Hypertension (HTN) places over 70 million Americans (and approximately one billion individuals worldwide) at substantially increased risk for stroke, heart attack, renal failure, and heart failure, and is the most common chronic disease for which medications are prescribed. There are numerous acceptable first line treatment options for HTN, yet selection of a specific drug for a given patient is empiric, only about 50% of patients have acceptable blood pressure (BP) lowering with a given antihypertensive drug, some experience adverse metabolic effects and develop diabetes, gout or metabolic syndrome as a result of their therapy, and individual long-term outcomes vary despite equivalent BP lowering. Pharmacogenomics offers the clinical potential for individualized therapy based on genetic make-up. We propose genetic variability plays an important role in the effects of antihypertensive drugs, including their BP lowering, adverse metabolic effects, and their influence on clinical outcomes. Our overall aims are to discover, replicate and define the mechanistic basis for genetic determinants of the BP lowering responses, adverse metabolic responses and long-term clinical outcomes (death, stroke, heart attack, diabetes) to two commonly prescribed classes of antihypertensive drugs, thiazide diuretics and p-blockers. Our approach will also provide insight into the consistency of genetic associations we study across drugs within a class (i.e. the drug class effect).
Specific Aims 1 and 2) Using PEARI data, discover genetic determinants of antihypertensive and adverse metabolic responses (glucose, triglycerides, uric acid) to thiazide diuretics and (31-selective blockers. We will replicate findings in variety of thiazide and p-blocker-treated cohorts through established international collaborations. Additionally we will conduct a 400 subject randomized crossover study of metoprolol and chlorthalidone for additional replication and to establish a class effect for the genetic associations.
Specific Aims 3 and 4) Using the INVEST-GENES clinical trial cohort, identify genetic predictors for prevention of death, heart attack, stroke and new-onset diabetes with p-blocker+thiazide therapy, followed by replication in the ASCOT clinical trial genetic cohort.
Specific Aim 5) Define functional polymorphisms and their mechanistic basis for Aim 1-4 discoveries. Specifically: 5a. Resequence genomic regions of interest in individuals sampled from the clinical response phenotype extremes, and 5b. Investigate causal mechanisms for differential gene expression, using a variety of sophisticated molecular genetic experimental approaches. Discoveries from this work could lead to genotype-guided selection of antihypertensive drugs.

Public Health Relevance

Hypertension (HTN) affects about 75 million Americans, or 1 in 3 adults. Many effective drugs are available to treat HTN, but individual responses vary. We will study genetic factors that influence BP lowering, adverse metabolic responses, long-term risk for diabetes and prevention of adverse cardiovascular outcomes like heart attack and stroke for two commonly used drug classes, p-blockers and thiazide diuretics In the future genetic information might be used to guide selection of drug therapy for individual patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM074492-07
Application #
8111201
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Long, Rochelle M
Project Start
2005-08-03
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$1,976,439
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Sá, Ana Caroline C; Sadee, Wolfgang; Johnson, Julie A (2017) Whole Transcriptome Profiling: An RNA-Seq Primer and Implications for Pharmacogenomics Research. Clin Transl Sci :
Magvanjav, Oyunbileg; Gong, Yan; McDonough, Caitrin W et al. (2017) Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/?-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) Trials. J Am Heart Assoc 6:
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Cavallari, Larisa H; Weitzel, Kristin W; Elsey, Amanda R et al. (2017) Institutional profile: University of Florida Health Personalized Medicine Program. Pharmacogenomics 18:421-426
Sá, Ana Caroline C; Webb, Amy; Gong, Yan et al. (2017) Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics. Sci Rep 7:16068
Salvi, Erika; Wang, Zhiying; Rizzi, Federica et al. (2017) Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide. Hypertension 69:51-59
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Cavallari, L H; Beitelshees, A L; Blake, K V et al. (2017) The IGNITE Pharmacogenetics Working Group: An Opportunity for Building Evidence with Pharmacogenetic Implementation in a Real-World Setting. Clin Transl Sci 10:143-146

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