosterone and renin responses to metoclopramide, indicating that metoclopramide-induced plasma aldosterone and plasma renin activity increments are mediated by a direct effect of blockade of dopamine receptors rather than other effects of this drug. 3. Pre-administration of angiotensin converting enzyme inhibitor, captopril (SQ 14 225) and the angiotensin II antagonist, saralasin, as well as bilateral nephrectomy did not significantly affect the aldosterone response to metoclopramide, Thus dopaminergic modulation of aldosterone secretion occurs independently of alterations in the renin-angiotensin system. 4. Modulating effects of dopamine on plasma aldosterone are probably mediated by direct effects as well as by interaction with other factors influencing aldosterone secretion at the adrenal zona glomerulosa.

Download Full-text

Combination of β Adrenergic Receptor Block and Renin–Angiotensin System Inhibition Diminished the Angiotensin II-Induced Vasoconstriction and Increased Bradykinin-Induced Vasodilation in Hypertension

Dose-Response ◽

10.1177/1559325817737932 ◽

2017 ◽

Vol 15 (4) ◽

pp. 155932581773793 ◽

Cited By ~ 3

Author(s):

Diego Lezama-Martínez ◽

Ignacio Valencia-Hernández ◽

Jazmin Flores-Monroy ◽

Luisa Martínez-Aguilar

Keyword(s):

Angiotensin Ii ◽

Vascular Reactivity ◽

Enzyme Inhibitor ◽

Spontaneously Hypertensive Rat ◽

Combined Therapy ◽

Combined Treatment ◽

Renin Angiotensin System ◽

Response Curves ◽

Angiotensin System ◽

Renin Angiotensin

In hypertension, the combination therapy is frequently used to obtain a better therapeutic effect and reduce adverse effects. One effective combination is with inhibitors and β-blockers of renin–angiotensin system. Although the mechanisms of action of each drug are already known, the antihypertensive mechanism is more complex and therefore the combined treatment mechanism is unclear. Specifically, the effect of the treatments of angiotensin-converting enzyme inhibitor or AT1 receptor antagonist with β-blocker on the angiotensin II and bradykinin reactivity has not been studied. For this reason, we evaluated the interaction between propranolol and captopril or losartan on vascular reactivity to bradykinin and angiotensin II in spontaneously hypertensive rat. We constructed concentration–response curves to angiotensin II and bradykinin after treatment of SHR with propranolol–captopril or propranolol–losartan by using rat aortic rings. While losartan or captopril with propranolol potentiated bradykinin-induced vasodilation effect, the propranolol–losartan interaction decreased the angiotensin II-induced vasoconstriction. In addition, the combinations did not reduce the heart rate significantly. These results suggest that the combined therapy decreased blood pressure to normotensive values and showed less effect for angiotensin II and greater effect for bradykinin than monotherapy which could contribute in the antihypertensive effect.

Download Full-text

Generalized Structured Component Analysis in candidate gene association studies: applications and limitations

Wellcome Open Research ◽

10.12688/wellcomeopenres.15396.2 ◽

2020 ◽

Vol 4 ◽

pp. 142

Author(s):

Paul A. Thompson ◽

Dorothy V. M. Bishop ◽

Else Eising ◽

Simon E. Fisher ◽

Dianne F. Newbury

Keyword(s):

Structural Equation ◽

Multiple Testing ◽

Association Studies ◽

Component Analysis ◽

Candidate Snps ◽

Nucleotide Polymorphisms ◽

Association Analyses ◽

Generalized Structured Component Analysis ◽

Replication Studies ◽

Candidate Gene Association

Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing. Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9. Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects. Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.

Download Full-text

Generalized Structured Component Analysis in candidate gene association studies: applications and limitations

Wellcome Open Research ◽

10.12688/wellcomeopenres.15396.1 ◽

2019 ◽

Vol 4 ◽

pp. 142 ◽

Cited By ~ 2

Author(s):

Paul A. Thompson ◽

Dorothy V. M. Bishop ◽

Else Eising ◽

Simon E. Fisher ◽

Dianne F. Newbury

Keyword(s):

Structural Equation ◽

Multiple Testing ◽

Association Studies ◽

Component Analysis ◽

Candidate Snps ◽

Nucleotide Polymorphisms ◽

Association Analyses ◽

Generalized Structured Component Analysis ◽

Replication Studies ◽

Candidate Gene Association

Download Full-text

Abstract P127: Sex-differences In The Association Of TMEM27 Variants With Hypertension Traits

Hypertension ◽

10.1161/hyp.76.suppl_1.p127 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Nora Franceschini ◽

Thu H Le

Keyword(s):

Multiple Testing ◽

African Ancestry ◽

Low Frequency ◽

Clinic Visit ◽

Nucleotide Polymorphisms ◽

Latino Men ◽

Single Nucleotide ◽

Association Analyses ◽

Two Measures ◽

Experimental Findings

Introduction: The global deletion of collectrin encoded by the TMEM27 gene leads to endothelial dysfunction, salt sensitivity and hypertension. To translate experimental findings to population studies, we studied the association of single nucleotide polymorphisms (SNPs) with blood pressure (BP) traits. Methods: We examined the SNP associations within TMEM27 with BP traits in 11,926 Hispanics/Latinos. BP was measured during a clinic visit and two measures were averaged. Genotypes were imputed from 1000 Genomes Project (1000G). Analyses were stratified by sex, given TMEM27 is located on the chromosome X. We used linear or logistic mixed models for association analyses with systolic and diastolic BP, or hypertension, respectively, in models adjusted for age, body mass index, relatedness and population stratification. Results: The mean age was 46 years-old (standard deviation 14), 41% were men, 28% had hypertension (BP> 140/90 mm Hg). Two intronic SNPs were associated with BP traits in men but not women, when adjusting for multiple testing (Table). SNP rs5936004 associated with lower diastolic BP is more common in Admixed Americans in the 1000G samples (minor allele frequency [MAF] 0.15), and low frequency in European and African ancestry (0.02 and 0.04). SNP rs183583165 is more common in 1000G African sample (MAF 0.03) but rare in other populations. These SNPs were not in linkage disequilibrium with SNPs in the nearby ACE2 gene, which has a role in BP control. Conclusion: This study identified associations of TMEM27 SNPs with BP traits in Hispanic/Latino men but not women, for variants present in higher frequency in Amerindian and African ancestries.

Download Full-text

Effect of Angiotensin II and Converting Enzyme Inhibitor (Captopril) on Blood Pressure, Plasma Renin Activity and Aldosterone in Primary Aldosteronism

Clinical Science ◽

10.1042/cs061289s ◽

1981 ◽

Vol 61 (s7) ◽

pp. 289s-293s ◽

Cited By ~ 33

Author(s):

F. Mantero ◽

F. Fallo ◽

G. Opocher ◽

D. Armanini ◽

M. Boscaro ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Plasma Renin Activity ◽

Primary Aldosteronism ◽

Enzyme Inhibitor ◽

Plasma Renin ◽

Renin Activity ◽

Converting Enzyme ◽

Converting Enzyme Inhibitor ◽

Idiopathic Hyperaldosteronism

1. Patients with idiopathic hyperaldosteronism (IHA) show a response of aldosterone to posture which is not present in patients with aldosterone-producing adenoma (APA). We have determined whether this could be explained by a different sensitivity to angiotensin II. 2. Angiotensin II was infused in gradually increasing doses in six patients with APA and in seven patients with IHA. No changes in aldosterone concentration were found at the end of each period in APA, whereas there was a significant increase in IHA; blood pressure rose by a similar extent in both groups. 3. In order to evaluate the role of endogenous angiotensin II, captopril, a converting enzyme inhibitor, was administered to six patients with APA and five patients with IHA at a dose of 75 mg/day for 1 week. There was a significant fall of mean blood pressure in IHA and only minimal changes in APA. Plasma renin activity and plasma and urinary aldosterone were unchanged in APA. In IHA there was a small increase in upright plasma renin activity and a slight decrease in both plasma and urinary aldosterone, but these changes were not significant. 4. These findings further support the idea that idiopathic hyperaldosteronism is a clinical state different from that occurring in primary aldosteronism due to adenoma, and may be more closely related to essential hypertension.

Download Full-text

Endogenous renin-angiotensin system and drinking behavior in flounder

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1985.248.2.r157 ◽

1985 ◽

Vol 248 (2) ◽

pp. R157-R160 ◽

Cited By ~ 5

Author(s):

R. J. Balment ◽

S. Carrick

Keyword(s):

Angiotensin Ii ◽

Enzyme Inhibitor ◽

Drinking Behavior ◽

Renin Angiotensin System ◽

Simultaneous Administration ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

Physiological Importance ◽

Plasma Chloride

High rates of drinking in seawater-adapted, compared with freshwater (FW)-adapted, flounder were associated with raised plasma chloride and osmotic concentrations. Hypotension in FW-adapted fish, after papaverine administration, gave rise to greatly elevated rates of drinking. This dipsogenic response apparently relied on activation of the endogenous renin-angiotensin system (RAS) and was abolished by simultaneous administration of the converting enzyme inhibitor, captopril. Exogenous angiotensin II was shown to be dipsogenic and vasopressor in the FW-adapted fish. The physiological importance of the activation of the RAS in the control of drinking behavior in euryhaline fish is discussed.

Download Full-text

Response of Blood Pressure and the Renin—Angiotensin—Aldosterone System to Chronic Ambulatory Peritoneal Dialysis in Hypertensive End-Stage Renal Failure

Clinical Science ◽

10.1042/cs063207s ◽

1982 ◽

Vol 63 (s8) ◽

pp. 207s-209s ◽

Cited By ~ 13

Author(s):

Ph. Glasson ◽

H. Favre ◽

M. B. Vallotton

Keyword(s):

Blood Pressure ◽

Peritoneal Dialysis ◽

Angiotensin Ii ◽

Plasma Renin Activity ◽

Plasma Renin ◽

Renin Activity ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

End Stage ◽

Chronic Ambulatory Peritoneal Dialysis

1. Chronic ambulatory peritoneal dialysis allows good control of blood pressure in patients with hypertensive end-stage renal disease. The role of the renin-angiotensin-aldosterone system has therefore been studied in seven patients during the first 6 months of chronic ambulatory peritoneal dialysis treatment. 2. Steady increases in plasma renin activity and aldosterone were observed with a good correlation between these two variables. Plasma electrolytes, renin substrate and body weight did not change significantly. 3. Angiotensin II perfusion tests, performed at the end of the study, showed a relative vascular resistance to angiotensin II. 4. Stimulation of the renin-angiotensin-aldosterone system may be partially explained by this last observation or by removal of an unknown vasopressor substance responsible for the inhibition of the plasma renin activity.

Download Full-text

Renin gene polymorphism: its relationship to hypertension, renin levels and vascular responses

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311405873 ◽

2011 ◽

Vol 12 (4) ◽

pp. 564-571 ◽

Cited By ~ 14

Author(s):

Bei Sun ◽

Jonathan S Williams ◽

Luminita Pojoga ◽

Bindu Chamarthi ◽

Jessica Lasky-Su ◽

...

Keyword(s):

Angiotensin Ii ◽

Plasma Renin ◽

Underlying Mechanism ◽

Renin Activity ◽

P Value ◽

Nucleotide Polymorphisms ◽

Gene Variation ◽

Hypertension Risk ◽

Increased Risk ◽

Renin Gene

The renin gene has been previously reported to be associated with essential hypertension in a variety of ethnic groups. However, no studies have systematically evaluated the relationship between single nucleotide polymorphisms (SNPs) representing coverage of the entire renin gene and hypertension risk. To evaluate the association between renin gene variation and hypertension we investigated data on HyperPATH cohort with 570 hypertensive and 222 normotensive Caucasian subjects. Six tagging SNPs and resultant haplotypes were tested for associations with hypertension risk, followed by mean arterial pressure (MAP), plasma renin activity (PRA) and the change in MAP in response to angiotensin II (AngII) infusion (AngII ΔMAP). The A allele of SNP rs6693954 and the haplotype containing rs6696954A were significantly associated with higher risk for hypertension (OR = 1.98, p = 0.0001; OR = 1.63 p = 0.0005, respectively). The same haplotype block was also associated with altered PRA levels and blunted AngII ΔMAP (global p-value = 0.02, 0.047, respectively). Our results confirm that polymorphisms in the renin gene are associated with increased risk for hypertension in an independent cohort, and that the underlying mechanism may reside in the interaction of renin activity and vascular responsiveness to angiotensin II.

Download Full-text

Transcription Factor Enrichment Analysis in Enhancers Identifies EZH2 as a Susceptibility Gene for Osteoporosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz270 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1152-e1161

Author(s):

Meng Li ◽

Shi Yao ◽

Yuan-Yuan Duan ◽

Yu-Jie Zhang ◽

Yan Guo ◽

...

Keyword(s):

Chinese Population ◽

Multiple Testing ◽

Association Studies ◽

Susceptibility Gene ◽

Enrichment Analysis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

Association Analyses ◽

Hip Bmd

Abstract Purpose Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with osteoporosis. Most of these SNPs are noncoding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs; thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis. Methods We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. Results After functional annotation, a total of 5081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = .028) and NRSF (Padj = .038). We also found 1 SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32 × 10–4; spine BMD: P = 2.72 × 10–3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice. Conclusions By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis.

Download Full-text