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（由适用提供）：低钠血症是总体水的相对过量，是最常遇到的电解质异常；它在最古老的，急性和长期疾病以及服用某些药物的患者中尤为普遍。即使是适度的水（即等离子体钠浓度的适度降低）也与大量发病率和死亡率有关。水调节基因的罕见突变会导致孟德尔疾病的水平衡；但是，这些仅解释了少数低钠血症病例。我们的初步数据表明，血浆钠浓度高度个性。也就是说，水平平衡在健康无关的个体之间有所不同，但在任何一个人中，随着时间的流逝都是相对恒定的。我们应用了这一原则，以表明血浆钠浓度是可遗传的。我们完善了这种特征，以消除或减少非遗传因素的贡献（例如药物和合并症）。在全基因组关联分析中，一个具有高生物学合理性的基因，但以前与与该表型相关的全身水平平衡没有联系。先前的研究尚无人口范围的水平遗传学，目前尚无预测谁对响应易感药物或疾病状态的最大风险患有低钠血症的风险。该提案的整个目标是使用先前的大规模NHLBI赞助的（和其他）同类研究得出的数据来定义系统水平的人群基因。在AIM 1中，我们将使用来自NHLBI资助的和国际人群的同伙的数据来扩展和复制我们的发现元基因组范围的协会研究。我们先前的努力导致我们将这种表型与具有浓厚兴趣和高生物学合理性的基因中的常见变异联系起来，但以前与这种重要的临床表型没有联系。在AIM 2中，我们将研究稀有变体在该候选水平衡基因中的作用，以及在NHLBI资助的NHLBI资助和其他基于人群的同类群体中的dysnatremic极端。在AIM 3中，我们试图确定我们的铅变体（该基因的关键调节区域中的常见多态性）代表因果变体，它基于其在基因中的位置，其影响的基础和已知的分子机制来调节该基因。