Physiologic effects of natriuretic peptide genetic variation

利尿钠肽遗传变异的生理效应

• 批准号: 8213466
• 负责人: Christopher Holmes Newton-Cheh
• 金额: $ 75.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-12 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213466
• 关键词: Acute; Alleles; Attention; Bacterial Artificial Chromosomes; Behavioral; Blood Pressure; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cerebrovascular Disorders; Chronic; Clinical; DNA Resequencing; DNA Sequence; Data; Diet; Disease; Echocardiography; Equilibrium; Excretory function; Family Study; Feedback; Frequencies; General Population; Genetic; Genetic Variation; Genotype; Heart; Heart Atrium; Hormones; Human; Hypertension; In Vitro; Individual; Intervention; Intravenous; Investigation; Kidney; Kidney Diseases; Maps; Modeling; Morbidity - disease rate; Natriuretic Peptides; Pathway interactions; Phenotype; Physiological; Prevalence; Proteins; Reading; Recruitment Activity; Renin-Angiotensin-Aldosterone System; Reporting; Research; Research Personnel; Rest; Risk; Risk Factors; Role; Saline; Sampling; Scandinavian; Signal Transduction; Sodium; Sodium Chloride; Stress; Structure-Activity Relationship; Syndrome; System; Testing; Variant; Work; base; blood pressure regulation; experience; follow-up; genetic association; genetic variant; hot climate; insight; molecular phenotype; mortality; normotensive; novel; population based; public health relevance; response; saluretic; trait; urinary

DESCRIPTION (provided by applicant): High blood pressure is a potent risk factor for cardiovascular, cerebrovascular, and kidney disease. Although it is highly heritable, the genetic causes of blood pressure variation in the general population have been ill-defined. An important challenge to the study of blood pressure is its multifactorial origins, motivating the division of hypertension into discrete physiologic subtypes. Abnormal salt-handling has received much attention, given the implications of "salt-sensitivity" for behavioral and pharmacologic interventions. Several physiologic systems have evolved to handle salt, and these may contribute to blood pressure regulation. The best- studied system is the renin-angiotensin-aldosterone system (RAAS), which likely evolved to promote salt retention in hot climates with limited access to dietary salt. The endogenous system that counter-balances the RAAS is the natriuretic peptide (NP) system. The NP are natriuretic and vasodilatory molecules produced by the heart in response to increased wall stress in the atria and ventricles. Relatively little is known regarding the homeostatic role of NP in "healthy" individuals. The low resting levels of NP in ambulatory individuals and the involvement of the NP axis in a feedback loop have presented challenges to defining the physiologic implications of alterations in NP activity. In preliminary work, we have identified a common genetic variant at the NPPA/NPPB locus associated with resting NP concentrations and blood pressure. Using data from up to 60,000 individuals, we observed that genetically-determined lower NP levels were related to higher blood pressure and increased risk of hypertension, directly implicating the NP in human blood pressure regulation. In Aim 1, we seek to fine map the NPPA/NPPB common variant association and identify novel low-frequency, high-effect alleles through large-scale resequencing of the locus. In Aim 2, we will assess the impact of genetically- determined low NP levels on salt-handling by recruiting individuals with genetically low and with genetically high NP levels and assessing the response to intravenous saline challenge on the background of low- and high-salt diets. In Aim 3, we will manipulate the human NPPA/NPPB locus using a bacterial artificial chromosome in cellular systems to establish the variants that are sufficient to alter NPPA or NPPB expression. The investigators' proposed use of high- throughput resequencing and genotyping, detailed physiologic phenotyping, and molecular characterization of the DNA sequence variation identified promise to yield fundamental insights into structure/function relationships at the NPPA/NPPB locus, as well as elucidate the role of NP in acute and chronic salt responses and blood pressure regulation in the general population. PUBLIC HEALTH RELEVANCE: High blood pressure leads to substantial morbidity and mortality, but its causes are not well established. The proposed research investigates the role of hormones produced by the heart in the regulation of blood pressure and responses to dietary salt, which could have important implications for behavioral and pharmacologic treatments to control blood pressure.

描述（由申请人提供）：高血压是心血管、脑血管和肾脏疾病的潜在危险因素。尽管具有高度遗传性，但普通人群血压变异的遗传原因尚不清楚。血压研究的一个重要挑战是其多因素起源，促使高血压分为不同的生理亚型。鉴于“盐敏感性”对行为和药物干预的影响，异常的盐处理受到了广泛关注。一些生理系统已经进化来处理盐，这些可能有助于血压调节。研究最透彻的系统是肾素-血管紧张素-醛固酮系统（RAAS），该系统的进化可能是为了在膳食盐摄入量有限的炎热气候下促进盐分滞留。平衡 RAAS 的内源性系统是利尿钠肽 (NP) 系统。 NP 是心脏响应心房和心室壁应力增加而产生的利尿钠和血管舒张分子。关于 NP 在“健康”个体中的稳态作用知之甚少。步行个体中 NP 的静息水平较低，并且 NP 轴参与反馈回路，这对定义 NP 活性变化的生理影响提出了挑战。在初步工作中，我们在 NPPA/NPPB 基因座上发现了一个与静息 NP 浓度和血压相关的常见遗传变异。使用来自多达 60,000 名个体的数据，我们观察到基因决定的较低 NP 水平与较高的血压和高血压风险增加有关，直接暗示了 NP 在人类血压调节中的作用。在目标 1 中，我们寻求精细绘制 NPPA/NPPB 常见变异关联图，并通过大规模基因座重测序来识别新的低频、高效等位基因。在目标 2 中，我们将通过招募基因低 NP 水平和基因高 NP 水平的个体，并评估低盐和高盐饮食背景下对静脉注射盐水挑战的反应，来评估基因决定的低 NP 水平对盐处理的影响。在目标 3 中，我们将使用细胞系统中的细菌人工染色体操纵人类 NPPA/NPPB 基因座，以建立足以改变 NPPA 或 NPPB 表达的变体。研究人员提议使用高通量重测序和基因分型、详细的生理表型分析以及已确定的 DNA 序列变异的分子表征，有望对 NPPA/NPPB 基因座的结构/功能关系产生基本见解，并阐明 NP 在普通人群中急性和慢性盐反应以及血压调节中的作用。 公众健康相关性：高血压会导致大量的发病率和死亡率，但其原因尚不明确。拟议的研究调查了心脏产生的激素在血压调节和对膳食盐的反应中的作用，这可能对控制血压的行为和药物治疗产生重要影响。