Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies

Ana Caroline C. Sá, Amy Webb, Yan Gong, Caitrin W. McDonough, Mohamed H. Shahin, Somnath Datta, Taimour Y. Langaee, Stephen T. Turner, Amber L. Beitelshees, Arlene B. Chapman, Eric Boerwinkle, John G. Gums, Steven E. Scherer, Rhonda M. Cooper-DeHoff, Wolfgang Sadee, Julie A. Johnson

Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics. We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone. FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10- 6), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: β = - 2.1; p = 1.7 × 10- 3; DBP: β = - 1.4; p = 2.9 × 10- 3). These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics. NCT00246519 , NCT01203852 www.clinicaltrials.gov.