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。虽然它是高度遗传的，但一般人群中血压变化的遗传原因一直不清楚。血压研究的一个重要挑战是其多因素起源，促使高血压分为离散的生理亚型。由于盐敏感性对行为和药物干预的影响，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），它可能进化为在饮食盐摄入有限的炎热气候中促进盐潴留。平衡RAAS的内源性系统是利钠肽（NP）系统。NP是由心脏响应于心房和心室中增加的壁应力而产生的利钠和血管舒张分子。关于NP在“健康”个体中的稳态作用，我们知之甚少。低静息水平的NP在走动的个人和参与的NP轴的反馈回路提出了挑战，以确定在NP活动的改变的生理意义。在初步工作中，我们已经确定了一个共同的遗传变异在NPPA/NPPB基因座与静息NP浓度和血压。使用来自多达60，000人的数据，我们观察到遗传决定的较低NP水平与较高的血压和高血压风险增加有关，直接涉及NP在人类血压调节中。在目标1中，我们寻求精细定位NPPA/NPPB常见变异关联，并通过对该基因座的大规模重测序来鉴定新的低频、高效等位基因。在目标2中，我们将通过招募具有遗传低NP水平和具有遗传高NP水平的个体并评估在低盐和高盐饮食背景下对静脉内盐水激发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操纵人NPPA/NPPB基因座，以建立足以改变NPPA或NPPB表达的变体。研究人员提出的使用高通量重测序和基因分型，详细的生理表型，以及DNA序列变异的分子表征，有望产生对NPPA/NPPB基因座结构/功能关系的基本见解，以及阐明NP在一般人群中急性和慢性盐反应和血压调节中的作用。 公共卫生相关性：高血压导致大量的发病率和死亡率，但其原因尚不明确。这项拟议的研究调查了心脏产生的激素在调节血压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。

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.