Genetics of water balance

水平衡的遗传学

• 批准号: 7889338
• 负责人: DAVID M COHEN
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889338
• 关键词: Accounting; Address; Adverse effects; Agreement; Ancillary Study; Antidepressive Agents; Antipsychotic Agents; Candidate Disease Gene; Caring; Chronic; Chronically Ill; Clinical; Code; Cohort Studies; Complication; DNA; Data; Data Aggregation; Data Set; Databases; Defect; Development; Disease; Diuretics; Duct (organ) structure; Elderly; Electrolytes; Elements; Equilibrium; Ethnic Origin; Exclusion Criteria; Familial disease; Family; Framingham Heart Study; Funding; Gene Frequency; Generations; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomics; Genotype; Heart; Heredity; Heritability; Human; Human Genetics; Hypernatremia; Hyponatremia; Hypothalamic structure; In Vitro; Intervention; Medical; Metabolism; Minority; Morbidity - disease rate; Mutation; National Health and Nutrition Examination Survey; National Heart, Lung, and Blood Institute; Parents; Patients; Pharmaceutical Preparations; Phenotype; Population; Protein Isoforms; Proteins; Regulation; Regulator Genes; Risk; Series; Serum; Severities; Single Nucleotide Polymorphism; Sodium; Vasopressin Receptor; Water; aquaporin-2; base; cohort; density; gene environment interaction; genetic regulatory protein; genome wide association study; indexing; interest; men; mortality; non-genetic; novel; osteoporosis with pathological fracture; outcome forecast; public health relevance; sensor

DESCRIPTION (provided by applicant): Disorders of water metabolism are common among the elderly, the acutely and chronically ill, and among patients taking certain medications. Abnormal water balance is detected clinically by an increase or decrease in the serum sodium concentration (hyper- and hyponatremia, respectively). Hyponatremia is the most common of the electrolyte abnormalities and even a modest reduction in serum sodium concentration (i.e., water excess) is associated with substantial morbidity and mortality. Rare mutations in water-regulatory genes cause familial abnormalities of water balance; however, these account for only a small minority of cases of hyponatremia. Our preliminary data strongly support the heritability of systemic water balance; in addition, we have identified a non-synonymous polymorphism in a water-regulatory gene that is associated with hyponatremia in several human populations. 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 from medications or disease states statistically associated with the development of hyponatremia. The over-arching objective of this proposal is to define the genetics of systemic water balance on a population-wide basis using data derived from prior large-scale NHLBI-sponsored (and other NIH-sponsored) cohort and family-based studies. In Aim I, we will quantify the heritability of water balance in additional human populations using data from family-based components of large NHLBI-funded cohort studies. In Aim II, we will identify human genetic polymorphisms associated with aberrant water balance via a candidate gene approach. Banked genomic DNA previously obtained in the course of large NHLBI-funded cohort studies will be used. In Aim III, genome-wide association studies will be performed to identify in an unbiased fashion genetic polymorphisms associated with aberrant systemic water balance in large cohorts. For this Aim, we will use high-density genotyping data generated as part of ongoing analysis in several NHLBI-funded cohort studies. Through this combination of approaches made possible by NHLBI-supported data generation, we hope to elucidate the human genetic basis for systemic water balance and identify polymorphisms associated with hypo- and hypernatremia. PUBLIC HEALTH RELEVANCE: Disorders of water metabolism cause substantial morbidity and mortality among the elderly, the acutely and chronically ill, and among patients taking certain commonly- prescribed medications. Our preliminary data indicate that heredity determines, in large part, which patients are most susceptible to this complication. We will use an array of data generated in the course of multiple large NHLBI-funded cohort studies to elucidate the human genetic basis for abnormalities in systemic water balance.

描述（由申请人提供）： 水代谢紊乱在老年人、急慢性病患者以及服用某些药物的患者中很常见。临床上通过血清钠浓度的增加或减少（分别为高钠血症和低钠血症）来检测水平衡异常。低钠血症是最常见的电解质异常，即使血清钠浓度适度降低（即水分过多）也会导致严重的发病率和死亡率。水调节基因的罕见突变会导致家族性水平衡异常；然而，这些仅占低钠血症病例的一小部分。我们的初步数据有力地支持了系统水平衡的遗传性；此外，我们还发现了与几个人群中的低钠血症相关的水调节基因的非同义多态性。此前还没有研究涉及全人群水平衡的遗传学问题，目前还没有办法预测哪些人最容易受到与低钠血症发生统计相关的药物或疾病状态的影响。该提案的首要目标是使用从先前由 NHLBI 资助（和其他 NIH 资助）的大规模队列和家庭研究中获得的数据，在全人群的基础上定义系统水平衡的遗传学。在目标 I 中，我们将使用 NHLBI 资助的大型队列研究中基于家庭的数据来量化其他人群的水平衡遗传力。在目标 II 中，我们将通过候选基因方法识别与水平衡异常相关的人类遗传多态性。将使用先前在 NHLBI 资助的大型队列研究过程中获得的基因组 DNA 库。在目标 III 中，将进行全基因组关联研究，以公正的方式识别与大群体中系统水平衡异常相关的遗传多态性。为了实现这一目标，我们将使用 NHLBI 资助的多项队列研究中正在进行的分析的一部分生成的高密度基因分型数据。通过 NHLBI 支持的数据生成所实现的方法组合，我们希望阐明全身水平衡的人类遗传基础，并识别与低钠血症和高钠血症相关的多态性。 公众健康相关性：水代谢紊乱导致老年人、急性和慢性病患者以及服用某些常用药物的患者发病率和死亡率很高。我们的初步数据表明，遗传在很大程度上决定了哪些患者最容易出现这种并发症。我们将使用 NHLBI 资助的多项大型队列研究过程中生成的一系列数据来阐明系统水平衡异常的人类遗传基础。