title: A meta-analysis of gene expression signatures of blood pressure and hypertension.
abstract: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Huan
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden and Rotterdam, The Netherlands.
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.affiliation: Epidemiology and Public Health Group, Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Pilling
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, München, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; The Charles Bronfman Institute for Personalized Medicine, Genetics of Obesity & Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Chen
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Hebrew SeniorLife, Boston, Boston, Massachusetts, United States of America.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sai-Xia
authors.initials: SX
authors.lastname: Ying
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Courchesne
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
authors.affiliation: Division of Geriatrics and Clinical Gerontology National Institute on Aging, Bethesda, Maryland, United States of America.
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.affiliation: Genomics Core facility Genetics & Developmental Biology Center, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Wang
authors.affiliation: Genomics Core facility Genetics & Developmental Biology Center, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Poching
authors.initials: P
authors.lastname: Liu
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden and Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden and Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden and Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Epidemiology and Public Health Group, Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Partner Munich, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, München, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Partner Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Düsseldorf, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: University Medicine Greifswald, Department of Internal Medicine B-Cardiology, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dörr
authors.affiliation: University Medicine Greifswald, Department of Internal Medicine B-Cardiology, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.affiliation: Universitäres Herzzentrum Hamburg, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Vasan
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, München, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden and Rotterdam, The Netherlands.
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
mesh_terms: D001794:Blood Pressure / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome / Q000235:genetics*