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

Elizabeth S Barrie1, David Weinshenker1, Anurag Verma1

  • 1From 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.).

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|October 19, 2014
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Summary

Genetic variants in dopamine β-hydroxylase (DBH) significantly impact its expression in the liver and lung, influencing sympathetic tone and potentially protecting against heart attack.

Keywords:
dopamine β-hydroxylasegene expression/regulationgenetic associationgenetic polymorphismhumanmyocardial infarction

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Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Science

Background:

  • Dopamine β-hydroxylase (DBH) is crucial for norepinephrine synthesis in the nervous system and periphery.
  • DBH variants are linked to various disorders, but their tissue-specific effects and causal roles are not fully understood.

Purpose of the Study:

  • To investigate regulatory variants in DBH.
  • To determine the impact of these variants on DBH mRNA expression.
  • To assess their role in modulating sympathetic tone and disease risk.

Main Methods:

  • Analysis of DBH mRNA expression across human tissues.
  • Allele-specific mRNA assays to quantify expression differences.
  • Association studies with sympathetic phenotypes and cardiovascular disease risk.

Main Results:

  • DBH mRNA is highly expressed in the locus coeruleus, adrenal gland, liver, lung, and heart.
  • Specific DBH variants (rs1611115, rs1108580) showed significant allelic expression differences in the liver (2- to 11-fold).
  • These variants were linked to reduced mRNA expression in the liver and lung, and associated with sympathetic phenotypes like angina pectoris; they suggested protection against myocardial infarction in clinical cohorts.

Conclusions:

  • DBH variants profoundly affect gene expression in the liver and lung, but not the brain or adrenal glands.
  • These variants are associated with clinical conditions influenced by peripheral sympathetic activity.
  • A dual mechanism is proposed: endocrine effects via circulating DBH and direct effects within sympathetically innervated target organs.