Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure

• DOI: 10.1097/hjh.0b013e328332bc87
• Publication Date: 2009-12-17T15:33:20Z
• Authors: Yuqing Chen; Gen Wen; Fangwen Rao; Kuixing Zhang; Lei Wang; Juan L Rodriguez-...; 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
• Keywords: Adult; Aged, 80 and over; Male; 0301 basic medicine; Adolescent; Black People; Genetic Variation; Nigeria; Blood Pressure; Dopamine beta-Hydroxylase; Middle Aged; Autonomic Nervous System; Polymorphism, Single Nucleotide; United States; White People; 03 medical and health sciences; Heart Rate; Hypertension; Humans; Female; Genetic Predisposition to Disease; Aged

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 autonomic and blood pressure (BP)/disease phenotypes vivo. Methods results Seventy genetic variants were discovered at the locus; across ethnicities, much of promoter was spanned a 5' haplotype block, larger block spanning whites than blacks. secretion predicted promoter, rather amino acid coding region. The C allele common variant C-970T increased plasma activity, epinephrine excretion, heritable change BP during environmental stress twin pairs, also higher basal three independent populations. Mutagenesis expression studies isolated/transfected promoter/luciferase reporters chromaffin cells indicated that functional. partially disrupted consensus transcriptional motifs for n-MYC MEF-2, this affected not only expression, but response to exogenous/co-transfected or MEF-2; chromatin immunoprecipitation, these two endogenous factors interacted motif. Conclusions These suggest pathogenesis human hypertension: variation region seems initiate cascade biochemical physiological changes eventuating alterations BP. observations new molecular strategies probing pathophysiology, risk, rational treatment systemic hypertension.