Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Abstract

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure response to hydrochlorothiazide was performed in 1739 white hypertensives from six clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS), making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8) and the suggestive regions (P<10−5) were cross-validated in two black cohorts treated with hydrochlorothiazide. Additionally, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in blood pressure regulation or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified two suggestive regulatory regions linked to GJA1 and FOXA1, relevant for cardiovascular and kidney function. With the gene-based approach, we identified HSD3B1 as significantly associated with blood pressure response (P<2.28×10−4). HSD3B1 encodes the 3beta-HSD enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of blood pressure response to hydrochlorothiazide, and using two different analytical approaches, we identified three novel loci influencing blood pressure response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, and which was not identified in the single-SNP analysis due to high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.

Pharmacogenomics in Hypertension: Where We Stand Today

“…An illustration of this is the combination of multiple data sets in a GWAS of HCTZ response in a combined cohort of over 1700 patients from the GENRES, GERA1, HCTZ-Milan, PHSS (Pharmacogenomics of Hydrochlorothiazide Sardinian Study), NORDIL, and PEAR1 studies. This meta-analysis did not find any Bonferroni-corrected variants of significance, but did find two suggestive (P < 10 -5 ) SNPs which correlated with response to HCTZ, and which were validated the African American group from the same studies [31]. rs177848 and rs177852 (in Caucasians and African Americans respectively) are located near FOXA1, which encodes a transcription factor, Forkhead Box A1, expressed in the collecting duct of the kidney, where it could play a role in water and solute handling [32].…”

“…Also identified in this analysis were rs11750990 and rs1049911 near GJA1, which encodes connexin 43, which functions in electrochemical coupling in myocardium and vascular smooth muscle. Lastly, a parallel survey of HTN candidate genes from this meta-analysis also implicated a series of SNPs near HSD3B1, whose gene product has a role in aldosterone synthesis [31].…”

Comparative effectiveness of antihypertensive drugs prescribed in Ethiopian healthcare practice: A pilot prospective, randomized, open label study

“…The relatively lower effect of HCT compared to nifedipine could be related to genetic polymorphism as reported before [ 16 ] and, recently, a genome wide and gene based meta-analysis identified 3 novel loci (regulatory regions gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function and β- and steroid δ-isomerase 1 gene3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain influencing BP response to HCT [ 34 ]. Moreover, high levels of creatine kinase show a higher tendency to retain salt [ 32 ].…”

Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry

“…The second group of non-responders was identified through the analysis performed on the AA population with the Δ DBP phenotype. Intergenic SNP rs146535276 (MAF AA: 0.99%) is located in a 1 Mb genomic region on chromosome 8 previously associated with SBP, DBP, and AT (arterial tonometry) (Evangelou et al, 2018;Levy et al, 2007;Salvi et al, 2017). On average, the 21 AA carriers of rs146535276 have a Δ SBP of -2 mmHg (± 26) mmHg, while the rest of the AA cohort have a Δ SBP of 15 mmHg (± 25) (Table 3, Figure 3, Figure 4, Supplementary Figure 9).…”

“…AT: arterial tonometry (Andreassen et al, 2014;. Ehret et al, 2016;Evangelou et al, 2018;Giri et al, 2019;Kichaev et al, 2019;Levy et al, 2007;Liu et al, 2016;Nielsen et al, 2018;Roselli et al, 2018;Salvi et al, 2017;Taylor et al, 2016)…”