Pharmacogenomic Evaluation of Antihypertensive Responses

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 34% 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 (atenolol) and a thiazide
diuretic (hydrochlorothiazide) given initially as monotherapy, and subsequently in
combination, to 800 individuals with uncomplicated hypertension. High quality phenotype data,
including both home and ambulatory measures of blood pressure (BP) response, and lipid and
insulin sensitivity measures of adverse metabolic responses will be related to genetic
variation through two approaches. First, testing 7 single nucleotide polymorphisms (SNPs) in
each of 70 candidate genes, we will examine the influence of these genes' variation on
responses to beta-blockers and diuretics (Specific Aim 1). This will include assessment of
genetic associations with: antihypertensive responses to monotherapy (Aim 1a), addition of a
second drug to monotherapy (Aim 1b), and combination therapy (Aim 1c); and adverse metabolic
responses to mono and combination therapy (Aim 1d). This candidate gene approach will be
supplemented by discovery of novel genes involved in variable BP and metabolic responses to
beta-blockers and diuretics through testing of 20,000 putative functional SNPs that span the
human genome (Specific Aim 2). As in Aim 1, Aim 2 will include testing for associations with
antihypertensive and adverse metabolic responses to monotherapy and combination therapy. The
proposed research will substantially increase our understanding of the pharmacogenetics of
mono- and combination antihypertensive drug therapy. It will also lead to creation of data
sets and samples that can be used by others in the field, through deposit of data to
PharmGKB, and creation of immortalized cell lines from all study participants to share data
and biological samples with other researchers. 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 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 HTN, patients currently treated with three or more antihypertensive
drugs, isolated systolic HTN, other diseases requiring treatment with BP lowering
medications, heart rate < 55 beats/min, 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.