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）：压力引起的压力受损大约是黑色年轻人的两倍。盐，压力和遗传学是考虑到差异的三个因素。拟议的项目将通过鉴定负责压力诱导的压力纳地硫酸盐受损的遗传易感性来扩展该领域的先前研究，该研究的重点是激素反应。总体目的是确定肾小管在肾小管中涉及的基因在肾小管中涉及的基因在肾小管中的钠级联反应对钠稳态的动态调节和黑人压力下的血压的动态调节。其中包括编码上皮钠通道（Alpha ENAC，Beta ENAC和Gamma ENAC）的五个基因及其辅助调节蛋白，例如血清糖皮质激素可诱导激酶（SGKK-1）以及神经前体细胞表达的发育下调的4（NEDD4-2）（NEDD4-2）。一致的NEDD4-SGK-ENAC相互作用在ENAC活性和管状钠处理中起着重要作用。环境压力可以通过内在的ENAC活性促进钠的保留率。因此，主要目的是检验黑人青年的以下假设。与没有基因型或单倍型的人相比，具有不利的基因型或单倍型的个体将显示1）尿液钠排泄量的增加降低； 2）压力后延迟收缩压恢复； 3）在应激后恢复期间，恢复过程中较大的血浆肾素活性抑制（低肾素高血压）。第二个目的是探索与三个主要结果变量相关的五个基因之间的基因相互作用。总共将研究300名黑人青年，其中包括等同数量的15-19岁的男孩和女孩。所有受试者将通过延长的应力方案进行测试，包括恢复期。五个基因中的单核苷酸多态性（SNP）将在这些受试者中使用直接（即功能性SNP）和间接（即单倍型标记SNPS）的关联方法进行系统检查。将收集这些青年父母的颊细胞DNA，以促进（1）单倍型重建和分析以及（2）传播不平衡测试（TDTS）。分类和回归树技术将用于探索可能的基因 - 基因相互作用。这项拟议的研究将为遗传学，盐和环境压力之间的相互作用及其对基本高血压发病机理的贡献提供新的见解。该项目旨在研究盐，胁迫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危险因素提供新的方法。