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| ID | Type | Description | Link |
|---|---|---|---|
| R21DK084566 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Salt-loading and thiazide diuretic (HCTZ) | Other | Salt loading:2 L of 0.9% NaCl. HCTZ:12.5/ 25 mg of HCTZ for 1 week |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Salt loading | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Every 15 minutes for 4 hours |
| 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. | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 |
| 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. | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 |
| Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Values on Day 8 subtracts Day 0. | Fasting glucose was measured on day 0 and day 8 |
| Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Values on Day 8 subtracts Day 0. | Fasting glucose was measured on day 0 and day 8 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Aldosterone was measured from blood collected pre and post salt loading |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yen Pei C. Chang, Ph.D. | University of Maryland, Baltimore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amish Research Clinics | Lancaster | Pennsylvania | 17607 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19114657 | Background | Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim JD, Subramanya AR, Steinle NI, Parsa A, Ober CC, Welling PA, Chakravarti A, Weder AB, Cooper RS, Mitchell BD, Shuldiner AR, Chang YP. From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31. doi: 10.1073/pnas.0808358106. Epub 2008 Dec 29. | |
| 18092945 | Background |
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| ID | Title | Description |
|---|---|---|
| FG000 | Salt-loading and Thiazide Diuretics (HCTZ) | Salt loading: 2 liters (L) of 0.9% sodium chloride (NaCl). HCTZ:12.5 or 25 mg of HCTZ for 1 week |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Salt Loading |
| |||||||||||||
| HCTZ Low Dose |
| |||||||||||||
| HCTZ High Dose |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Only subjects whose baseline blood pressure is high enough (SBP>120 or DBP>80 mmHg) and willing to undergo the multi-week intervention were enrolled into the HCTZ part of the study. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Error | mmHg | Every 15 minutes for 4 hours |
|
1 year, 9 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Yen Pei Christy Chang | University of Maryland, Baltimore | 410-706-6737 | cchang@som.umaryland.edu |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D006852 | Hydrochlorothiazide |
| ID | Term |
|---|---|
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
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|
| Hydrochlorothiazide (HCTZ) | Drug | 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. |
|
|
| 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 |
| Renin was measured from blood collected pre and post salt loading |
| Change in Plasma Sodium/Potassium Level Due to Salt-loading | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading |
| Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading |
| Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading |
| Delpire E, Gagnon KB. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J. 2008 Jan 15;409(2):321-31. doi: 10.1042/BJ20071324. |
| 18800028 | Background | Chiga M, Rai T, Yang SS, Ohta A, Takizawa T, Sasaki S, Uchida S. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008 Dec;74(11):1403-9. doi: 10.1038/ki.2008.451. Epub 2008 Sep 17. |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Systolic blood pressure | Only subjects whose baseline blood pressure is high enough (SBP>120 or DBP>80 mmHg) and willing to undergo the multi-week intervention were enrolled into the HCTZ part of the study. | Mean | Standard Deviation | mmHg |
|
| Diastolic blood pressure | Only subjects whose baseline blood pressure is high enough (SBP>120 or DBP>80 mmHg) and willing to undergo the multi-week intervention were enrolled into the HCTZ part of the study. | Mean | Standard Deviation | mmHg |
|
| BMI | Mean | Standard Deviation | kg/m2 |
|
| creatinine | Mean | Standard Deviation | mg/dL |
|
|
|
|
| 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 | 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. | Posted | Mean | Standard Error | ng/dL | Aldosterone was measured from blood collected pre and post salt loading |
|
|
|
|
| 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 | 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. | Posted | Mean | Standard Error | ng/ml/h | Renin was measured from blood collected pre and post salt loading |
|
|
|
|
| Secondary | Change in Plasma Sodium/Potassium Level Due to Salt-loading | Na/K ratio is a function of kidney function | 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. | Posted | Mean | Standard Error | ratio | Plasma sodium and potassium measured from blood collected pre and post salt loading |
|
|
|
|
| Secondary | Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Na/K ratio is a function of kidney function | 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. | Posted | Mean | Standard Error | ratio | Plasma sodium and potassium measured from blood collected pre and post salt loading |
|
|
|
|
| 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. | 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. | Posted | Mean | Standard Error | mmHg | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 |
|
|
|
|
| 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. | 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. | Posted | Mean | Standard Error | mmHg | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 |
|
|
|
|
| Primary | Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Values on Day 8 subtracts Day 0. | 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. | Posted | Mean | Standard Error | mmHg | Fasting glucose was measured on day 0 and day 8 |
|
|
|
|
| Primary | Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Values on Day 8 subtracts Day 0. | 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. | Posted | Mean | Standard Error | mmHg | Fasting glucose was measured on day 0 and day 8 |
|
|
|
|
| Secondary | Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Na/K ratio is a function of kidney function | 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. | Posted | Mean | Standard Error | ratio | Plasma sodium and potassium measured from blood collected pre and post salt loading |
|
|
|
|
| 0 |
| 124 |
| 0 |
| 124 |
| 0 |
| 124 |
| EG001 | HCTZ | 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. | 0 | 28 | 0 | 28 | 0 | 28 |
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| D013457 |
| Sulfur Compounds |
| D009930 | Organic Chemicals |
| D049971 | Thiazides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Genotype AA |
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| Genotype AA |
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| Genotype AA |
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| Genotype AA |
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| DBP, Genotype AA |
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| SBP, Genotype GG |
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| SBP, Genotype AG |
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| SBP, Genotype AA |
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| DBP, Genotype AA |
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| SBP, Genotype GG |
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| SBP, Genotype AG |
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| SBP, Genotype AA |
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| Fasting glucose, AA Genotype |
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| Fasting glucose, AA Genotype |
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| Genotype AA |
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