Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.
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.
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.). erika.salvi@unimi.it.
Erika
E
Salvi
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Zhiying
Z
Wang
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Federica
F
Rizzi
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Yan
Y
Gong
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Caitrin W
CW
McDonough
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Sandosh
S
Padmanabhan
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Timo P
TP
Hiltunen
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Chiara
C
Lanzani
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Roberta
R
Zaninello
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Martina
M
Chittani
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Kent R
KR
Bailey
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Antti-Pekka
AP
Sarin
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Matteo
M
Barcella
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Olle
O
Melander
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Arlene B
AB
Chapman
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Paolo
P
Manunta
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Kimmo K
KK
Kontula
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Nicola
N
Glorioso
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Daniele
D
Cusi
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Anna F
AF
Dominiczak
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Julie A
JA
Johnson
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Cristina
C
Barlassina
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Eric
E
Boerwinkle
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Rhonda M
RM
Cooper-DeHoff
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
Stephen T
ST
Turner
D004232:Diuretics / Q000494:pharmacology; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology
D004232:Diuretics; D006852:Hydrochlorothiazide
blood pressure response; diuretics; genome-wide association study; hydrochlorothiazide; hypertension; meta-analysis; pharmacogenomics