Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.
Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.
复制标题
DOI：
10.1097/hjh.0b013e328332bc87
复制
发表时间：
2010-01
影响因子：
4.9
通讯作者：
O'Connor DT
中科院分区：
文献类型：
--
作者：
Chen Y;Wen G;Rao F;Zhang K;Wang L;Rodriguez-Flores JL;Sanchez AP;Mahata M;Taupenot L;Sun P;Mahata SK;Tayo B;Schork NJ;Ziegler MG;Hamilton BA;O'Connor DT
多巴胺-羟化酶（DBH）通过将多巴胺转化为去甲肾上腺素，在儿茶酚胺合成中起着重要作用。在这里，我们系统地研究了DBH多态性与体内酶活性以及自主神经和BP/疾病表型相关。在该位点发现了70个遗传变异；在不同种族中，大部分启动子由一个5 '单倍型片段跨越，白人的启动子长度比黑人大。DBH分泌是由DBH启动子的遗传变异预测的，而不是氨基酸编码区。共同启动子变异C- 970t的C等位基因增加了双胞胎中血浆DBH活性、肾上腺素分泌、环境胁迫下血压的遗传变化，并预测了三个独立人群中较高的基础血压。用分离的/转染的DBH启动子/荧光素酶报告基因在染色质细胞中的诱变和表达研究表明，变异体C-970T具有功能。C-970T部分破坏了n-MYC和MEF-2的一致转录基序，这种变异不仅影响基础表达，还影响对外源/共转染n-MYC或MEF-2的反应；在ChIP过程中，这两个内源性因子与基序相互作用。这些结果表明，常见的DBH启动子变异C-970T在人类原发性高血压的发病机制中起作用：DBH启动子区域的常见遗传变异似乎启动了一系列生化和生理变化，最终导致基础血压的改变。这些观察结果为探索全身性高血压的病理生理、风险和合理治疗提供了新的分子策略。
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. 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. 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.