Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated with Thiazide Diuretics Blood Pressure Response

Background-Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to novel biomarkers of thiazide diuretics BP response. Methods and Results-Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P < 5 x 10(-5) were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (A systolic BP/A diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mmHg, respectively, Delta systolic BP P = 3x10(-4), Delta diastolic BP P = 5x10(-5)). This association replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P = 0.01). This finding was replicated in independent participants treated with chlorthalidone (P = 0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r(2) = 0.7) with rs 10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. Conclusions-This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response.