Genetics of water balance

水平衡的遗传学

• 批准号: 9095708
• 负责人: DAVID M COHEN
• 金额: $ 9.45万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095708
• 关键词: Accounting; Address; Biological; Body Water; Chronically Ill; Clinical; Code; Cohort Studies; Comorbidity; Data; Data Set; Disease; Elderly; Electrolytes; Enhancers; Equilibrium; Exhibits; Exons; Family; Funding; Gene Dosage; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Health; Hypernatremia; Hyponatremia; Individual; Individual Differences; International; Investigation; Lead; Link; Location; Mendelian disorder; Minority; Molecular; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Nucleic Acid Regulatory Sequences; Osmoregulation; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Population; Population Genetics; Proteins; Quantitative Trait Loci; Regulator Genes; Relative (related person); Risk; Role; Sodium; Testing; Time; Transcriptional Regulation; Variant; Water; Water Stress; Work; base; clinical phenotype; cohort; enhancer binding protein; genetic makeup; genome wide association study; interest; mortality; non-genetic; novel; population based; rare variant; response; trait; transcription factor

 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.

 描述（由申请人提供）：低钠血症是指体内水分相对过多，是最常见的电解质异常；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。水调节基因的罕见突变（即血浆钠浓度的适度降低）与导致孟德尔水平衡紊乱的发病率和死亡率相关。我们的初步数据表明，血浆钠浓度具有很大的个体差异，即，健康的无关个体之间的水平衡存在差异，但在任何个体中，随着时间的推移，血浆钠浓度都相对恒定。我们改进了这一性状，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，该基因具有高度的生物学合理性，但之前并未与与该表型相关的系统水平衡相关。没有事先。研究已经解决了全人群水平衡的遗传学问题，目前还没有办法预测谁因诱发药物或疾病状态而最有可能发生低钠血症。该提案的首要目标是。使用来自先前由 NHLBI 资助的（和其他）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。使用来自的数据NHLBI 资助的基于国际人群的队列研究使我们将这种表型与一个非常感兴趣且具有高度生物学合理性的基因中的常见变异联系起来，但在目标 2 中，我们将与这种重要的临床表型联系起来。研究该候选水平衡基因中的罕见变异在钠血症个体和家庭中以及在 NHLBI 资助的和其他基于人群的极端钠血症中的作用。在目标 3 中，我们试图确定我们的主要变异 -该基因关键调控区域中的常见多态性 - 代表因果变异，基于其在基因内的位置、其影响的基序以及调控该基因的已知分子机制。