Genetics of Hypertension Associated Treatments (GenHAT) (GenHAT)

Pharmacological Association of the Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism on Blood Pressure and Cardiovascular Risk in Relation to Anti-hypertensive Treatment

To examine whether the association between selected hypertensive genes and combined fatal coronary heart disease and nonfatal myocardial infarction in high-risk hypertensives is modified by the type of antihypertensive treatment, leading to differential risks of coronary heart disease.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Heart Diseases; Cardiovascular Diseases; Coronary Disease; Hypertension
• Intervention / Treatment: Drug: Chlorthalidone; Drug: Amlodipine; Drug: Lisinopril; Drug: Doxazosin

Detailed Description

BACKGROUND:

The study might shed important light on the variation in patient response to antihypertensive agents, and improve the ability to pick the right antihypertensive for specific patients. GenHAT is an ancillary study to ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). ALLHAT recruited 42,515 hypertensives and randomized them to one of four antihypertensive agents (lisinopril, chlorthalidone, amlodipine, and doxazosin); follow-up will be completed in March, 2002.

DESIGN NARRATIVE:

GenHAT, a prospective study ancillary to ALLHAT, will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to coronary heart disease (CHD). DNA from frozen clots stored at the ALLHAT Central Laboratory will be used to genotype variants of hypertension genes (angiotensinogen -6, angiotensin converting enzyme insertion/deletion, angiotensin type- 1 receptor, alpha-adducin, beta2 adrenergic receptor, lipoprotein lipase, and 10 new hypertension variants expected to be discovered during the course of the study). In addition to the primary aim, a number of secondary aims will be undertaken to evaluate gene- treatment interactions in relation to other endpoints, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering. Because of the ethnic and gender diversity of ALLHAT, an assessment will be made of the effects of these variants on outcomes in key subgroups (age >65 years, women, African Americans, Type II diabetics), and whether the gene-treatment interactions in relation to outcomes are consistent across subgroups.

• Study Type: Observational
• Enrollment (Actual): 37939

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Hypertensive individuals, multiple races and ethnic groups are represented in this study population

Description

• not taking anti-hypertensive medication
• use of anti-hypertensives for less than two months with a baseline blood pressure between 140/90 and 180/110
• use of anti-hypertensives for greater than two months with a blood pressure not greater than 160/100
• at least one additional cardiovascular risk factor such as previous MI, stroke, type 2 diabetes, smoking, left ventricular hypertrophy or dyslipidemia

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Chlorthalidone; Participants will take chlorthalidone at recommended doses to control hypertension	Drug: Chlorthalidone; participant's drug dose will be titrated from 12.5mg to 25mg over the course of the study; Other Names: Hygroton, Thalitone, Chlorthalid
Amlodipine; Participants will take Amlodipine at recommended doses to control hypertension	Drug: Amlodipine; participant's drug dose will be titrated from 10mg to 40mg over the course of the study; Other Names: Norvasc
Lisinopril; Participants will take Lisinopril at recommended doses to control hypertension	Drug: Lisinopril; participant's drug dose will be titrated from 10mg to 40mg over the course of the study; Other Names: Zestoretic
Doxazosin; Participants will take Doxazosin at recommended doses to control hypertension	Drug: Doxazosin; participant's drug dose will be titrated from 2mg to 8mg over the course of the study; Other Names: Cardura

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure	Blood pressure will be measured to determine the effect of the prescribed anti-hypertensive . Data will be presented as the change in blood pressure over the course of six months	baseline and six month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of genotype on event rates	The rate of fatal myocardial infarction (MI) was evaluated in relation to the ACE I/D genotype and anti-hypertensive used. Data are presented as the incidence of fatal MI after six years of follow up	6 years

Collaborators and Investigators

• Sponsor: Donna Arnett, 257-5678
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Minnesota
• Investigators: Principal Investigator: Donna Arnett, University of Kentucky

Publications and helpful links

General Publications

• Zhang X, Lynch AI, Davis BR, Ford CE, Boerwinkle E, Eckfeldt JH, Leiendecker-Foster C, Arnett DK. Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study. PLoS One. 2012;7(3):e34217. doi: 10.1371/journal.pone.0034217. Epub 2012 Mar 28.
• Arnett DK, Boerwinkle E, Davis BR, Eckfeldt J, Ford CE, Black H. Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study. Pharmacogenomics J. 2002;2(5):309-17. doi: 10.1038/sj.tpj.6500113.
• Arnett DK, Davis BR, Ford CE, Boerwinkle E, Leiendecker-Foster C, Miller MB, Black H, Eckfeldt JH. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study. Circulation. 2005 Jun 28;111(25):3374-83. doi: 10.1161/CIRCULATIONAHA.104.504639. Epub 2005 Jun 20.

Study record dates

Study Major Dates

• Study Start: September 1, 1999
• Primary Completion (Actual): August 1, 2005
• Study Completion (Actual): August 1, 2005

Study Registration Dates

• First Submitted: September 25, 2000
• First Submitted That Met QC Criteria: September 25, 2000
• First Posted (Estimate): September 26, 2000

Study Record Updates

• Last Update Posted (Actual): April 6, 2018
• Last Update Submitted That Met QC Criteria: April 4, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Vascular Diseases; Myocardial Infarction; Infarction; Heart Diseases; Coronary Disease; Hypertension; Cardiovascular Diseases; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Natriuretic Agents; Cardiotonic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride Symporter Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Amlodipine; Chlorthalidone; Lisinopril; Doxazosin
• Other Study ID Numbers: 911 (Urochester); R01HL063082 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No