Physiologic effects of natriuretic peptide genetic variation

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。尽管它具有很高的遗传性，但在普通人群中，血压变异的遗传原因一直没有明确的定义。血压研究的一个重要挑战是它的多因素起源，促使高血压分为不同的生理亚型。考虑到“盐敏感性”对行为和药物干预的影响，异常的盐处理受到了极大的关注。有几个生理系统已经进化来处理盐，这些系统可能有助于调节血压。研究最多的系统是肾素-血管紧张素-醛固酮系统(RAAS)，它的进化可能是为了在炎热气候下促进盐分保留，而饮食中的盐分获取有限。平衡RAAS的内源性系统是利钠肽(NP)系统。NP是心脏产生的利钠和扩张血管的分子，对心房和脑室壁应力的增加做出反应。关于NP在“健康”个体中的体内平衡作用，我们知之甚少。在活动个体中，NP的静息水平较低，NP轴参与反馈环路，这对确定NP活动变化的生理意义提出了挑战。在前期工作中，我们已经确定了NPPA/NPPB基因座上与静息NP浓度和血压相关的一个常见的遗传变异。使用多达60,000人的数据，我们观察到遗传决定的较低NP水平与更高的血压和更高的高血压风险相关，直接暗示NP参与人类血压调节。在目标1中，我们试图通过大规模的基因重新测序来精细定位NPPA/NPPB共同的变异关联，并识别新的低频、高效等位基因。在目标2中，我们将通过招募遗传低NP水平和遗传高NP水平的个体，并在低盐和高盐饮食的背景下评估静脉注射盐水挑战的反应，来评估遗传决定的低NP水平对盐处理的影响。在目标3中，我们将在细胞系统中使用细菌人工染色体来操纵人类NPPA/NPPB基因座，以建立足以改变NPPA或NPPB表达的变体。研究人员建议使用高通量重测序和基因分型、详细的生理表型分析和DNA序列变异的分子特征确定了对NPPA/NPPB基因座结构/功能关系的基本见解，并阐明了NP在普通人群急、慢性盐反应和血压调节中的作用。 与公共卫生相关：高血压会导致大量的发病率和死亡率，但其原因尚未完全确定。这项拟议的研究调查了心脏产生的激素在调节血压和对饮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具有重要意义。

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.