scholarly journals GNAI2 polymorphic variance associates with salt sensitivity of blood pressure in the Genetic Epidemiology Network of Salt Sensitivity study

2018 ◽  
Vol 50 (9) ◽  
pp. 724-725 ◽  
Author(s):  
Xiaoling Zhang ◽  
Alissa A. Frame ◽  
Jonathan S. Williams ◽  
Richard D. Wainford
Keyword(s):  
Blood Pressure ◽  
Genetic Epidemiology ◽  
Animal Studies ◽  
Sensitivity Study ◽  
Salt Sensitivity ◽  
Nucleotide Polymorphisms ◽  
Data Set ◽  
Hypertension Risk ◽  
Sensitivity Data ◽  
Continuous Phenotype

Salt sensitivity of blood pressure (BP) increases hypertension risk and associated adverse cardiovascular outcomes. At present, there are no validated rapid tests or diagnostic markers to identify salt sensitivity of BP in clinical practice. Based on our prior animal studies that report a role for brain Gαi2 proteins in the salt sensitivity of BP and evidence that GNAI2 single nucleotide polymorphisms (SNPs) associate with hypertension risk, we investigated the hypothesis that GNAI2 SNPs associate with salt sensitivity of BP in humans. Our data provide the first evidence that a GNAI2 SNP ( rs10510755 ) positively associates with salt sensitivity of BP in the Genetic Epidemiology of Salt Sensitivity data set (continuous phenotype P = 0.049, case-control phenotype P = 0.039; n = 968), independently of subject sex or age. These observations suggest that genotyping at GNAI2 may be a useful biomarker in identifying individuals at risk for developing salt-sensitive BP and related complications or in identifying salt sensitivity within the hypertensive population.

scholarly journals Physical Activity Reduces Salt Sensitivity of Blood Pressure: The Genetic Epidemiology Network of Salt Sensitivity Study

2012 ◽  
Vol 176 (suppl 7) ◽  
pp. S106-S113 ◽  
Author(s):  
C. M. Rebholz ◽  
D. Gu ◽  
J. Chen ◽  
J.-F. Huang ◽  
J. Cao ◽  
...  
Keyword(s):  
Physical Activity ◽  
Blood Pressure ◽  
Genetic Epidemiology ◽  
Sensitivity Study ◽  
Salt Sensitivity

scholarly journals Effects of environmental and genetic risk factors for salt sensitivity on blood pressure in northern China: the systemic epidemiology of salt sensitivity (EpiSS) cohort study

BMJ Open ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. e023042 ◽  
Author(s):  
Han Qi ◽  
Bin Liu ◽  
Chunyue Guo ◽  
Zheng Liu ◽  
Han Cao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Northern China ◽  
Salt Sensitivity ◽  
Urine Samples ◽  
Liaoning Province ◽  
Nucleotide Polymorphisms ◽  
Spot Urine ◽  
Face To Face ◽  
Non Coding Rnas

PurposeThe systemic epidemiology of salt sensitivity (EpiSS) study aims to combine molecular biology, epidemiology and bioinformatics methods to discover the potential causes of salt sensitivity of blood pressure (SSBP) using single-nucleotide polymorphisms in the genome and non-coding RNAs in the transcriptome to uncover both the genetic and environmental factors of SSBP.ParticipantsBetween July 2014 and July 2016, we enrolled adults from 11 study centres in Beijing and Liaoning Province; participants were of the Han population and were 35–70 years of age. We collected blood samples, spot urine samples and 24-hour urine samples, in addition to baseline data on demographics, health-related lifestyle factors, chronic diseases, family history of illness and anthropometric information through face-to-face interviews using a standardised questionnaire. EpiSS uses the modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) to evaluate the effects of salt on blood pressure.Findings to dateIn total, 2163 participants were included in the EpiSS, of which 2144 participants completed the questionnaire, 2120 (98.0%) completed the MSAOSL-DST and 2083 (96.3%) provided a 24-hour urine sample. A total of 2057 participants (1501 women and 556 men) completed all the steps of the investigation and were included in the analysis. Among them, 583 (28.3%) subjects were classified as having salt sensitivity of blood pressure, and 1061 (51.6%) had hypertension.Future plansThe next step of our study is to evaluate the incidence of cardiovascular disease in the participants. Biennial follow-up, including face-to-face questionnaire surveys, laboratory measurements of blood, urinary creatinine, glomerular filtration rate and anthropometric measurements, will occur two additional times. DNA and RNA will be collected for subsequent genetic biomarker studies. We plan on screening the salt-sensitive-related gene loci and non-coding RNAs based on relative environmental risk factors.Trial registration numberChiCTR-EOC-16009980; Pre-results.

Abstract P242: Role of Human Renal Proximal Tubule Sodium Bicarbonate Cotransporter NBCe2 (SLC4A5) in Salt Sensitivity of Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Julia M Carlson ◽  
Tran T Hanh ◽  
Dora Bigler Wang ◽  
Peng Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Bicarbonate ◽  
Sodium Transport ◽  
Renal Tissue ◽  
Salt Sensitivity ◽  
Bicarbonate Transport ◽  
Nucleotide Polymorphisms ◽  
High Sodium ◽  
Sodium Bicarbonate Cotransporter ◽  
Renal Tubular

The sodium bicarbonate cotransporter NBCe2 (encoded by SLC4A5) partially regulates renal tubular sodium bicarbonate transport. Hypothesis: since SLC4A5 single nucleotide polymorphisms (SNPs, rs10177833 and rs7571842) are associated with salt sensitivity of blood pressure, the gene product, NBCe2, would be involved with the etiology of human salt sensitivity. NBCe2 was localized in freshly fixed renal tissue and in primary and immortalized RPT cell (RPTC) cultures from tissue or isolated from urine. Basal expression of NBCe2 mRNA and protein was not different between RPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, total transcellular sodium transport, NHE3 protein expression, and Cl-/HCO3- exchanger activity were higher in SLC4A5 HV than WT RPTCs (WT: 8.6±1.2 mM NaCl n=6, 5207.1±386.4 RFU n=36, 0.265±0.006 pH unit/min, n=33 respectively; VS HV: 14.75±0.7 mM NaCl n=4, 6946.2±500.4 RFU n=48, 0.314±0.018 pH unit/min n=35 respectively, p<0.01). Aberrant sodium transport was even more evident after increasing intracellular sodium, which resulted in increased NBCe2 mRNA, NBCe2 protein and bicarbonate transport in HV RPTCs compared to WT (WT 146% ± 24% , 109% ± 4.7%, 89% ± 4.5%, respectively, VS HV 214% ± 23%, 128% ± 5.7%, 141% ± 4.8%, respectively N=8-12, p<0.05). RPTCs carrying HV variants showed increased binding of HNF4A to SLC4A5 DNA, which was blocked by two HNF4A antagonists. Assays in RPTCs isolated from urine showed increased bicarbonate-dependent pH recovery in RPTCs from salt-sensitive subjects who are HV for SLC4A5. NBCe2 under high sodium is hyper-responsive in RPTCs carrying SLC4A5 HV through an aberrant HNF4A-mediated mechanism.

Abstract P232: Common Variants of the Estrogen Receptor 1 Gene Predict Decreased Blood Pressure Salt-Sensitivity in Men: The GenSalt Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Tanika N Kelly ◽  
Casey M Rebholz ◽  
Dongfeng Gu ◽  
James E Hixson ◽  
Dabeeru C Rao ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Sex Hormones ◽  
Heart Association ◽  
Complex Trait ◽  
Salt Sensitivity ◽  
Nucleotide Polymorphisms ◽  
High Sodium ◽  
Low Sodium ◽  
Estrogen Receptor 1

Previous reports have documented increased blood pressure (BP) salt-sensitivity in women compared to men, suggesting that genes encoding sex hormones could influence BP response to sodium. In the current study, we examined the association between 799 single nucleotide polymorphisms (SNPs) in 44 genes involved in sex hormone biosynthesis, bioavailability and metabolism for their association with BP responses to sodium intervention separately in men and women. A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day) was conducted among 1,906 participants from 633 Han Chinese families. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Additive associations between each SNP and BP responses to low and high-sodium interventions were assessed using a mixed linear regression model to account for familial dependencies. Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453 and rs9383951. For example, men with genotypes C/C, C/T, and T/T of rs9397453 had respective mean DBP responses [95% confidence intervals (CI)] of: -2.67 (-3.13, -2.22), -1.23 (-1.98, -0.48), and 0.08 (-2.31, 2.47) mmHg to low-sodium intervention [p=1×10 -4 ; false discovery rate (FDR)-q=0.04]; and 1.46 (1.03, 1.89), 0.19 (-0.54, 0.91), and -1.10 (-2.82, 0.61) mmHg to high-sodium intervention (p=2×10 -4 ; FDR-q=0.04). In addition, mean SBP responses (95% CI) were: -5.70 (-6.19, -5.20), -4.34 (-5.37, -3.31), and -2.65 (-5.15, -0.16) mmHg, respectively, for low-sodium intervention (p=2×10 -3 ; FDR-q=0.17); and 4.56 (4.12, 4.99), 3.47 (2.63, 4.30), and 1.97 (-0.49, 4.43) mmHg, respectively, for high-sodium intervention (p=3×10 -3 ; FDR-q=0.40). ESR1 variants were not associated with BP responses in women, with highly significant genotype-gender interactions noted. In summary, we identified strong, consistent associations between genetic variants in the ESR1 gene and decreased salt-sensitivity in men. Although replication of these findings is needed, our results support a role for sex-hormones in the etiology of this complex trait. Funding(This research has received full or partial funding support from the American Heart Association, National Center)

Abstract 089: Dopamine D 2 Receptor is Associated with Inverse Salt Sensitivity

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Peng Xu ◽  
John J Gildea ◽  
Pedro A Jose ◽  
Robert M Carey ◽  
Robin A Felder
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Salt Sensitivity ◽  
T Test ◽  
Receptor Expression ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Tissue Slices ◽  
Type D

Our previous studies of salt sensitivity of blood pressure have demonstrated that approximately 11% of study participants have a paradoxical increase in blood pressure (> or = to 7-mm Hg) on a low NaCl diet (defined as inverse salt sensitivity (ISS)). However the mechanisms responsible for this effect are not known. We demonstrated that single nucleotide polymorphisms (SNPs) in the dopamine type 2 receptor (D 2 R) (RS6276 and 6267) are highly associated with ISS ( P values of 1.0х10 –2 and 3.8х10 –2 with odds ratios of 0.32 and 0.48 in unadjusted regression models, respectively). The C allele at both sites confers protection. The D 2 R is strongly expressed throughout the cytoplasm of proximal tubule cells in human kidney tissue slices. We also cultured RPTC from the urine from 4 salt resistant (SR) and 3 ISS participants enrolled in our clinical salt sensitivity studies. We hypothesize that D 2 R containing SNPs have altered receptor expression, and altered signaling compared to wild type controls. ISS participants were homozygous variant for the two D 2 R alleles and showed more D 2 R expression than SR RPTC heterozygous variant (HV) for the two alleles (ISS: 1.166±0.059 n=3 vs SR: 0.969±0.024 n=4, P<0.05, t-test). D 2 R expression was increased when the ISS cells were stimulated by a non-selective D 2 R agonist bromocriptine to a greater extent in the D 2 R SNP cell lines (ISS: VEH 1.166±0.059, vs bromocriptine 1.474 ± 0.040, n=3, P<0.05, t-test). Using the ROS reagent assay, dihydroethidium, there was found to be more ROS products in ISS cells than SR cells when stimulated under low salt (ISS: 1.145 ± 0.053, n=3 vs SR: 0.722 ± 0.101, n=4, P<0.05, t-test). We used a highly selective D 2 R agonist (sumanirole) to stimulate wild-type and SNPed cells, and the results demonstrated no effect in the cells with wild type D 2 R but an increase in ROS in cells heterozygous for the D 2 R SNPs (SNP: VEH 38,364±1,266, sumanirole 50,926 ± 3,310, VS WT: VEH 34,562±1,831 sumanirole 34,435 ± 1,614 RFU n=12, P<0.05, t-test) consistent with the higher expression of D 2 R found in ISS urine cells. We hypothesize that SNPs in the D 2 R lead to increased reactive oxygen species which has previously been associated with renal fibrosis and hypertension.

Homozygosity for an Alpha-Adducin Polymorphism (460TRP) Is Associated with Salt-Sensitivity and Low-Renin Hypertension in Humans

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 717-717
Author(s):  
Frederick D Grant ◽  
Jose R Romero ◽  
Xavier Jeunemaitre ◽  
Steven C Hunt ◽  
Paul N Hopkins ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Blood Pressure Response ◽  
Plasma Renin ◽  
Salt Sensitivity ◽  
Dietary Sodium ◽  
Nucleotide Polymorphisms ◽  
Intermediate Phenotypes ◽  
Low Renin Hypertension ◽  
The Mean

P133 Single nucleotide polymorphisms of the adducin genes have been associated with the development of elevated blood pressure in the rat. However, previous studies of the 460Trp polymorphism of human alpha-adducin have not clearly identified an association with the development of human hypertension. In this study, 281 hypertensive subjects were subgrouped by the intermediate phenotypes of plasma renin status and sensitivity of systolic blood pressure to dietary sodium. The frequency of the 460Trp allele was 19% and 9 of 281 subjects (3.2%) were homozygous (TT) for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium (>150 meq/d vs. ≤30 meq/d) was significantly (p < 0.05) greater in TT subjects (25 ± 2 mmHg) compared to those heterozygous (GT) for the 460Trp allele (12 ± 2 mmHg) or homozygous (GG) for the 460Gly allele (14 ± 1 mmHg). There was a significant (p < 0.005) association between homozygosity for the 460Trp allele and low-renin hypertension. Six of 67 (9%) low-renin subjects, but only 3 of 214 (1.4%) normal- renin subjects had the TT genotype. Heterozygous (GT) subjects did not have increased salt-sensitivity of systolic blood pressure and did not have an increased frequency of low-renin hypertension. Erythrocyte sodium content was significantly (p < 0.01) less in subjects with the TT genotype (24.5 ± 1.0 mmol/kgHgb) compared to all subjects (33.2 ± 0.4 mmol/kgHgb). Subjects with the TT genotype had a significantly (p < 0.05) lower sodium-lithium countertransport (SLC) (0.16 ± 0.04 mmol/l/h) than other subjects (0.28 ± 0.01 mmol/l/h). However, the mean SLC of all low-renin hypertensive subjects (0.25 ± 0.02 mmol/l/h) was not significantly different than the mean SLC of normal-renin hypertensive subjects (0.26 ± 0.01 mmol/l/h). Thus, a decreased SLC is associated with the TT genotype and is not a characteristic of all individuals with low-renin hypertension. These findings suggest that homozygous expression of the 460Trp polymorphism of the alpha-adducin gene alters sodium handling in humans and may be an important contributor to the development of low-renin hypertension in some individuals.

scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

2017 ◽  
Vol 234 (1) ◽  
pp. T93-T106 ◽  
Author(s):  
Maria-Christina Zennaro ◽  
Fabio Fernandes-Rosa
Keyword(s):  
Blood Pressure ◽  
General Population ◽  
Mineralocorticoid Receptor ◽  
Genetic Diagnosis ◽  
Plasma Renin ◽  
Salt Sensitivity ◽  
Nucleotide Polymorphisms ◽  
Loss Of Function ◽  
Familial Form ◽  
Number Of Patients

Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of-function mutations of the MR are responsible for renal pseudohypoaldosteronism type 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone. In contrast, a MR gain-of-function mutation has been associated with a familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In addition to rare variants, frequent functional single nucleotide polymorphisms of the MR are associated with salt sensitivity, blood pressure, stress response and depression in the general population. This review will summarize our knowledge on MR mutations in PHA1, reporting our experience on the genetic diagnosis in a large number of patients performed in the last 10 years at a national reference center for the disease. We will also discuss the influence of rare MR variants on blood pressure and salt sensitivity as well as on stress and cognitive functions in the general population.

scholarly journals Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway

Hypertension ◽  
2021 ◽  
Vol 78 (6) ◽  
pp. 1809-1817
Author(s):  
Andrea V. Haas ◽  
Li En Yee ◽  
Yan E. Yuan ◽  
Yin H. Wong ◽  
Paul N. Hopkins ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Risk Allele ◽  
Salt Sensitivity ◽  
Nucleotide Polymorphisms ◽  
Aldosterone Secretion ◽  
Mineralocorticoid Receptor Antagonist ◽  
Single Nucleotide ◽  
Genetic Predictors ◽  
Serum Aldosterone ◽  
Cardiovascular Morbidity And Mortality

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype—a risk allele associated with increased aldosterone secretion (either β2AR or ESR2 ) and a risk allele associated with amplification of aldosterone’s effects ( SGK1 ) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/SGK, ESR2/SGK , and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the β2AR/SGK (β=5.46; P <0.001) and ESR2/SGK ( β =4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/SGK and ESR2/SGK . On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of β2AR/SGK1 and ESR2 / SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy—gene-driven, personalized medicine.

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