Genetics of Stress Induced Hypertension in Black Youth

黑人青年压力诱发高血压的遗传学

• 批准号: 7095684
• 负责人: Yanbin Dong
• 金额: $ 36.56万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095684
• 关键词: African American; adolescence (12-20); angiotensin /renin /aldosterone hypertension; blood pressure; clinical research; environmental stressor; essential hypertension; gene environment interaction; gene interaction; genetic susceptibility; hemodynamics; human genetic material tag; human subject; interactive multimedia; linkage disequilibriums; psychosomatic disorders; renal tubule; saluresis; serine threonine protein kinase; single nucleotide polymorphism; single strand conformation polymorphism; sodium channel; ubiquitin protein ligase

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.

描述（由申请人提供）：黑人青年中压力诱导的压力性尿钠排泄受损的发生率大约是白色青年的两倍。盐，压力和遗传是三个假设的因素来解释这种差异。拟议的项目将扩大以前的调查，在这方面的重点是激素反应，确定遗传易感性受损的压力引起的压力尿钠排泄。总体目标是确定参与肾小管钠处理级联反应的基因对黑人在压力下钠稳态和血压动态调节的作用。这些包括编码上皮钠通道（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（Nedd 4 -2）的五个基因。协同的Nedd 4-SGK-ENaC相互作用在ENaC活性和肾小管钠处理中起重要作用。环境应激可能通过内在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;与没有不利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显示1）减少应激诱导的尿钠排泄增加; 2）应激后收缩压恢复延迟; 3）应激后恢复期间更大的血浆肾素活性抑制（低肾素高血压）。第二个目的是探索组成ENaC通路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。总共将对300名黑人青年进行研究，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SNP）和间接（即，单体型标记SNP）关联方法。将收集这些青少年父母的颊细胞DNA，以促进（1）单倍型重建和分析以及（2）传递不平衡测试（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。这项研究将为遗传、盐和环境应激之间的相互作用及其在原发性高血压发病机制中的作用提供新的见解。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、压力和遗传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。