Genetics of Stress Induced Hypertension in Black Youth

描述（由申请人提供）：压力引起的压力性尿钠损伤在黑人青年中大约是白人青年的两倍。盐、压力和遗传是造成这种差异的三个假设因素。拟议的项目将扩展先前在这一领域的研究，通过确定负责受损应激诱导的压力性尿钠的遗传倾向来关注激素反应。总体目标是确定参与肾小管钠处理级联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5个编码上皮钠通道的基因（α ENaC， β ENaC和γ ENaC）及其辅助调节蛋白，如血清糖皮质激素诱导激酶（SGK-1）和神经前体细胞表达的发育下调4 （Nedd4-2）。Nedd4-SGK-ENaC相互作用在ENaC活性和管状钠处理中起重要作用。环境应激可通过ENaC活性促进钠潴留。因此，主要目的是在黑人青年中检验以下假设；与没有基因型或单倍型的个体相比，具有不利基因型或单倍型的个体将表现出1)应激诱导的尿钠排泄量增加减少；2)应激后收缩压恢复延迟；3)应激后恢复期更大的血浆肾素活性抑制（低肾素高血压）。第二个目的是探索构成ENaC通路的五个基因之间的基因相互作用与三个主要结果变量的关系。总共300名黑人青年将被研究，其中包括相同数量的15-19岁的男孩和女孩。所有受试者都将接受包括恢复期在内的长期压力测试。这五个基因的单核苷酸多态性（SNPs）将在这些受试者中使用直接（即功能SNPs）和间接（即单倍型标记SNPs）关联方法进行系统检查。将收集这些年轻人父母的颊细胞DNA，以便进行(1)单倍型重建和分析，(2)传播不平衡测试（tdt）。分类和回归树技术将用于探索可能的基因-基因相互作用。本研究将为遗传学、盐和环境应激之间的相互作用及其对原发性高血压发病机制的贡献提供新的见解。该项目旨在研究盐、压力和基因对人体释放钠的能力的影响。了解盐、压力和基因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.