Genetic Epidemiology of Responses to Antihypertensives - Full Text View

Purpose

To determine whether measured variation in genes coding for components of vasoconstriction and volume regulating systems predict interindividual differences in blood pressure response to therapy with a thiazide diuretic, hydrochlorothiazide, or an angiotensin II receptor blocker, candesartan, in hypertensive African-Americans (N=300 treated with each drug) and in hypertensive European Americans (N=300 treated with each drug).

Condition	Intervention
Cardiovascular Diseases Heart Diseases Hypertension	Drug: Hydrochlorothiazide Drug: Candesartan

Study Type:	Observational
Study Design:	Observational Model: Cohort Time Perspective: Prospective
Official Title:	Genetic Epidemiology of Responses to Antihypertensives

Resource links provided by NLM:

MedlinePlus related topics: Blood Pressure Medicines Heart Diseases High Blood Pressure

Drug Information available for: Hydrochlorothiazide Candesartan Candesartan cilexetil

U.S. FDA Resources

Further study details as provided by Mayo Clinic:

Primary Outcome Measures:

Change in blood pressure [ Time Frame: 4 weeks for hydrochlorothiazide; 6 weeks for candesartan ] [ Designated as safety issue: No ]
The blood pressure response to antihypertensive drug therapy was defined by the difference between blood pressure levels prior to and at the end of drug therapy.

Secondary Outcome Measures:

Adverse metabolic changes [ Time Frame: 4 weeks for hydrochlorothiazide only ] [ Designated as safety issue: No ]
Potentially adverse metabolic changes in response to hydrochlorothiazide include changes in fasting serum glucose and insulin; serum potassium; serum lipids (triglycerides, HDL-cholesterol, total cholesterol); and serum uric acid.

Biospecimen Retention: Samples With DNA

Serum, plasma, buffy coat, urine.

Enrollment:	1200
Study Start Date:	February 1997
Study Completion Date:	January 2008
Primary Completion Date:	January 2008 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
African American hydrochlorothiazide 300 African American hypertensives were treated with hydrochlorothiazide 25 mg daily for 4 weeks.	Drug: Hydrochlorothiazide
European American hydrochlorothiazide 300 European American hypertensives were treated with hydrochlorothiazide 25 mg daily for 4 weeks	Drug: Hydrochlorothiazide
African American candesartan 300 African American hypertensives were treated with candesartan 16 mg daily for 2 weeks followed by 32 mg daily for 4 weeks	Drug: Candesartan
European American candesartan 300 European American hypertensives were treated with candesartan 16 mg daily for 2 weeks followed by 32 mg daily for 4 weeks	Drug: Candesartan

Detailed Description:

BACKGROUND:

Essential hypertension is a common disorder that contributes to morbidity, mortality, and cost of health care, especially among African-Americans. Although a single-drug therapy is commonly prescribed for treatment of hypertension, blood pressure levels are controlled in some individuals but not in others. The study has the potential to identify genes contributing to the etiology of interindividual differences in blood pressure response to diuretic therapy in African-Americans and European Americans.

DESIGN NARRATIVE:

Hypertensive adults were treated with the diuretic hydrochlorothiazide, 25 mg/day, for four weeks; or with the angiotensin II receptor blocker candesartan, 16 mg/day for 2 weeks followed by 32 mg/day for 4 weeks. Interindividual variations in blood pressure responses and in candidate genes coding for components of systems regulating vasoconstriction and volume were measured. In addition, a panel of 500,000 single nucleotide polymorphisms genome-wide was measured in subsets of the most extreme responders and nonresponders to each drug for genome-wide association of analyses.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Adult African American men and women with previously diagnosed primary hypertension were recruited from Atlanta, Georgia; and adult European American man and women with previously diagnosed primary hypertension were recruited from Rochester, Minnesota.

Criteria

Primary (essential) hypertension

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00005520

Locations

United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States

Sponsors and Collaborators

Mayo Clinic

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:

Stephen T. Turner, M.D.

Mayo Foundation

More Information

Publications:

Turner ST, Schwartz GL, Chapman AB, Beitelshees AL, Gums JG, Cooper-Dehoff RM, Boerwinkle E, Johnson JA, Bailey KR. Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response. J Transl Med. 2012 Mar 13;10:47. doi: 10.1186/1479-5876-10-47.

Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension. 2001 Feb;37(2 Part 2):739-43.

Turner ST, Boerwinkle E. Genetics of hypertension, target-organ complications, and response to therapy. Circulation. 2000 Nov 14;102(20 Suppl 4):IV40-5. Review. No abstract available.

Turner ST, Schwartz GL, Chapman AB, Hall WD, Boerwinkle E. Antihypertensive pharmacogenetics: getting the right drug into the right patient. J Hypertens. 2001 Jan;19(1):1-11. Review.

Montori VM, Schwartz GL, Chapman AB, Boerwinkle E, Turner ST. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc. 2001 Sep;76(9):877-82.

Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. Use of gene markers to guide antihypertensive therapy. Curr Hypertens Rep. 2001 Oct;3(5):410-5. Review.

Schwartz GL, Chapman AB, Boerwinkle E, Kisabeth RM, Turner ST. Screening for primary aldosteronism: implications of an increased plasma aldosterone/renin ratio. Clin Chem. 2002 Nov;48(11):1919-23.

Garovic VD, Joyner MJ, Dietz NM, Boerwinkle E, Turner ST. Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. J Physiol. 2003 Jan 15;546(Pt 2):583-9.

Turner ST, Boerwinkle E. Genetics of blood pressure, hypertensive complications, and antihypertensive drug responses. Pharmacogenomics. 2003 Jan;4(1):53-65. Review.

Schwartz GL, Turner ST. Pharmacogenetics of antihypertensive drug responses. Am J Pharmacogenomics. 2004;4(3):151-60. Review.

Frazier L, Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. Multilocus effects of the renin-angiotensin-aldosterone system genes on blood pressure response to a thiazide diuretic. Pharmacogenomics J. 2004;4(1):17-23.

Turner ST, Chapman AB, Schwartz GL, Boerwinkle E. Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. Am J Hypertens. 2003 Oct;16(10):834-9.

Finkielman JD, Schwartz GL, Chapman AB, Boerwinkle E, Turner ST. Lack of agreement between office and ambulatory blood pressure responses to hydrochlorothiazide. Am J Hypertens. 2005 Mar;18(3):398-402.

Turner ST, Schwartz GL. Gene markers and antihypertensive therapy. Curr Hypertens Rep. 2005 Feb;7(1):21-30.

Schwartz GL, Turner ST. Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem. 2005 Feb;51(2):386-94.

Maitland-van der Zee AH, Turner ST, Schwartz GL, Chapman AB, Klungel OH, Boerwinkle E. A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide. Pharmacogenet Genomics. 2005 May;15(5):287-93.

Responsible Party:	Stephen T. Turner, Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier:	NCT00005520 History of Changes
Other Study ID Numbers:	05-004017, R01HL053330, R01HL074735
Study First Received:	May 25, 2000
Last Updated:	January 15, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Mayo Clinic:

Hypertension
Pharmacogenetics
Hydrochlorothiazide
Candesartan

Additional relevant MeSH terms:

Cardiovascular Diseases
Heart Diseases
Hypertension
Vascular Diseases
Candesartan
Candesartan cilexetil
Antihypertensive Agents
Hydrochlorothiazide
Cardiovascular Agents
Therapeutic Uses

Pharmacologic Actions
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on May 19, 2013

Genetic Epidemiology of Responses to Antihypertensives (GERA)