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 - 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 -