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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 69; no. 1; pp. 51 - 59
• Main Authors: Salvi, Erika, Wang, Zhiying, Rizzi, Federica, Gong, Yan, McDonough, Caitrin W, Padmanabhan, Sandosh, Hiltunen, Timo P, Lanzani, Chiara, Zaninello, Roberta, Chittani, Martina, Bailey, Kent R, Sarin, Antti-Pekka, Barcella, Matteo, Melander, Olle, Chapman, Arlene B, Manunta, Paolo, Kontula, Kimmo K, Glorioso, Nicola, Cusi, Daniele, Dominiczak, Anna F, Johnson, Julie A, Barlassina, Cristina, Boerwinkle, Eric, Cooper-DeHoff, Rhonda M, Turner, Stephen T
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.01.2017
• Subjects: Diuretics - pharmacology; Genome-Wide Association Study - methods; Humans; Hydrochlorothiazide - pharmacology; Hypertension - drug therapy; Hypertension - genetics; Hypertension - physiopathology; pharmacogenomics; diuretics; genome-wide association study; hydrochlorothiazide; meta-analysis; blood pressure response; hypertension
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.116.08267

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10), and the suggestive regions (P<10) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP 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, which was not identified in the genome-wide meta-analysis because of 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.