Hypertension
Conditions
Keywords
hypertension, hydrochlorothiazide, HCTZ, Salt sensitivity, Hydrochlorothiazide induced hyperglycemia
Brief summary
The investigators of this study propose to examine the relationships between STK39 (Serine Threonine Kinase 39) genotypes and responses to salt loading and to thiazide diuretics, hydrochlorothiazide. The investigators hypothesize that STK39 genotypes will be associated with the outcome of both interventions and can contribute to personalized care for hypertension.
Detailed description
Although hypertension can be easily diagnosed and there are many medications available to treat hypertension, this condition is poorly managed in many patients and is a leading cause of morbidity and mortality worldwide. Because a newly identified hypertension susceptibility gene, STK39 (Serine Threonine Kinase 39), plays a central role in kidney sodium transport, the investigators propose a pharmacogenetics study to examine the relationships between STK39 genotypes and blood pressure responses to salt loading and to thiazide diuretics, hydrochlorothiazide. In addition, STK39 genotypes may also predict those hypertension patients more likely to develop thiazide-induced hyperglycemia. The investigators hypothesize that STK39 genotypes of those single nucleotide polymorphisms (SNPs) that are associated with baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension status, will be associated with the outcome of both interventions. Therefore these SNPs can act as markers and contribute to personalized care for hypertension by identifying patients most likely to effectively control their blood pressure by adopting salt-reducing diet versus patients most likely to effectively and safely control their blood pressure by taking thiazide diuretics.
Interventions
PROCEDURESalt loading
Subjects will arrive at the Amish Research Clinics after overnight fasting. After taking height, weight, BP, and body temperature, subjects will receive 2 liters (L) of 0.9% sodium chloride (NaCl) saline over 4 hours while their blood pressure is monitored every 15 minutes. Blood pressure will be taken every 15 minutes during this procedure. Blood and urine samples will be collected from all subjects pre- and post-infusion.
We will perform short-term HCTZ intervention on the same 120 subjects. After overnight fasting and having their height, weight, and BP measured, subjects are given seven 12.5 mg HCTZ tablets and instructed to take 1 tablet daily for one week. Ambulatory blood pressure will be measured and blood and urine will be collected on both day 1 and day 8. After a minimum 6-week wash-out period, the subjects will repeat the 7-day HCTZ intervention, taking 25 mg of HCTZ instead. Subjects with plasma potassium levels below 3.6 mmol/L on day 8 of 12.5 mg HCTZ will be given a daily supplement of 16 milliequivalents of potassium to prevent harmful loss of potassium while taking HCTZ.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Maryland, Baltimore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Old Order Amish * Age 18 to 65 * Have systolic blood pressure between 120 and 160 and diastolic blood pressure between 80 and 100
Exclusion criteria
* History of myocardial infarction, stroke, congestive heart failure, liver disease * Known cause of secondary hypertension * Diabetes or Fasting glucose \> 100 mg/dL * Women who are pregnant, on oral contraceptives, or menstruating * Used hydrochlorothiazide (HCTZ) in the last 8 weeks or known allergy to HCTZ * Taking non-steroidal anti-inflammatory drugs * Estimated glomerular filtration rate \< 80 mL/m * Intention to alter dietary habit during the study * Abuse of alcohol or drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Fasting glucose was measured on day 0 and day 8 | Values on Day 8 subtracts Day 0. |
| Blood Pressure Change During Salt Loading | Every 15 minutes for 4 hours | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured every 15 minutes for 4 hours. Blood pressure change is calculated by the trapezoid method. Essentially we use the average of blood pressure at each pair of time points (for example, DBP 30min + DBP 15min)/2 + (DBP 45min + DBP 30min)/2 + … up to 4 hours.) normalized by baseline SBP/DBP. |
| Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 | Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0. |
| Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 | Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0. |
| Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Fasting glucose was measured on day 0 and day 8 | Values on Day 8 subtracts Day 0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Aldosterone Level Due to Salt-loading | Aldosterone was measured from blood collected pre and post salt loading | Aldosterone is a hormone that plays a critical role in homeostatic regulation of blood pressure. Change is defined as the post-salt loading values minus the pre-salt loading values |
| Change in Plasma Renin Activity Due to Salt-loading | Renin was measured from blood collected pre and post salt loading | Renin is an enzyme that mediates extracellular fluid and regulates blood pressure. Plasma renin activity (PRA) is a measure of the activity of the plasma enzyme renin. PRA is measured in the laboratory by incubating plasma at physiologic temperature in a buffer that facilitates its enzymatic activity. The natural substrate for the enzyme renin is angiotensinogen. Exogenous angiotensinogen is not added to the reaction mixture. This means that, in effect, the PRA results reported are dependent on both renin concentration and the concentration of its substrate in the patient's plasma. Renin cleaves angiotensinogen to produce a decapeptide, angiotensin I, the concentration of which is assayed using liquid chromatography accompanied by tandem mass spectroscopic detection (LC/MS/MS). PRA levels are reported as the amount of angiotensin I generated per unit of time. Change is defined as the post-salt loading values minus the pre-salt loading values |
| Change in Plasma Sodium/Potassium Level Due to Salt-loading | Plasma sodium and potassium measured from blood collected pre and post salt loading | Na/K ratio is a function of kidney function |
| Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Plasma sodium and potassium measured from blood collected pre and post salt loading | Na/K ratio is a function of kidney function |
| Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Plasma sodium and potassium measured from blood collected pre and post salt loading | Na/K ratio is a function of kidney function |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Salt-loading and Thiazide Diuretic (HCTZ) Salt loading: Subjects will arrive at the Amish Research Clinics after overnight fasting. After taking height, weight, BP, and body temperature, subjects will receive 2 L of 0.9% NaCl (sodium chloride) saline over 4 hours while their blood pressure is monitored every 15 minutes. Blood pressure will be taken every 15 minutes during this procedure. Blood and urine samples will be collected from all subjects pre- and post-infusion.
Hydrochlorothiazide (HCTZ): After overnight fasting and having their height, weight, and BP measured, subjects are given 12.5 mg HCTZ tablets and instructed to take 1 tablet daily for one week. Ambulatory blood pressure, blood and urine will be collected on both day 1 and day 8. After a wash-out period, the subjects will repeat the HCTZ intervention, taking 25 mg HCTZ instead. | 124 |
| Total | 124 |
Baseline characteristics
| Characteristic | Salt-loading and Thiazide Diuretic (HCTZ) |
|---|---|
| Age, Continuous saline infusion and HCTZ | 53 years STANDARD_DEVIATION 9 |
| Age, Continuous Saline infusion only | 50 years STANDARD_DEVIATION 7 |
| BMI | 26.1 kg/m2 STANDARD_DEVIATION 2.8 |
| creatinine | 0.74 mg/dL STANDARD_DEVIATION 0.12 |
| Diastolic blood pressure HCTZ | 80 mmHg STANDARD_DEVIATION 7 |
| Diastolic blood pressure Salt Loading | 71 mmHg STANDARD_DEVIATION 7 |
| Sex: Female, Male Female | 71 Participants |
| Sex: Female, Male Male | 53 Participants |
| Systolic blood pressure HCTZ | 126 mmHg STANDARD_DEVIATION 10 |
| Systolic blood pressure Salt loading | 114 mmHg STANDARD_DEVIATION 11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 28 |
| other Total, other adverse events | 0 / 124 | 0 / 28 |
| serious Total, serious adverse events | 0 / 124 | 0 / 28 |
Outcome results
Primary
Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ
Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0.
Time frame: 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8
Population: 25 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | DBP, Genotype GG | -2 mmHg | Standard Error 0 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | DBP, Genotype AG | 0.7 mmHg | Standard Error 2.4 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | DBP, Genotype AA | -1.7 mmHg | Standard Error 1.1 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | SBP, Genotype GG | 1 mmHg | Standard Error 0 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | SBP, Genotype AG | -1.3 mmHg | Standard Error 4.2 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | SBP, Genotype AA | -4.5 mmHg | Standard Error 1.3 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Primary
Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ
Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0.
Time frame: 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8
Population: 28 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | DBP, Genotype GG | 0 mmHg | Standard Error 0 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | DBP, Genotype AG | 2.0 mmHg | Standard Error 2.4 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | DBP, Genotype AA | -1.1 mmHg | Standard Error 1.1 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | SBP, Genotype GG | 1.0 mmHg | Standard Error 0 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | SBP, Genotype AG | -0.7 mmHg | Standard Error 4.3 |
| rs35929607 SNP | Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | SBP, Genotype AA | -4.2 mmHg | Standard Error 1.3 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Primary
Blood Pressure Change During Salt Loading
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured every 15 minutes for 4 hours. Blood pressure change is calculated by the trapezoid method. Essentially we use the average of blood pressure at each pair of time points (for example, DBP 30min + DBP 15min)/2 + (DBP 45min + DBP 30min)/2 + … up to 4 hours.) normalized by baseline SBP/DBP.
Time frame: Every 15 minutes for 4 hours
Population: 124 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, and genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Blood Pressure Change During Salt Loading | DBP, Genotype GG | -25.5 mmHg | Standard Error 4.3 |
| rs35929607 SNP | Blood Pressure Change During Salt Loading | DBP, Genotype AG | 34.6 mmHg | Standard Error 11.6 |
| rs35929607 SNP | Blood Pressure Change During Salt Loading | DBP, Genotype AA | 23.2 mmHg | Standard Error 7.7 |
| rs35929607 SNP | Blood Pressure Change During Salt Loading | SBP, Genotype GG | -41.4 mmHg | Standard Error 8.4 |
| rs35929607 SNP | Blood Pressure Change During Salt Loading | SBP, Genotype AG | 62.9 mmHg | Standard Error 15.7 |
| rs35929607 SNP | Blood Pressure Change During Salt Loading | SBP, Genotype AA | 44.8 mmHg | Standard Error 10.6 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Primary
Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ
Values on Day 8 subtracts Day 0.
Time frame: Fasting glucose was measured on day 0 and day 8
Population: 25 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype 11 is homozygous for the minor allele G, genotype 12 is heterozygous, genotype 22 is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Fasting glucose, GG Genotype | 1.0 mmHg | Standard Error 0 |
| rs35929607 SNP | Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Fasting glucose, AG Genotype | 1.0 mmHg | Standard Error 2.3 |
| rs35929607 SNP | Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Fasting glucose, AA Genotype | 2.3 mmHg | Standard Error 2.1 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Primary
Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ
Values on Day 8 subtracts Day 0.
Time frame: Fasting glucose was measured on day 0 and day 8
Population: 28 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Fasting glucose, GG Genotype | 9 mmHg | Standard Error 0 |
| rs35929607 SNP | Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Fasting glucose, AG Genotype | 2 mmHg | Standard Error 2.5 |
| rs35929607 SNP | Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Fasting glucose, AA Genotype | -0.1 mmHg | Standard Error 1.2 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Secondary
Change in Plasma Aldosterone Level Due to Salt-loading
Aldosterone is a hormone that plays a critical role in homeostatic regulation of blood pressure. Change is defined as the post-salt loading values minus the pre-salt loading values
Time frame: Aldosterone was measured from blood collected pre and post salt loading
Population: 124 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Change in Plasma Aldosterone Level Due to Salt-loading | Genotype GG | -7.5 ng/dL | Standard Error 4.5 |
| rs35929607 SNP | Change in Plasma Aldosterone Level Due to Salt-loading | Genotype AG | -1.2 ng/dL | Standard Error 0.7 |
| rs35929607 SNP | Change in Plasma Aldosterone Level Due to Salt-loading | Genotype AA | -1.9 ng/dL | Standard Error 0.6 |
p-value: <0.05Chi-squared
Secondary
Change in Plasma Renin Activity Due to Salt-loading
Renin is an enzyme that mediates extracellular fluid and regulates blood pressure. Plasma renin activity (PRA) is a measure of the activity of the plasma enzyme renin. PRA is measured in the laboratory by incubating plasma at physiologic temperature in a buffer that facilitates its enzymatic activity. The natural substrate for the enzyme renin is angiotensinogen. Exogenous angiotensinogen is not added to the reaction mixture. This means that, in effect, the PRA results reported are dependent on both renin concentration and the concentration of its substrate in the patient's plasma. Renin cleaves angiotensinogen to produce a decapeptide, angiotensin I, the concentration of which is assayed using liquid chromatography accompanied by tandem mass spectroscopic detection (LC/MS/MS). PRA levels are reported as the amount of angiotensin I generated per unit of time. Change is defined as the post-salt loading values minus the pre-salt loading values
Time frame: Renin was measured from blood collected pre and post salt loading
Population: 124 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Change in Plasma Renin Activity Due to Salt-loading | Genotype AG | -0.3 ng/ml/h | Standard Error 0.1 |
| rs35929607 SNP | Change in Plasma Renin Activity Due to Salt-loading | Genotype AA | -0.4 ng/ml/h | Standard Error 0.1 |
| rs35929607 SNP | Change in Plasma Renin Activity Due to Salt-loading | Genotype GG | -0.8 ng/ml/h | Standard Error 0.3 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35909607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Secondary
Change in Plasma Sodium/Potassium Level Due to Salt-loading
Na/K ratio is a function of kidney function
Time frame: Plasma sodium and potassium measured from blood collected pre and post salt loading
Population: 124 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level Due to Salt-loading | Genotype GG | 0.3 ratio | Standard Error 0.8 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level Due to Salt-loading | Genotype AG | -0.3 ratio | Standard Error 0.4 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level Due to Salt-loading | Genotype AA | 0.1 ratio | Standard Error 0.2 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35909607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Secondary
Change in Plasma Sodium/Potassium Level During High Dose of HCTZ
Na/K ratio is a function of kidney function
Time frame: Plasma sodium and potassium measured from blood collected pre and post salt loading
Population: 25 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype GG is homozygous for the minor allele G, genotype AG is heterozygous, genotype AA is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Genotype GG | 1 ratio | Standard Error 0 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Genotype AG | 0 ratio | Standard Error 2.3 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Genotype AA | 2.3 ratio | Standard Error 2.1 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35929607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared
Secondary
Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ
Na/K ratio is a function of kidney function
Time frame: Plasma sodium and potassium measured from blood collected pre and post salt loading
Population: 28 subjects were divided into 3 genotype groups based on their rs35929607 genotypes. Genotype 11 is homozygous for the minor allele G, genotype 12 is heterozygous, genotype 22 is homozygous for the major allele A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Genotype GG | 0 ratio | Standard Error 0 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Genotype AG | 1.0 ratio | Standard Error 0.6 |
| rs35929607 SNP | Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Genotype AA | 0.6 ratio | Standard Error 0.4 |
Comparison: Null hypothesis: There is no association between STK39 SNP rs35909607 genotype group and phenotypes collected in this study.p-value: >0.05Chi-squared