Loci influencing blood pressure identified using a cardiovascular gene-centric array

Santhi K. Ganesh(Michigan Medicine), Vinicius Tragante(Lung Institute), Wei Guo, Yiran Guo(Children's Hospital of Philadelphia), Matthew B. Lanktree(Western University), Erin N. Smith(Rady Children's Hospital-San Diego), Toby Johnson(Queen Mary University of London), Berta Almoguera Castillo(Children's Hospital of Philadelphia), John Barnard(Cleveland Clinic Lerner College of Medicine), Jens Baumert, Yen-Pei C. Chang(University of Maryland, Baltimore), Clara C. Elbers(University Medical Center Utrecht), Martin Farrall(Centre for Human Genetics), Mary Fischer(University of Wisconsin–Madison), Nora Franceschini(University of North Carolina at Chapel Hill), Tom R. Gaunt(University of Bristol), Johannes M.I.H. Gho(Lung Institute), Christian Gieger, Yan Gong, Aaron Isaacs(MRC Epidemiology Unit), Marcus E. Kleber(University of Mannheim), Irene Mateo Leach(Institute of Cardiology), Caitrin W. McDonough, Matthijs F.L. Meijs(Lung Institute), O. MELLANDER(Lund University), Cliona Molony(Rosetta Stone (United States)), Ilja M. Nolte, Sandosh Padmanabhan(University of Glasgow), Tom S. Price(Psychiatry Research Trust), Ramakrishnan Rajagopalan(University of Washington Medical Center), Jonathan A. Shaffer(Columbia University), Sonia Shah(University College London), Haiqing Shen, Nicole Soranzo(Institute of Human Genetics), Peter J. van der Most, Erik P.A. van Iperen, Jessic A. Van Setten, Judith M. Vonk, Li Zhang(Cleveland Clinic Lerner College of Medicine), Amber L. Beitelshees(Cleveland Clinic Lerner College of Medicine), Gerald S. Berenson(Tulane University), Deepak L. Bhatt(Brigham and Women's Hospital), Jolanda M.A. Boer(National Institute for Public Health and the Environment), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Ben Burkley, Amber Burt(University of Washington Medical Center), Aravinda Chakravarti, Wei Chen(Tulane University), Rhonda M. Cooper‐DeHoff, Sean Curtis(Merck & Co., Inc., Rahway, NJ, USA (United States)), Albert W. Dreisbach, David Duggan(Translational Genomics Research Institute), Georg Ehret, Richard R. Fabsitz(National Heart Lung and Blood Institute), Myriam Fornage(The University of Texas Health Science Center at Houston), Ervin R. Fox, Clement E. Furlong(University of Washington Medical Center), Ron T. Gansevoort, Marten H. Hofker, G. Kees Hovingh, Susan Kirkland(Dalhousie University), Kandice Kottke‐Marchant(Cleveland Clinic), Abdullah Kutlar(Augusta University), Andrea Z. LaCroix(Fred Hutch Cancer Center), Taimour Langaee, Leslie A. Lange(Children's Hospital of Philadelphia), Honghuang Lin(Boston University), Kiang Liu(Northwestern University), S. Maiwald(University of Amsterdam), Rainer Malik(Ludwig-Maximilians-Universität München), CARDIOGRAM, METASTROKE(Cleveland Clinic), Gurunathan Murugesan(Broad Institute), Christopher Newton‐Cheh(Broad Institute), Jeffery R. O’Connell(University of Maryland, Baltimore), N. Charlotte Onland‐Moret(NHS Blood and Transplant), Willem H. Ouwehand(NHS Blood and Transplant), Walter Palmas(Amsterdam Public Health), Brenda W.J.H. Penninx(University of Florida), Carl J. Pepine(University of Florida), Mary Pettinger(Tufts Medical Center), Joseph F. Polak(Boston University), Ramachandran S. Vasan(Boston University), Jane Ranchalis(Brigham and Women's Hospital), Susan Redline(Brigham and Women's Hospital), Paul M. Ridker(Brigham and Women's Hospital), Lynda M. Rose(Brigham and Women's Hospital), Hubert Scharnag(Scripps Research Institute), Nicholas J. Schork(Scripps Research Institute), Daichi Shimbo(University of Maryland, Baltimore), Alan R. Shuldiner(Tulane University), Sathanur R. Srinivasan(Tulane University), Ronald P. Stolk, Herman A. Taylor, Barbara Thorand, Mieke D. Trip(MRC Epidemiology Unit), Cornelia M. van Duijn(National Institute for Public Health and the Environment), W. M. Monique Verschuren(National Institute for Public Health and the Environment), Cisca Wijmenga(Kardiologie Frankfurt-Sachsenhausen), Bernhard R. Winkelmann(University of Mississippi Medical Center), Sharon B. Wyatt(Johns Hopkins University), J. Hunter Young(Johns Hopkins University), Bernhard O. Boehm(William Harvey Research Institute), Mark J. Caulfield(Brigham and Women's Hospital), Daniel I. Chasman(Brigham and Women's Hospital), Karina W. Davidson(Lung Institute), Pieter A. Doevendans(Lung Institute), Garret A. FitzGerald(University of Florida), John G. Gums(Children's Hospital of Philadelphia), Håkon Håkonarson(Children's Hospital of Philadelphia), Hans L. Hillege(Helmholtz Zentrum München), Thomas Illig(University of Washington Medical Center), Gail P. Jarvik(University of Washington Medical Center), Julie A. Johnson, John J.P. Kastelein(Universität Ulm), Wolfgang Köenig(University of Mannheim), LifeLines Cohort Study(University of Maryland, Baltimore), Winfried März(Scripps Research Institute), Braxton D. Mitchell(University of Maryland, Baltimore), Sarah S. Murray(Scripps Research Institute), Albertine J. Oldehinkel(University Medical Center Groningen), Daniel J. Rader(Cardiovascular Institute of the South), Muredach P. Reilly(Cardiovascular Institute of the South), Alex P. Reiner(Cleveland Clinic Lerner College of Medicine), Eric E. Schadt(Icahn School of Medicine at Mount Sinai), Roy L. Silverstein(Royal College of Surgeons in Ireland), Harold Snieder(Erasmus MC), Alice Stanton(Royal College of Surgeons in Ireland), André G. Uitterlinden(Erasmus MC), Pim van der Harst(University of Leicester), Yvonne T. van der Schouw(University Medical Center Utrecht), Nilesh J. Samani(University of Leicester), Andrew D. Johnson(Broad Institute), Patricia B. Munroe(Queen Mary University of London), Paul I. W. de Bakker(Broad Institute), Xiaofeng Zhu(Children's Hospital of Philadelphia), Daniel Levy(University Medical Center Utrecht), Brendan J. Keating(Children's Hospital of Philadelphia), Folkert W. Asselbergs(University Medical Center Utrecht)
Human Molecular Genetics
January 8, 2013
10.1093/hmg/dds555
Cited by 158Open Access
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Abstract

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

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