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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity
Circulation Research, Volume 115, No. 12, Year 2014
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Description
Rationale: 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.; Methods and 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. (Circ Res. 2014;115:1017-1025.). © 2014 American Heart Association, Inc.
Authors & Co-Authors
Weinshenker, David
United States, Atlanta
Emory University School of Medicine
Verma, Anurag
United States, University Park
Pennsylvania State University
Pendergrass, Sarah A.
United States, University Park
Pennsylvania State University
Lange, Leslie A.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Ritchie, Marylyn D.
United States, University Park
Pennsylvania State University
Wilson, James G.
United States, Jackson
University of Mississippi Medical Center
Kuivaniemi, Helena
United States
Geisinger Health System
Tromp, Gerard C.
United States
Geisinger Health System
Carey, David J.
United States
Geisinger Health System
Gerhard, Glenn S.
United States, Hershey
Penn State College of Medicine
Brilliant, Murray H.
United States, Marshfield
Marshfield Clinic
Hebbring, Scott Joseph
United States, Marshfield
Marshfield Clinic
Sadee, Woldgang
United States, Columbus
The Ohio State University
Statistics
Citations: 18
Authors: 13
Affiliations: 9
Identifiers
Doi:
10.1161/CIRCRESAHA.116.304398
ISSN:
00097330
Research Areas
Genetics And Genomics
Noncommunicable Diseases
Study Design
Cohort Study