| Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. | |
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MedLine Citation:
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PMID: 20009769 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Dopamine beta-hydroxylase (DBH) plays an essential role in catecholamine synthesis by converting dopamine into norepinephrine. Here we systematically investigated DBH polymorphisms associated with enzymatic activity as well as autonomic and blood pressure (BP)/disease phenotypes in vivo. METHODS AND RESULTS: Seventy genetic variants were discovered at the locus; across ethnicities, much of the promoter was spanned by a 5' haplotype block, with a larger block spanning the promoter in whites than blacks. DBH secretion was predicted by genetic variants in the DBH promoter, rather than the amino acid coding region. The C allele of common promoter variant C-970T increased plasma DBH activity, epinephrine excretion, the heritable change in BP during environmental stress in twin pairs, and also predicted higher basal BP in three independent populations. Mutagenesis and expression studies with isolated/transfected DBH promoter/luciferase reporters in chromaffin cells indicated that variant C-970T was functional. C-970T partially disrupted consensus transcriptional motifs for n-MYC and MEF-2, and this variant affected not only basal expression, but also the response to exogenous/co-transfected n-MYC or MEF-2; during chromatin immunoprecipitation, these two endogenous factors interacted with the motif. CONCLUSIONS: These results suggest that common DBH promoter variant C-970T plays a role in the pathogenesis of human essential hypertension: common genetic variation in the DBH promoter region seems to initiate a cascade of biochemical and physiological changes eventuating in alterations of basal BP. These observations suggest new molecular strategies for probing the pathophysiology, risk, and rational treatment of systemic hypertension. |
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Authors:
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Yuqing Chen; Gen Wen; Fangwen Rao; Kuixing Zhang; Lei Wang; Juan L Rodriguez-Flores; Amber P Sanchez; Manjula Mahata; Laurent Taupenot; Ping Sun; Sushil K Mahata; Bamidele Tayo; Nicholas J Schork; Michael G Ziegler; Bruce A Hamilton; Daniel T O'Connor |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Twin Study |
Journal Detail:
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Title: Journal of hypertension Volume: 28 ISSN: 1473-5598 ISO Abbreviation: J. Hypertens. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-17 Completed Date: 2010-03-09 Revised Date: 2011-07-19 |
Medline Journal Info:
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Nlm Unique ID: 8306882 Medline TA: J Hypertens Country: England |
Other Details:
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Languages: eng Pagination: 76-86 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of California at San Diego, La Jolla, California 92093-0838, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult African Continental Ancestry Group / genetics Aged Aged, 80 and over Autonomic Nervous System / physiology* Blood Pressure / genetics*, physiology Dopamine beta-Hydroxylase / genetics* European Continental Ancestry Group / genetics Female Genetic Predisposition to Disease* Genetic Variation Heart Rate / genetics Humans Hypertension / epidemiology, genetics*, physiopathology Male Middle Aged Nigeria / epidemiology Polymorphism, Single Nucleotide* United States / epidemiology Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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MD000220/MD/NCMHD NIH HHS; P01 HL058120-01A1/HL/NHLBI NIH HHS; P01 HL058120-01A10004/HL/NHLBI NIH HHS; P60 MD000220-019004/MD/NCMHD NIH HHS; R01 HL053353-12A1/HL/NHLBI NIH HHS; RR00827/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 1.14.17.1/Dopamine beta-Hydroxylase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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