TY - JOUR
T1 - Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated with Thiazide Diuretics Blood Pressure Response
AU - Shahin, Mohamed H.
AU - Sá, Ana C.
AU - Webb, Amy
AU - Gong, Yan
AU - Langaee, Taimour
AU - McDonough, Caitrin W.
AU - Riva, Alberto
AU - Beitleshees, Amber L.
AU - Chapman, Arlene B.
AU - Gums, John G.
AU - Turner, Stephen T.
AU - Boerwinkle, Eric
AU - Scherer, Steven E.
AU - Sadee, Wolfgang
AU - Cooper-Dehoff, Rhonda M.
AU - Johnson, Julie A.
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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 (r2=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.
AB - 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 (r2=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.
KW - blood pressure
KW - genomics
KW - hypertension
KW - pharmacogenetics
KW - transcriptome
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U2 - 10.1161/CIRCGENETICS.116.001404
DO - 10.1161/CIRCGENETICS.116.001404
M3 - Article
C2 - 28115488
AN - SCOPUS:85013418932
SN - 1942-325X
VL - 10
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 1
M1 - 001404
ER -