Pharmacogenomic Evaluation of Antihypertensive Responses 2

The proposed work should help move toward the long-term goal of selection of antihypertensive
drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common
chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart
attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy
exhibit considerable interpatient variability, contributing to poor rates of HTN control
(currently about 40-50% in the US), and frequent nonadherence and dropout from therapy. We
propose to identify genetic predictors of the antihypertensive and adverse metabolic
responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker
(metoprolol) and a thiazide diuretic (chlorthalidone) in a sequential monotherapy design in
400 hypertensive individuals. Data collected will include home and clinic blood pressure,
blood samples for testing for adverse metabolic effects and other biomarkers, RNA, and DNA
and urine sample. We will conduct genome-wide association single nucleotide polymorphism
(SNP) genotyping and data from the study will be used for replication of findings from the
previous PEAR trial, along with new discoveries. The primary aims are to define the genetic
determinants of the antihypertensive response and adverse metabolic responses (e.g. changes
in glucose, triglycerides and uric acid). The proposed research is significant because
genetically-targeted antihypertensive therapy could lead to dramatically higher response
rates and fewer adverse effects than the usual trial-and-error approach. This would likely
lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs,
and improved outcomes.

Inclusion Criteria:

- An average seated home diastolic blood pressure (DBP) > 85 mmHg and < 110 mmHg and
home systolic blood pressure (SBP) < 180 mmHg.

- Subjects must also have an average seated (> 5 minutes) clinic DBP between 90 mmHg and
110 mmHg and SBP < 180 mmHg

Exclusion Criteria:

- Secondary forms of hypertension (HTN) (including sleep apnea)

- Isolated systolic HTN

- Other diseases requiring treatment with BP lowering medications

- Heart rate < 55 beats/min (for metoprolol only)

- Known cardiovascular disease (including history of angina pectoris, heart failure,
presence of a cardiac pacemaker, history of myocardial infarction or revascularization
procedure, or cerebrovascular disease, including stroke and TIA)

- Diabetes mellitus (Type 1 or 2)

- Renal insufficiency (serum creatinine > 1.5 in men or 1.4 in women)

- Primary renal disease

- Pregnancy or lactation

- Liver enzymes > 2.5 upper limits of normal

- Current treatment with NSAIDS, cyclooxygenase-2 (COX2) inhibitors, oral contraceptives
or estrogen.