Genome-wide and gene-based meta-analyses identify novel loci influencing blood pressure response to hydrochlorothiazide

Salvi, E. et al. (2017) Genome-wide and gene-based meta-analyses identify novel loci influencing blood pressure response to hydrochlorothiazide. Hypertension, 69(1), pp. 51-59. (doi: 10.1161/HYPERTENSIONAHA.116.08267) (PMID:27802415) (PMCID:PMC5145728)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: Salvi, E., Wang, Z., Rizzi, F., Gong, Y., McDonough, C. W., Padmanabhan, S., Hiltunen, T. P., Lanzani, C., Zaninello, R., Chittani, M., Bailey, K. R., Sarin, A.-P., Barcella, M., Melander, O., Chapman, A. B., Manunta, P., Kontula, K. K., Glorioso, N., Cusi, D., Dominiczak, A. F., Johnson, J. A., Barlassina, C., Boerwinkle, E., Cooper-DeHoff, R. M., and Turner, S. T.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Hypertension
Publisher:American Heart Association
ISSN (Online):1524-4563
Published Online:31 October 2016
Copyright Holders:Copyright © 2016 American Heart Association
First Published:First published in Hypertension 2016
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
676621Ancestry and biological informative markers for stratification of hypertension - The AIM HY studySandosh PadmanabhanMedical Research Council (MRC)MR/M016560/1RI CARDIOVASCULAR & MEDICAL SCIENCES
570081Genetic, molecular and functional dissection of a novel pathway for hypertension: Uromodulin, renal function, sodium homeostasis and blood pressure.Sandosh PadmanabhanBritish Heart Foundation (BHF)PG/12/85/29925RI CARDIOVASCULAR & MEDICAL SCIENCES
689911Clinical study of UMOD NKCC2 interaction on salt-sensitivity in hypertensionSandosh PadmanabhanBritish Heart Foundation (BHF)CS/16/1/31878RI CARDIOVASCULAR & MEDICAL SCIENCES
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS