Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response. (February 2017)

• Record Type: Journal Article
• Authors: Shahin, Mohamed H.; Sá, Ana C.; Webb, Amy; Gong, Yan; Langaee, Taimour; McDonough, Caitrin W.; Riva, Alberto; Beitleshees, Amber L.; Chapman, Arlene B.; Gums, John G.; Turner, Stephen T.; Boerwinkle, Eric; Scherer, Steven E.; Sadee, Wolfgang; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.
• Is Part Of: Circulation. Volume 10:Number 1(2017)
• Publication Date: 2017-02
• Subjects: blood pressure -- genomics -- hypertension -- pharmacogenetics -- transcriptome; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.116.001404
• Languages: English
• ISSNs: 1942-325X

Abstract

Abstract : 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 identify 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 <5×10 − 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 (Δ systolic BP/Δ diastolic BP: −12.3/−8.2 versus −6.8/−3.5 mm Hg, respectively, Δ systolic BP P =3×10 −4, Δ diastolic BP P =5×10 −5 ). This association was 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 rs10995, 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. Clinical Trial Registration—: URL:http://www.clinicaltrials.gov . Unique identifiers: NCT00246519 and NCT01203852. Abstract : Supplemental Digital Content is available in the text.