TY - JOUR
T1 - Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide
AU - Salvi, Erika
AU - Wang, Zhiying
AU - Rizzi, Federica
AU - Gong, Yan
AU - McDonough, Caitrin W.
AU - Padmanabhan, Sandosh
AU - Hiltunen, Timo P.
AU - Lanzani, Chiara
AU - Zaninello, Roberta
AU - Chittani, Martina
AU - Bailey, Kent R.
AU - Sarin, Antti Pekka
AU - Barcella, Matteo
AU - Melander, Olle
AU - Chapman, Arlene B.
AU - Manunta, Paolo
AU - Kontula, Kimmo K.
AU - Glorioso, Nicola
AU - Cusi, Daniele
AU - Dominiczak, Anna F.
AU - Johnson, Julie A.
AU - Barlassina, Cristina
AU - Boerwinkle, Eric
AU - Cooper-DeHoff, Rhonda M.
AU - Turner, Stephen T.
N1 - Funding Information:
GENRES was supported by the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research. The HCTZ-Milan and the PHSS studies were supported by the HYPERGENES project (European Network for Genetic-Epidemiological Studies; FP7-HEALTH-F4-2007-201550), InterOmics (PB05 MIUR-CNR Italian Flagship Project), and the Associazione per lo sviluppo della ricerca sull ipertensione arteriosa e sulle malattie cardiovascolari ONLUS. The PEAR study was supported by the National Institute of Health Pharmacogenetics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida), UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. C. Lanzani and P. Manunta are funded by the Italian Ministry of Health Grant No. RF-2011-02347356. S. Padmanabhan is funded by the Medical Research Council (MR/M016560/1, the AIM-HY Study [Ancestry and Biological Informative Markers for Stratification of Hypertension Study]) and the British Heart Foundation (PG/12/85/29925, CS/16/1/31878). A.F. Dominiczak has funding from the Scottish Ecosystem for Precision Medicine.
Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - blood pressure response
KW - diuretics
KW - genome-wide association study
KW - hydrochlorothiazide
KW - hypertension
KW - meta-analysis
KW - pharmacogenomics
UR - http://www.scopus.com/inward/record.url?scp=84994158694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994158694&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.116.08267
DO - 10.1161/HYPERTENSIONAHA.116.08267
M3 - Article
C2 - 27802415
AN - SCOPUS:84994158694
SN - 0194-911X
VL - 69
SP - 51
EP - 59
JO - Hypertension
JF - Hypertension
IS - 1
ER -