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: 7426331
• 负责人: Yanbin Dong
• 金额: $ 35.68万
• 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/7426331
• 关键词: Accounting; Adult; Aldosterone; Alleles; Amiloride; Angiotensin II; Area; Arousal; Blood Pressure; Catecholamines; Cells; Classification; Condition; DNA; Data; Development; Disease regression; Diuretics; Environmental Exposure; Epinephrine; Epithelial; Equilibrium; Essential Hypertension; Excretory function; Exposure to; Feedback; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glucocorticoids; Goals; Haplotypes; High Blood Pressure; Homeostasis; Hormonal; Hypertension; Individual; Investigation; Kidney; Knowledge; Masks; Modeling; Natriuresis; Nerve; Neurological observations; Norepinephrine; Numbers; Organ; Outcome; Parents; Pathogenesis; Pathway interactions; Pattern; Phosphotransferases; Plasma; Play; Process; Protocols documentation; Rate; Recovery; Regulation; Renal tubule structure; Renin; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Risk; Risk Factors; Role; Serum; Single Nucleotide Polymorphism; Sodium; Sodium Channel; Sodium Chloride; Standards of Weights and Measures; Stress; Sympathetic Nervous System; Techniques; Testing; Theoretical model; Thinking; Trees; Tubular formation; Youth; aged; blood pressure regulation; boys; design; epithelial Na+ channel; extracellular; gamma ENaC; gene interaction; genetic regulatory protein; girls; in vivo; insight; interest; low renin hypertension; normotensive; novel; precursor cell; pressure; programs; reconstruction; relating to nervous system; response; salt sensitive; transmission process; urinary

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）：压力引起的压力性尿钠排泄障碍在黑人青少年中的患病率大约是白人青少年的两倍。盐、压力和遗传是推测造成这种差异的三个因素。拟议的项目将扩展该领域之前的研究，重点是通过识别导致压力引起的压力性尿钠排泄受损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对黑人压力下钠稳态和血压动态调节的作用。其中包括编码上皮钠通道的五个基因（α ENaC、β ENaC 和 γ ENaC）及其辅助调节蛋白，例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 的协同相互作用在 ENaC 活性和肾小管钠处理中发挥着重要作用。环境压力可能通过内在的 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) 应激引起的尿钠排泄增加减少； 2）压力后收缩压恢复延迟； 3) 在应激后的恢复过程中，血浆肾素活性受到更大的抑制（低肾素高血压）。第二个目标是探索构成 ENaC 通路的五个基因之间与三个主要结果变量的关系。总共 300 名黑人青少年将接受研究，其中包括同等数量的 15 至 19 岁男孩和女孩。所有受试者都将接受延长的压力方案（包括恢复期）的测试。将使用直接（即功能性 SNP）和间接（即单倍型标记 SNP）关联方法在这些受试者中系统地检查五个基因中的单核苷酸多态性（SNP）。将收集这些青少年父母的口腔细胞 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间相互作用。这项拟议的研究将为遗传、盐和环境压力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、压力和遗传之间的联系将为评估高血压的危险因素提供一种新的方法。