Genetics of water balance

 说明(申请人提供)：低钠血症是一种相对过量的全身水分，是最常见的电解质异常；它在老年人、急性和慢性病患者以及服用某些药物的患者中尤其常见。即使是适度的水分过剩(即血浆钠浓度的适度降低)也会导致相当大的发病率和死亡率。水分调节基因的罕见突变会导致孟德尔式的水分平衡失调；然而，这些突变只占低钠血症的一小部分。我们的初步数据显示，血浆钠浓度具有高度的个体化。也就是说，水平衡在健康的无关个体之间是不同的，但在任何一个个体中，随着时间的推移，水平衡相对稳定。我们应用这一原理来证明血浆钠浓度是可遗传的。我们改进了这一特征，以消除或减少非遗传因素(例如，药物和合并症)的影响。在全基因组关联分析中，一个具有很高生物学可信度的基因，但以前没有与与这种表型相关的系统水平衡有关。以前没有研究在全人群的基础上解决水平衡的遗传学问题，目前还没有办法预测谁因易感药物或疾病状态而发生低钠血症的风险最大。这项建议的总体目标是使用来自NHLBI赞助的(和其他)先前大规模队列研究的数据来定义系统水平衡的群体遗传学。在目标1中，我们将使用NHLBI资助的和基于国际人口的队列数据来扩展和复制我们关于水平衡的发现阶段元基因组范围关联研究。我们先前的努力导致我们将这种表型与一个极具兴趣和高度生物学合理性的基因的常见变异联系在一起，但以前没有与这种重要的临床表型相关。在目标2中，我们将研究这个候选水平衡基因的罕见变异在钠代谢障碍的个人和家庭中的作用，以及在NHLBI资助的和其他基于人群的队列中的极端钠代谢障碍中的作用。在目标3中，我们试图根据它在基因中的位置、它所影响的基序以及该基因被调控的已知分子机制，来确定我们的先导变体--该基因关键调控区域中的一个常见多态--代表了因果变体。

 DESCRIPTION (provided by applicant): Hyponatremia, a relative excess of total body water, is the most frequently encountered electrolyte abnormality; it's especially common among the elderly, the acutely and chronically ill, and among patients taking certain medications. Even a modest water excess (i.e., a modest reduction in plasma sodium concentration) is associated with substantial morbidity and mortality. Rare mutations in water- regulatory genes cause Mendelian disorders of water balance; however, these account for only a small minority of cases of hyponatremia. Our preliminary data show that the plasma sodium concentration is highly individual. That is, water balance differs between healthy unrelated individuals but is relatively constant over time in any one individual. We applied this principle to show that plasma sodium concentration is heritable. We refined this trait to eliminate or reduce the contribution of non-genetic factors (e.g., medications and co-morbidities). In genome-wide association analyses, a gene of high biological plausibility but not previously linked to systemic water balance associated with this phenotype. No prior studies have addressed the genetics of water balance on a population-wide basis, and there is at present no way to predict who is at greatest risk of developing hyponatremia in response to predisposing medications or disease states. The over-arching objective of this proposal is to define the population genetics of systemic water balance using data derived from prior large-scale NHLBI-sponsored (and other) cohort studies. In Aim 1, we will expand and replicate our discovery-phase meta-genome-wide association study on water balance using data from NHLBI-funded and international population-based cohorts. Our prior efforts led to our association of this phenotype with common variants in a gene of great interest and high biological plausibility, but not previously linked to this important clinical phenotype. In Aim 2, we will investigate the role of rare variants in this candidate water-balance gene in dysnatremic individuals and families, and in the dysnatremic extremes of NHLBI-funded and other population-based cohorts. In Aim 3, we seek to establish that our lead variant - a common polymorphism in a key regulatory region of this gene - represents the causal variant, based upon its location within the gene, the motif it impacts, and the known molecular mechanisms through which this gene is regulated.