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

15 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Barrie, E. S., Weinshenker, D., Verma, A., Pendergrass, S. A., Lange, L. A., Ritchie, M. D., Wilson, J. G., Kuivaniemi, H., Tromp, G., Carey, D. J., Gerhard, G. S., Brilliant, M. H., Hebbring, S. J., Cubells, J. F., Pinsonneault, J. K., Norman, G. J., & 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