Physiologic effects of natriuretic peptide genetic variation

利尿钠肽遗传变异的生理效应

基本信息

项目摘要

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有效危险因素。尽管这是高度遗传的,但普通人群血压变化的遗传原因已被不确定。血压研究的一个重要挑战是其多因素的起源,激发了高血压分为离散的生理亚型。鉴于“盐敏感性”对行为和药理干预的意义,异常的盐处理引起了很多关注。几种生理系统已经进化为处理盐,这些系统可能导致血压调节。最佳研究的系统是肾素 - 血管紧张素 - 醛固酮系统(RAAS),它们可能进化为在饮食中有限的炎热气候中促进盐含量。与raas相抵触的内源系统是纳地尿肽(NP)系统。 NP是源自心脏和心室壁应力增加的心脏产生的亚钠和血管舒张分子。关于NP在“健康”个体中的稳态作用相对鲜为人知。卧床个体中NP的静息水平较低,而NP轴参与反馈循环已经提出了定义NP活性改变的生理意义的挑战。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基因座的常见遗传变异。使用最多60,000名个体的数据,我们观察到遗传确定的较低的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在人体血压调节中。在AIM 1中,我们试图详细绘制NPPA/NPPB公共变体关联,并通过大规模重新统计的基因座来识别新型的低频,高效应等位基因。在AIM 2中,我们将通过募集遗传较低且遗传较高的NP水平的个体来评估遗传确定的低NP水平对盐处理的影响,并评估对静脉盐水挑战的反应在低盐和高盐饮食的背景下。在AIM 3中,我们将使用细菌性人工染色体在细胞系统中操纵人NPPA/NPPB基因座,以建立足以改变NPPA或NPPB表达的变体。研究者提出了对高吞吐量的重新取样和基因分型的使用,详细的生理表型以及DNA序列变化的分子表征确定了有望在NPPA/NPPB基因座的结构/功能关系中产生基本见解,并阐明NP在急性和慢性盐反应中的作用,并在急性盐反应和血液中均可调节。 公共卫生相关性:高血压会导致大量的发病率和死亡率,但其原因尚未确定。拟议的研究调查了心脏在调节血压和对饮食盐的反应中产生的激素的作用,这可能对控制血压具有重要意义。

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(1)

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Christopher Holmes Newton-Cheh其他文献

Christopher Holmes Newton-Cheh的其他文献

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{{ truncateString('Christopher Holmes Newton-Cheh', 18)}}的其他基金

Influence of genetic variation on QT prolongation over the lifecourse and as a cardiotoxic drug response
遗传变异对整个生命过程中 QT 延长的影响以及作为心脏毒性药物反应的影响
  • 批准号:
    9921476
  • 财政年份:
    2018
  • 资助金额:
    $ 67.06万
  • 项目类别:
Influence of genetic variation on QT prolongation over the lifecourse and as a cardiotoxic drug response
遗传变异对整个生命过程中 QT 延长的影响以及作为心脏毒性药物反应的影响
  • 批准号:
    10246254
  • 财政年份:
    2018
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic profiling of sGC genetic variants
sGC 遗传变异的生理学分析
  • 批准号:
    8439108
  • 财政年份:
    2013
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic profiling of sGC genetic variants
sGC 遗传变异的生理学分析
  • 批准号:
    8714033
  • 财政年份:
    2013
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic Profiling of sGC Genetic Variants
sGC 遗传变异的生理分析
  • 批准号:
    8866446
  • 财政年份:
    2013
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8213466
  • 财政年份:
    2010
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8435332
  • 财政年份:
    2010
  • 资助金额:
    $ 67.06万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8011974
  • 财政年份:
    2010
  • 资助金额:
    $ 67.06万
  • 项目类别:
Genetic determinants of cardiac repolarization
心脏复极的遗传决定因素
  • 批准号:
    7058314
  • 财政年份:
    2005
  • 资助金额:
    $ 67.06万
  • 项目类别:
Genetic determinants of cardiac repolarization
心脏复极的遗传决定因素
  • 批准号:
    7228133
  • 财政年份:
    2005
  • 资助金额:
    $ 67.06万
  • 项目类别:

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