Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity.
Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity.
复制标题
人DBH中的调节性多态性会影响外周基因表达和交感性活性。
DOI：
10.1161/circresaha.116.304398
复制
发表时间：
2014-12-05
影响因子：
20.1
通讯作者：
Sadee W
中科院分区：
文献类型：
--
作者：
Barrie ES;Weinshenker D;Verma A;Pendergrass SA;Lange LA;Ritchie MD;Wilson JG;Kuivaniemi H;Tromp G;Carey DJ;Gerhard GS;Brilliant MH;Hebbring SJ;Cubells JF;Pinsonneault JK;Norman GJ;Sadee W
多巴胺β-羟化酶（DBH）在中枢神经系统和外周神经系统中催化多巴胺转化为去甲肾上腺素。DBH变异与循环DBH的巨大变化相关，并与多种疾病有关;但因果关系和组织特异性影响仍未得到解决。表征DBH中的调节变体、对mRNA表达的影响以及在调节交感神经紧张和疾病风险中的作用。对人体组织中DBH mRNA的分析证实了在蓝斑（LC）和肾上腺中的高表达，而且在交感神经支配的器官（肝>肺>心脏）中也有高表达。等位基因特异性的mRNA检测显示，在肝脏（2-11倍）归因于启动子rs 1611115和外显子2 rs 1108580明显的等位基因表达差异，但只有小的差异，在LC和肾上腺。这些等位基因也与肝和肺中显著降低的mRNA表达相关。虽然DBH蛋白在其他交感神经支配的器官中表达，但mRNA水平太低而无法分析。在小鼠中，肝脏Dbh mRNA水平与心血管风险表型相关。次要等位基因rs 1611115和rs 1108580与心绞痛等交感神经表型相关。测试这些变体的组合效应表明在三个独立的临床队列中对心肌梗死的保护。我们证明了DBH变体对两个交感神经支配器官（肝脏和肺）中表达的深刻影响，但在肾上腺和大脑中没有。初步结果表明，这些变异体与外周交感神经紧张反应的临床表型相关。我们假设，除了通过循环DBH和去甲肾上腺素的内分泌效应，该变体在交感神经支配的靶器官中起作用。
Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the CNS and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus (LC) and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2–11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in LC and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in three separate clinical cohorts. We demonstrate profound effects of DBH variants on expression in two sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.