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.

scholarly journals Cardiovascular risk factor control: is it possible with a home-based cardiac rehabilitation program?

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
NPD Cunha ◽  
I Aguiar-Ricardo ◽  
T Rodrigues ◽  
S Couto Pereira ◽  
P Silverio Antonio ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Risk Factor ◽  
Cardiovascular Risk ◽  
Cardiac Rehabilitation ◽  
Cardiovascular Risk Factors ◽  
Rehabilitation Program ◽  
Cardiac Rehabilitation Program ◽  
Face To Face ◽  
Home Based

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiovascular risk factors (CVRF) control, needing different strategies, through patient education, lifestyle changes and therapeutic optimization is a central core of cardiac rehabilitation. However, further studies are needed to demonstrate effectiveness of home-based Cardiac Rehabilitation (CR-HB) programs in controlling CVRF.   Purpose To evaluate the effectiveness of a CR-HB program in controlling cardiovascular risk factors. Methods Prospective cohort study including patients who were previously participating in a centre-based CR program and accepted to participate in a CR-HB program due to forced closure of the centre-based CR program for COVID-19 pandemic. The CR-HB consisted of a multidisciplinary digital CR program, including patient regular assessment, exercise, educational, and psychological and relaxation sessions. A structured online educational program for patients and family members/caregivers was provided including educational videos, and powerpoints and webinars. A real time Webinar regarding "nutritional myths and facts" was organized with the duration of 90 minutes as a substitution of the regular face-to-face regular workshop provided at our centre-based CR program. Also, self-control of blood pressure and heart rate and of glycemia in diabetics were promoted, as well as smoking cessation. To assess the impact of the CR-HB on risk factors control, all the patients were submitted to a clinical and analytical evaluation before and after the end of this at distance program.  Results 116 cardiovascular disease patients (62.6 ± 8.9 years, 95 males) who were attending a face-to-face CR program were included in a CR-HB program. Almost 90% (n = 103) of the participants had coronary artery disease. Regarding risk factors, obesity was the most prevalent risk factor (74.7 %) followed by hypertension (59.6%), family history (41.8%), dyslipidaemia (37.9%), diabetes (18.1%), and smoking (12.9%).  Regarding the blood pressure control, 80% of the patients stated that almost daily they measured blood pressure at home; baseline systolic pressure decreased from 117 ± 13 to 113 ±12mmHg, p = 0.007, while there was no significant change in diastolic pressure.   The majority (76%) of diabetic patients said they controlled blood glucose; HbA1c decreased from 6.1 ± 1.1 to 5.9 ± 0.9mg/dL (p = 0.047). Considering the lipid profile, LDL decreased (from 75 ± 30 to 65 ± 26mg/dL, p = 0.012). The Nt-proBNP also decreased (818 ± 1332 vs 414pg/ml ± 591, p = 0.042). There were no other statistically significant differences concerning risk factors modification.  Conclusions Our study showed that a Home-based Cardiac Rehabilitation program can improve or maintain cardiovascular risk factors control, which has important prognostic implications and is frequently a difficult task to achieve.

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.

Modifiable risk factors for intracranial aneurysms: Evidence from genetic studies

2022 ◽  
pp. 174749302110656
Author(s):  
Xiaohui Sun ◽  
Bin Liu ◽  
Ying Chen ◽  
Linshuoshuo Lv ◽  
Ding Ye ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Educational Attainment ◽  
Genome Wide Association Study ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Health Concern ◽  
Modifiable Risk Factors ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

Background: Intracranial aneurysm (IA) is a crucial health concern with limited strategies for prevention and treatment. Aim: To identify potentially modifiable risk factors, such as socioeconomic, behaviors, dietary, and cardiometabolic factors, for IA and its subtypes. Methods: Summary statistics for IA were derived from a genome-wide association study with an overall 79,429 participants. Single nucleotide polymorphisms associated with modifiable risk factors at genome-wide significance ( P = 5 × 10–8) were used as instrumental variables. The inverse-variance-weighted method, weighted-median method, Mendelian randomization (MR)-Egger regression, MR-Pleiotropy RESidual Sum and Outlier, and multivariable MR analyses were performed to evaluate the effect estimates. Results: Genetically predicted educational attainment, insomnia, smoking, and systolic and diastolic blood pressure (SBP and DBP) were significantly associated with the risk of IA. The odds ratios (ORs) were 0.44 (95% confidence interval (CI): 0.37–0.52) for educational attainment, 1.15 (95% CI: 1.08–1.23) for insomnia, 1.56 (95% CI: 1.38–1.75) for smoking initiation, 2.69 (95% CI: 1.77–4.07) for cigarette per day, 2.65 (95% CI: 1.72–4.08) for lifetime smoking, 1.07 (95% CI: 1.06–1.09), and 1.06 (95% CI: 1.04–1.10) for SBP and DBP, respectively. Similar effect estimates were observed for unruptured IAs and aneurysmal subarachnoid hemorrhage. Conclusions: This study provided genetic evidence that several modifiable risk factors, including blood pressure, smoking, educational attainment, and insomnia were associated with the risk of IA.

Association of blood pressure with estimates of 24-h urinary sodium and potassium excretion from repeated single-spot urine samples

2018 ◽  
Vol 42 (3) ◽  
pp. 411-418 ◽  
Author(s):  
Trang Thi Minh Nguyen ◽  
◽  
Katsuyuki Miura ◽  
Sachiko Tanaka-Mizuno ◽  
Taichiro Tanaka ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urinary Sodium ◽  
Urine Samples ◽  
Potassium Excretion ◽  
Single Spot ◽  
Spot Urine ◽  
Sodium And Potassium

scholarly journals Community-Based Screening for Chronic Kidney Disease, Hypertension and Diabetes in Dharan

2013 ◽  
Vol 52 (189) ◽  
pp. 205-212 ◽  
Author(s):  
Sanjib Kumar Sharma ◽  
Subodh Dhakal ◽  
Lekhjung Thapa ◽  
Anup Ghimire ◽  
Rikesh Tamrakar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intervention Program ◽  
Lifestyle Modification ◽  
Fasting Blood Glucose ◽  
Management Program ◽  
Community Based ◽  
Spot Urine

Introduction: Nepal cannot afford renal replacement therapy for End Stage Renal Disease due to lack of resources. Early diagnosis of Chronic Kidney Disease and its risk factors may reduce the need of renal replacement therapy.Methods:A community-based screening on, 3218 people ≥20 years were assessed by door-to-door survey in Dharan, Nepal. Health status, lifestyle habit, physical examination and blood pressure were evaluated. Spot urine was examined for proteins and glucose by dipstick. Fasting blood glucose and serum creatinine were measured in a subset of 1000 people and the prevalence of Chronic Kidney Disease was evaluated.Results: Overweight, obesity, hypertension, diabetes and proteinuria were found in 20%, 5.0%, 38.6%, 7.5%, and 5.1% respectively. In the subset group, Chronic Kidney Disease was detected in 10.6%. Multivariate analysis indicated age (P <0.0001) and diabetes (P = 0.027) as statistically significant predictors for Chronic Kidney Disease. Total of 848 patients entered the management program of lifestyle modification and pharmacologic intervention. Glycemic and blood pressure control was achieved in 60% and 72%, respectively. Regression or stabilization of proteinuria was reported in 52% of patients. Conclusions: Burden of Chronic Kidney Disease and cardiovascular risk factors are high in Dharan. Reasonable control of blood sugar, hypertension and proteinuria was achieved in this program. Findings indicate that activation a large prevention and intervention program to tackle Chronic Kidney Disease and Cardiovascular Disease in Nepal is needed.Keywords: chronic kidney disease; community-screening; diabetes; hypertension; intervention; Nepal.

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.

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 MP039: Association Between Estimated 24-hour Urinary Sodium and Potassium Excretion and Blood Pressure in a Japanese Cohort: a Repeated Measure Analysis

Circulation ◽  
2017 ◽  
Vol 135 (suppl_1) ◽  
Author(s):  
Trang Nguyen ◽  
Katsuyuki Miura ◽  
Sachiko Tanaka ◽  
Taichiro Tanaka ◽  
Yasuyuki Nakamura ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urinary Excretion ◽  
Large Population ◽  
Population Based ◽  
Urine Samples ◽  
Repeated Measure ◽  
Spot Urine ◽  
Japanese Cohort ◽  
Population Strategy ◽  
Measure Analysis

Background: While measurement of sodium (Na) and potassium (K) from the collection of urine over a 24-hour period are associated with blood pressure, relationships with 24-hour urinary excretion estimates from more conveniently collected spot urine samples are less clear. Objectives: The purpose of this report is to examine the association of estimated 24-hour excretion of Na, K and their ratio from annually repeated spot urine samples with systolic (SBP) and diastolic (DBP) blood pressures. Methods: Data include 4,958 normotensive Japanese aged 19 to 55 years who participated in annual physical examinations over a 5-year period in the High-Risk and Population Strategy for Occupational Health Promotion Study (1999-2004). At each examination, spot urine samples were collected in the morning and blood pressure was measured following standardized procedures. 24-hour urinary excretion of Na and K were estimated from spot urine specimens using the formula of Tanaka. Adjustments were made for potential confounding from demographic, lifestyle education, body mass index, smoking, alcohol consumption and physical activity. Mixed-effects regression models were used to examine the association of the estimated 24-hour excretion of Na, K, and the sodium-to-potassium (Na:K) ratio with SBP and DBP over the 5-year period of study. Results: A one standard deviation (SD) increase in the estimated 24-hour excretion of Na (36.6 mmol/day) was associated with a 1.3 mm Hg higher SBP and a 0.8 mm Hg higher DBP (P<.001). The association between Na and SBP was greater in men (1.4 mm Hg per SD) than in women (0.9 mm Hg per SD, P=.003 for interaction) and increased with age (1.0 mm Hg per SD at <35 years of age, 1.2 mm Hg per SD at 35 to 45 years of age, and 1.8 mm Hg per SD at >45 years of age, P<.001 for interaction). Estimated 24-hour excretion of K was inversely associated with blood pressure where a one SD increase (8.9 mmol/day) was associated with a 1.1 mm Hg lower SBP and 0.7 mm Hg lower DBP (P<.001). Unlike the estimated 24-hour excretion of Na, interactions between K and age or sex were absent. Estimated 24-hour Na:K ratio were positively associated with SBP and DBP, with greater effects in men than in women and increasing positive associations with age (P<.01 for each interaction). Conclusions: Estimated 24-hour excretion of Na, K, and the Na:K ratio from spot urine samples have significant associations with blood pressure. Findings suggest that the less costly and more convenient collection of spot urine samples for estimating excretion of Na, K, and their ratio over a 24-hour period may be an efficient way of monitoring these electrolytes in large population-based samples.

Abstract P156: Effect of Socioeconomic and Demographic Factors on Control of Cardiovascular Risk in Elderly Hispanics

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Adriana J Higuera ◽  
David E Timaran ◽  
Eric B Rosero ◽  
Carlos H Timaran
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Health Care ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Poor Control ◽  
Face To Face ◽  
Socioeconomic Characteristics ◽  
Adequate Control ◽  
Socioeconomic And Demographic Factors

Introduction: In elderly Hispanics, the causes contributing to poor control of cardiovascular risk factors (CRF) are not well understood. The purpose of this study was to assess the effect of demographic and socioeconomic factors on CRF control among non-institutionalized elderly Hispanics. Methods: A prospective cohort of 350 elderly Hispanics was studied. A face-to-face interview was conducted to obtain data on comorbidities and demographic and socioeconomic characteristics. Anthropometric and blood pressure measurements were obtained for all participants. Fasting blood samples were collected to assess levels of blood glucose, LDL, HDL and total cholesterol. Univariate and logistic regression analyses were performed to test whether socioeconomic and demographic characteristics were independently associated with adequate control of hypertension, dyslipidemia, and diabetes. Results: Most subjects (72.5%) were women. Median age was 71 (interquartile range, 64-79) years. The prevalence of hypertension, diabetes, and dyslipidemia was 68%, 65%, and 64%, respectively. Of these, 93% of hypertensive, 87% of diabetics, and 78% of dyslipidemic subjects were on pharmacologic treatment. Adequate control of the CRF was achieved in 33%, 70%, and 68% of hypertensive, diabetic, and dyslipidemic subjects, respectively. In general, 63.5% of the subjects had at least one risk factor not controlled. Univariate analyses revealed that only the level of trust in the health care system was significantly associated with adequate control of dyslipidemia ( P =0.03) but not with control of the other risk factors. Multivariate analyses revealed that level of education (odds ratio [OR], 0.92; 95% confidence interval [95%CI], 0.86-0.99; P =0.03) and understanding of information obtained from health care provider (OR, 1.48; 95% CI, 1.01-2.1; P =0.04) were independently associated with adequate control of blood pressure. No other significant associations were found. Conclusions: Despite high rates of treatment, elderly Hispanics in our cohort exhibit poor control of cardiovascular risk factors. Demographic and socioeconomic characteristics do not seem to have a strong effect on CRF control among elderly Hispanics.

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.

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