Personalizing thiazide therapy through clinical and microRNA biomarkers of response to thiazides

Project: Research

Investigators

  • Lakshmi Manasa Sakuntala Chekka (PI)

Description

Hypertension (HTN) affects ~1 billion people globally and a causal factor for ~9 million deaths due to stroke and cardiovascular (CV) diseases annually. Despite treatment, blood pressure (BP) control rate in the population is only 50%, mostly due to empiric therapy selection overlooking the inter-patient differences in response to anti-HTN drugs both within and across drug classes. There is a need for efficient tools to predict patient responses and guide therapy selection. We will focus on thiazides (TZDs) and their subclasses thiazide-type (TT) and thiazide-like (TL) drugs. Current guidelines favor TL over TT for superior BP and CV risk reduction, but data are limited and inconsistent to support the choice of one over the other in clinical practice. Our work will provide evidence to guide selection of the most appropriate TZD (aim-1) and to identify biomarkers to select patients who might respond well to TZDs (aim-2), which together can lead to better BP control, and thus better CV outcomes. The first aim focuses on clinical trial data and the second on microRNAs, which have potential as biomarkers of drug response.Aim-1: We will compare antihypertensive and adverse metabolic effects of hydrochlorothiazide (HCTZ, TT drug) and chlorthalidone (CTD, TL drug) in two large clinical trials PEAR and PEAR-2, with a hypothesis that CTD is not superior to HCTZ in all patients. We will conduct paired comparisons in individuals treated with both drugs and also compare in larger cohorts across drugs and race to provide insights into whether one or the other drug is superior. These data may inform future HTN guidelines on the choice of TZD. Aim-2: We aim to find microRNAs associated with TZD response with a hypothesis that microRNAs play a role in anti-HTN drug response. Patients will be grouped as responders and non-responders based on their BP response to HCTZ in PEAR trial. Patients baseline plasma microRNAs will be profiled on a genome-wide high throughput platform to find differentially expressed ones between the two groups. MicroRNAs with statistically robust differences will be validated using qRT-PCR in 3 cohorts: GERA whites-HCTZ treated, PEAR-2 whites-CHTD treated, PEAR blacks-HCTZ treated, to confirm the association across both TZDs and in both races. MicroRNAs as drug response markers is a novel tool in HTN, which may yield vital information on TZD response and BP phenotype in general. Our work potentially advances precision medicine in HTN.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35210065
Effective start/end date01/01/202012/31/2021
StatusActive