Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity

Elizabeth S. Barrie, David Weinshenker, Anurag Verma, Sarah A. Pendergrass, Leslie A. Lange, Marylyn D. Ritchie, James G. Wilson, Helena Kuivaniemi, Gerard Tromp, David J. Carey, Glenn S. Gerhard, Murray H. Brilliant, Scott J. Hebbring, Joseph F. Cubells, Julia K. Pinsonneault, Greg J. Norman, Wolfgang Sadee

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.).

Original languageEnglish (US)
Pages (from-to)1017-1025
Number of pages9
JournalCirculation research
Volume115
Issue number12
DOIs
StatePublished - Dec 5 2014

Fingerprint

Gene Expression
Messenger RNA
Liver
Locus Coeruleus
Alleles
Phenotype
Lung
Dopamine
Norepinephrine
Angina Pectoris
Adrenal Glands
Mixed Function Oxygenases
Exons
Central Nervous System
Myocardial Infarction
Brain
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Barrie, E. S., Weinshenker, D., Verma, A., Pendergrass, S. A., Lange, L. A., Ritchie, M. D., ... Sadee, W. (2014). Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circulation research, 115(12), 1017-1025. https://doi.org/10.1161/CIRCRESAHA.116.304398
Barrie, Elizabeth S. ; Weinshenker, David ; Verma, Anurag ; Pendergrass, Sarah A. ; Lange, Leslie A. ; Ritchie, Marylyn D. ; Wilson, James G. ; Kuivaniemi, Helena ; Tromp, Gerard ; Carey, David J. ; Gerhard, Glenn S. ; Brilliant, Murray H. ; Hebbring, Scott J. ; Cubells, Joseph F. ; Pinsonneault, Julia K. ; Norman, Greg J. ; Sadee, Wolfgang. / Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. In: Circulation research. 2014 ; Vol. 115, No. 12. pp. 1017-1025.
@article{45182e769d884a4ca4d6ff34cb7c334e,
title = "Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity",
abstract = "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.).",
author = "Barrie, {Elizabeth S.} and David Weinshenker and Anurag Verma and Pendergrass, {Sarah A.} and Lange, {Leslie A.} and Ritchie, {Marylyn D.} and Wilson, {James G.} and Helena Kuivaniemi and Gerard Tromp and Carey, {David J.} and Gerhard, {Glenn S.} and Brilliant, {Murray H.} and Hebbring, {Scott J.} and Cubells, {Joseph F.} and Pinsonneault, {Julia K.} and Norman, {Greg J.} and Wolfgang Sadee",
year = "2014",
month = "12",
day = "5",
doi = "10.1161/CIRCRESAHA.116.304398",
language = "English (US)",
volume = "115",
pages = "1017--1025",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

Barrie, ES, Weinshenker, D, Verma, A, Pendergrass, SA, Lange, LA, Ritchie, MD, Wilson, JG, Kuivaniemi, H, Tromp, G, Carey, DJ, Gerhard, GS, Brilliant, MH, Hebbring, SJ, Cubells, JF, Pinsonneault, JK, Norman, GJ & Sadee, W 2014, 'Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity', Circulation research, vol. 115, no. 12, pp. 1017-1025. https://doi.org/10.1161/CIRCRESAHA.116.304398

Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. / Barrie, Elizabeth S.; Weinshenker, David; Verma, Anurag; Pendergrass, Sarah A.; Lange, Leslie A.; Ritchie, Marylyn D.; Wilson, James G.; Kuivaniemi, Helena; Tromp, Gerard; Carey, David J.; Gerhard, Glenn S.; Brilliant, Murray H.; Hebbring, Scott J.; Cubells, Joseph F.; Pinsonneault, Julia K.; Norman, Greg J.; Sadee, Wolfgang.

In: Circulation research, Vol. 115, No. 12, 05.12.2014, p. 1017-1025.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity

AU - Barrie, Elizabeth S.

AU - Weinshenker, David

AU - Verma, Anurag

AU - Pendergrass, Sarah A.

AU - Lange, Leslie A.

AU - Ritchie, Marylyn D.

AU - Wilson, James G.

AU - Kuivaniemi, Helena

AU - Tromp, Gerard

AU - Carey, David J.

AU - Gerhard, Glenn S.

AU - Brilliant, Murray H.

AU - Hebbring, Scott J.

AU - Cubells, Joseph F.

AU - Pinsonneault, Julia K.

AU - Norman, Greg J.

AU - Sadee, Wolfgang

PY - 2014/12/5

Y1 - 2014/12/5

N2 - 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.).

AB - 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.).

UR - http://www.scopus.com/inward/record.url?scp=84917672042&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84917672042&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.116.304398

DO - 10.1161/CIRCRESAHA.116.304398

M3 - Article

C2 - 25326128

AN - SCOPUS:84917672042

VL - 115

SP - 1017

EP - 1025

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 12

ER -

Barrie ES, Weinshenker D, Verma A, Pendergrass SA, Lange LA, Ritchie MD et al. Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circulation research. 2014 Dec 5;115(12):1017-1025. https://doi.org/10.1161/CIRCRESAHA.116.304398