title: Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity.
abstract: BACKGROUND
  Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the central nervous system and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved.
  
  
  OBJECTIVE
  To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk.
  
  
  RESULTS
  Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2- to 11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in locus coeruleus and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes, including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in 3 separate clinical cohorts.
  
  
  CONCLUSIONS
  We demonstrate profound effects of DBH variants on expression in 2 sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Barrie
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Anurag
authors.initials: A
authors.lastname: Verma
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hebbring
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cubells
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Julia K
authors.initials: JK
authors.lastname: Pinsonneault
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.).
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Norman
authors.affiliation: From the Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus (E.S.B., J.K.P., W.S.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (D.W., J.F.C.); Center for Systems Genomics, Pennsylvania State University, University Park (A.V., S.A.P., M.D.R.); Department of Genetics, University of North Carolina School of Medicine, Chapel Hill (L.A.L.); Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.); The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.K., G.T., D.J.C.); Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey (G.S.G.); Center for Human Genetics, Marshfield Clinic Research Foundation, WI (M.H.B., S.J.H.); and Department of Psychology, The University of Chicago, IL (G.J.N.). wolfgang.sadee@osumc.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D022981:Allelic Imbalance; D000818:Animals; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000294:innervation*; D006801:Humans; D008099:Liver / Q000294:innervation*; D008168:Lung / Q000294:innervation*; D008297:Male; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D065840:Protective Factors; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D013564:Sympathetic Nervous System / Q000201:enzymology* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D004299:Dopamine beta-Hydroxylase
keywords: dopamine β-hydroxylase; gene expression/regulation; genetic association; genetic polymorphism; human; myocardial infarction