Hypertension is the most common chronic disease and represents a major risk factor for development of ischemic heart disease, stroke, kidney failure and heart failure. Despite effective antihypertensive drugs, clinically important blood pressure reductions are only attained in about 50% of patients with any given therapy. Additionally, the two drug classes of focus in this proposal, thiazide diuretics and beta-blockers, are associated with racial differences in response and with adverse metabolic responses that increase cardiovascular risk. Thus, there is a critical need to better define biomarkers that associate with antihypertensive treatment response, and for advancing our understanding of the mechanisms by which these drug classes produce their efficacious and adverse effects, including differences in response by race and gender. To address this critical gap, we propose to utilize pharmacometabolomics to identify and validate pharmacometabolomic signatures that associate with (a) the blood pressure lowering effect and (b) the adverse cardiometabolic effects (on glucose, triglycerides, uric acid) of thiazide diuretics and beta blockers. We will further enhance the impact of the pharmacometabolomic data by combining them with the rich genomic dataset available on the study participants. This will be accomplished using samples from a completed clinical trial in which individuals with uncomplicated hypertension were treated with a beta-blocker or a thiazide diuretic given as monotherapy. The pharmacometabolomic signatures identified will be used to inform pharmacogenomics studies and functional/mechanistic studies. This approach provides an opportunity for substantial advances in understanding mechanisms of drug response through utilization of complementary “omics” technologies and may advance realization of personalized antihypertensive treatment.
|Julie Johnson||Reginald Frye||Rhonda DeHoff||Yan Gong|