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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. (2017)
Publisher: American Heart Association
Languages: English
Types: Article
Subjects: Article
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<5×10−8), and the suggestive regions (P<10−5) 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<2.28×10−4). 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.

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  • NIH | Mayo Clinic Center for Clin...
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