Physiologic effects of natriuretic peptide genetic variation

描述（由申请人提供）：高血压是心脑血管和肾脏疾病的潜在危险因素。虽然它是高度遗传的，但一般人群中血压变异的遗传原因一直不明确。对血压研究的一个重要挑战是它的多因素起源，促使高血压分为离散的生理亚型。鉴于“盐敏感性”对行为和药理学干预的影响，异常盐处理受到了广泛关注。一些生理系统已经进化到可以处理盐，这些可能有助于血压调节。研究得最好的系统是肾素-血管紧张素-醛固酮系统（RAAS），它可能在炎热的气候中促进盐潴留，而饮食中盐的获取有限。内源性平衡RAAS的系统是利钠肽（NP）系统。NP是心脏在心房和心室壁应力增加时产生的利钠和血管扩张分子。相对而言，我们对NP在“健康”个体中的稳态作用知之甚少。运动个体的低静息NP水平和NP轴在反馈回路中的参与为定义NP活动改变的生理含义提出了挑战。在初步工作中，我们已经确定了与静息NP浓度和血压相关的NPPA/NPPB位点的常见遗传变异。利用多达6万人的数据，我们观察到基因决定的低NP水平与高血压和高血压风险增加有关，直接暗示NP参与人类血压调节。在Aim 1中，我们试图通过对NPPA/NPPB基因座的大规模重测序，精细绘制NPPA/NPPB共同变异关联图谱，并鉴定出新的低频、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，并评估在低盐和高盐饮食背景下静脉盐水挑战的反应，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位点，以建立足以改变NPPA或NPPB表达的变体。研究人员建议使用高通量重测序和基因分型，详细的生理表型和DNA序列变异的分子表征，以期对NPPA/NPPB位点的结构/功能关系产生基本见解，并阐明NP在急性和慢性盐反应和血压调节中的作用。

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.