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

Abstract

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 BP/disease phenotypes in vivo. Methods and Results 70 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 ChIP, 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.

Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity

“…19 However, it remains unknown how rs1611115- T reduces circulating DBH and norepinephrine levels. Reporter gene assays in rat PC12 chromaffin cells have yielded opposing results with rs1611115, 17–19 and whether this effect applies in vivo in human cell types remains uncertain.…”

Dopamine β‐hydroxylase gene associates with stroop color‐word task performance in Han Chinese children with attention deficit/hyperactivity disorder

“…A single nucleotide polymorphism (SNP), located 1,021 bp 5 0 to the transcriptional start site of DBH (À1021C/T; rs1611115) has been reported to account for 30-50% of the variance in serum DbH, depending on the geographic origin or ethnicity of samples [Zabetian et al, 2001;Tang et al, 2005Tang et al, , 2006Tang et al, , 2007Bhaduri and Mukhopadhyay, 2008]. Individuals with CC genotype had the highest levels of DbH plasma activity and TT genotype was the lowest with CT being intermediate, suggesting a co-dominant inheritance or a gene-dose effect [Cubells and Zabetian, 2004;Tang et al, 2006], respectively Importantly, a recent study [Chen et al, 2010] reported in vitro and in cellar evidence that rs1611115 (reported as À970C>T in their study) alters the transcription of DBH, strongly supporting this SNP is functional.…”

“…We selected the À1021C/T polymorphism because it has thus far the strongest evidence to be a functional one in DbH [Chen et al, 2010] and at least one study suggests that CC genotype of this SNP was associated with a diminished performance of EF (as reflected by a composite measure, CPT, and Wisconsin card sorting test) [Kieling et al, 2008]. In addition, previous studies from our group have shown possible association between this polymorphism and ADHD phenotypes in Chinese population, but the preferentially transmitted alleles differ between subtypes [Zhang et al, 2004[Zhang et al, , 2005.…”

Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism

“…DBH is also released from central noradrenergic neurons. Variation in DBH activity appears highly heritable, with environmental factors having relatively little effect [15]. Studies have previously shown that DBH inhibition attenuates development of hypertension in the spontaneously hypertensive rat [16].…”

“…Chen and colleagues explored the role of DBH promoter variant C-970T, finding that this particular variant influenced heritable traits in twin pairs that may mark individuals at risk of developing hypertension in later life. Possession of the minor (T) allele appears to predict lower DBH activity, lower systolic blood pressure in response to stress, and decreased catecholamine excretion across a variety of ethnic groups [15]. The same researchers went on to identify C-2073T, a second functional variant in the DBH promoter.…”