PDF(Pubmed)
Abstract：
Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.
摘要：
具有较高比例的遗传西非血统（％GWAA）的高血压患者对噻嗪类利尿剂（TDs）的血压（BP）反应较好，对β受体阻滞剂（BBs）的反应较差，与他们较低的血浆肾素活性（PRA）有关。建议TDs和BBs通过不完全了解的机制通过血管舒张长期降低BP。这项研究旨在确定PRA祖先差异的潜在途径，这可能反映了TDs和BBs降低BP机制的潜在途径。在参加抗高血压反应药物基因组学评估（PEAR）和PEAR-2试验的高血压参与者中，我们之前确定了8种与基线PRA相关的代谢物和4种不同的代谢簇(包括39种代谢物),这些代谢物在GWAA<45%和≥45%之间存在差异.在目前的研究中,使用独创性路径分析(IPA)，我们整合了这些信号。在三个显著富集的途径中的三个重叠的代谢信号被鉴定为与PRA和%GWAA相关:神经酰胺信号,鞘氨醇1-磷酸信号，和内皮一氧化氮合酶信号。文献表明，所确定的途径涉及Rho激酶级联的调节，血管活性剂一氧化氮的产生，前列环素,血栓烷A2和内皮素1；提出的途径是TD和BB诱导的血管舒张的基础。这些发现可能会提高我们对TDs和BBs降低BP机制的理解。通过识别预期从这些药物中具有强大的降BP作用的患者，这可能为个性化抗高血压治疗提供可能的一步。
