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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Long, Rochelle M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Pharmacy
United States
Zip Code
El Rouby, Nihal; McDonough, Caitrin W; Gong, Yan et al. (2018) Genome-wide association analysis of common genetic variants of resistant hypertension. Pharmacogenomics J :
Wenger, Nanette K; Arnold, Anita; Bairey Merz, C Noel et al. (2018) Hypertension Across a Woman's Life Cycle. J Am Coll Cardiol 71:1797-1813
McDonough, Caitrin W; Magvanjav, Oyunbileg; Sá, Ana C C et al. (2018) Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses). Circ Genom Precis Med 11:e001854
Empey, Philip E; Stevenson, James M; Tuteja, Sony et al. (2018) Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy. Clin Pharmacol Ther 104:664-674
Chang, S-W; McDonough, C W; Gong, Y et al. (2018) Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes. Pharmacogenomics J 18:106-112
Wang, Danxin; Hartmann, Katherine; Seweryn, Michal et al. (2018) Interactions Between Regulatory Variants in CYP7A1 (Cholesterol 7?-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression. Circ Genom Precis Med 11:e002082
Sá, Ana Caroline C; Webb, Amy; Gong, Yan et al. (2018) Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies. BMC Med Genomics 11:55
Weitzel, Kristin W; Smith, D Max; Elsey, Amanda R et al. (2018) Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned. Clin Transl Sci 11:175-181
Cavallari, Larisa H; Lee, Craig R; Beitelshees, Amber L et al. (2018) Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. JACC Cardiovasc Interv 11:181-191
Smith, D Max; Weitzel, Kristin W; Cavallari, Larisa H et al. (2018) Clinical application of pharmacogenetics in pain management. Per Med 15:117-126

Showing the most recent 10 out of 178 publications