Pharmacogenomic Evaluation of Antihypertensive Responses
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      There are many medications available for the treatment of high blood pressure (hypertension),
      but finding the right one for a specific patient can be challenging. In fact, it is estimated
      that only 34% of people with hypertension have their blood pressure under control. The
      hypothesis is that genetic differences between individuals influence their response to
      antihypertensive medications. This study is aimed at determining the genetic factors that may
      influence a person's response to either a beta-blocker or a thiazide diuretic. The hope is
      that through this research, we may someday be able to use an individual's genetic information
      to guide the selection of their blood pressure medicine, leading to better control of blood
      pressure, and less need for the current trial and error process.
    

Detailed description: 
      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.
    

Intervention name(s): Hydrochlorothiazide; Atenolol
Intervention type(s): Drug; Drug
Intervention description(s): atenolol 50 or 100 mg hydrochlorothiazide 12.5 or 25 mg; atenolol 50 mg, then 100 mg if BP < 120/70, then add HCTZ 12.5 mg if BP < 120/70, then HCTZ 25 mg if BP < 120/70
Other intervention name(s): Aquazide H or HydroDIURIL or Microzide; Lopressor; Lopressor; Aquazide H or HydroDIURIL or Microzide
Intervention MeSH terms: Atenolol; Metoprolol; Hydrochlorothiazide; Trichlormethiazide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: hypertension; pharmacogenetics; pharmacogenomics; beta-blocker; atenolol; diuretic; hydrochlorothiazide; blood pressure; metabolic adverse effects