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

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 (HCTZ). Single nucleotide polymorphisms (SNPs) with p<5×10−5 were prioritized according to their biological function, using RegulomeDB, haploreg and GWAVA. The results from the prioritization approach revealed rs10995 as the most likely functional SNP, among SNPs tested, that has been associated with HCTZ BP response. The rs10995 G-allele was associated with better BP response to HCTZ vs. non-carriers (ΔSBP/ΔDBP:−12.3/−8.2 vs. −6.8/−3.5 mmHg, respectively, ΔSBP p=3×10−4, ΔDBP p=5×10−5). This association was replicated in independent participants treated with chlorthalidone (CLT). In addition, rs10995 G-allele was associated with increased mRNA expression of VASP, encoding vasodilator-stimulated phosphoprotein. Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good-responders to HCTZ compared to 25 poor-responders (p=0.01). This finding was replicated in independent participants treated with CLT (p=0.04). Lastly, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a SNP 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 Information ClinicalTrials.gov; Unique Identifiers: NCT00246519, NCT01203852.

Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

“…Over the past decade, pharmacogenomics studies have identified several promising genetic signatures associated with variability in response to thiazide diuretics . Additionally, pharmacometabolomics has been successful in identifying novel pathways and biomarkers influencing patients’ variability in response to different drugs .…”

“…Over the past decade, pharmacogenomics studies have identified several promising genetic signatures associated with variability in response to thiazide diuretics. 7,10,11 Additionally, pharmacometabolomics has been successful in identifying novel pathways and biomarkers influencing patients' variability in response to different drugs. [12][13][14] Recently, using an untargeted metabolomics approach, we were able to identify several novel metabolites significantly associated with the BP response to HCTZ.…”

Pharmacogenomics of Hypertension Treatment

“…Polymorphisms in genes not only modulate the pharmacodynamics of β-blockers but can also regulate their pharmacokinetics [ 1 ]. CYP2D6, a key cytochrome enzyme involved in the metabolism of β-blockers, seems to be a candidate gene [ 77 ]. Based on sound evidence indicating that CYP2D6 genotypes alter BP responses to β-blockers, the Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association has established recommendations on the therapeutic dose of metoprolol depending on the CYP2D6 genotype [ 78 ].…”

Pharmacogenomics in Hypertension: Where We Stand Today

“…Studies showing variation at rs10995, downstream of VASP, were also interesting in that they not only predicted better blood pressure response in two independent cohorts, but also associated with the baseline level of VASP mRNA [29]. Thus the number of genes that may influence diuretic response is continuing to grow.…”

“…A number of other reports have found gene variants associated with differential responses to thiazide diuretics, implicating variants in TET2, CSMD1 [27], GNB3 [28], and VASP (vasodilator associated phosphoprotein) [29]. While these variants have not been as consistently validated [30] and did not obtain p values < 10 -8 , they do have biologic rationale as an aldosterone sensitive regulator of ENaC (TET2), a prior association with vascular disease and HTN (CSMD1), an association with HTN and renin levels (GNB3), or a prominent role in vascular biology (VASP).…”