Genetics of Stress Induced Hypertension in Black Youth

描述(由申请者提供)：在黑人青年中，压力所致的压力性钠尿受损的发生率大约是白人青年的两倍。盐、压力和遗传是解释这种差异的假设因素中的三个。拟议的项目将扩展这一领域先前的研究，这些研究侧重于通过确定导致应激诱导的压力性钠尿受损的遗传易感性来研究荷尔蒙反应。总体目标是确定参与肾小管钠处理级联反应的基因在黑人应激下钠稳态和血压的动态调节中的作用。这些基因包括编码上皮性钠通道的5个基因(αENaC、βENaC和Gamma ENaC)及其辅助调节蛋白，如血清糖皮质激素诱导蛋白(SGK-1)和神经前体细胞表达的发育下调4(Nedd4-2)。协调的Nedd4-SGK-ENaC相互作用在ENaC活性和管状钠的处理中起着重要作用。环境应激可能通过内源性ENaC活性促进钠滞留。因此，主要目的是在黑人青年中检验以下假设；与非黑人青年相比，具有不利基因型或单倍型的个体将显示：1)压力诱导的尿钠排泄减少；2)应激后收缩压延迟恢复；以及3)在应激恢复期间，血浆肾素活性受到更大程度的抑制(低肾素高血压)。第二个目的是探索组成ENaC途径的五个基因之间的基因-基因相互作用与三个主要结果变量的关系。将对300名黑人青年进行研究，其中包括15-19岁的同等数量的男孩和女孩。所有受试者都将接受包括恢复期在内的延长压力方案的测试。将使用直接(即功能性SNPs)和间接(即单倍型标记SNPs)关联方法在这些受试者中系统地检查这五个基因的单核苷酸多态(SNPs)。将收集这些年轻人父母的口腔细胞DNA，以便于(1)单倍型重建和分析，(2)传递不平衡测试(TDT)。分类和回归树技术将被用来探索可能的基因-基因相互作用。这项拟议的研究将为了解遗传、盐和环境应激之间的相互作用以及它们在高血压发病机制中的作用提供新的见解。该项目旨在调查盐、压力和基因对人体释放钠的能力的影响。了解盐、压力和遗传学之间的联系将为评估高血压的风险因素提供一种新的方法。

DESCRIPTION (provided by applicant): Impaired stress-induced pressure natriuresis is approximately twice as prevalent in black as in white youth. Salt, stress and genetics are three of the factors hypothesized to account for the difference. The proposed project will extend previous investigations in this area that focused on hormonal responses by identifying genetic predispositions responsible for impaired stress-induced pressure natriuresis. The overall goal is to determine the role of genes involved in the sodium-handling cascade in the renal tubules on dynamic regulation of sodium homeostasis and blood pressure under stress in blacks. These include five genes encoding the epithelial sodium channel (alpha ENaC, beta ENaC and gamma ENaC) and its accessory regulatory proteins such as serum glucocorticoid-inducible kinase (SGK-1) and neural precursor cell-expressed developmentally down-regulated 4 (Nedd4-2). The concerted Nedd4-SGK-ENaC interaction plays an important role in ENaC activity and tubular sodium handling. Environmental stress may promote sodium retention via intrinsic ENaC activity. Therefore, the primary aims are to test the following hypotheses in black youth; individuals with unfavorable genotypes or haplotypes compared to those without will show 1) a reduced stress-induced increase in urinary sodium excretion; 2) delayed systolic blood pressure recovery following stress; and 3) greater plasma renin activity suppression (low-renin hypertension) during recovery following stress. The secondary aim is to explore gene-gene interactions among the five genes consisting of the ENaC pathway in relation to the three primary outcome variables. A total of 300 black youth will be studied which will include an equal number of boys and girls aged 15-19 yrs. All subjects will be tested with an extended stress protocol including a recovery period. Single nucleotide polymorphisms (SNPs) in the five genes will be systematically examined in these subjects using both direct (i.e., functional SNPs) and indirect (i.e., haplotype tagging SNPs) association approaches. Buccal cell DNA from the parents of these youth will be collected to facilitate (1) haplotype reconstruction and analyses and (2) transmission disequilibrium tests (TDTs). Classification and Regression Trees techniques will be used to explore possible gene-gene interactions. This proposed research will provide novel insight into the interactions between genetics, salt and environmental stress, and their contribution to the pathogenesis of essential hypertension. The project aims to investigate the influence of salt, stress and genes on the body's ability to release sodium. Understanding the connections between salt, stress and genetics will provide a fresh approach into evaluating risk factors for high blood pressure.