Genetic determinants of water balance in the elderly

老年人水平衡的遗传决定因素

• 批准号: 7569443
• 负责人: DAVID M COHEN
• 金额: $ 12.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569443
• 关键词: 3' Untranslated Regions; Accounting; Address; Affect; Aging; Alleles; Alzheimer' s Disease; Amino Acid Substitution; Amino Acids; Biological; Biological Assay; Brain; Cations; Cell Nucleus; Chronic Disease; Chronically Ill; Clinical; Comorbidity; Cultured Cells; DNA; Data Set; Disease; Diuretics; Elderly; Equilibrium; Exhibits; Exons; Functional RNA; Genes; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Haplotypes; Human; Hypernatremia; Hyponatremia; In Vitro; Inherited; Introns; Life; Link; Liquid substance; Measurement; Mediating; Membrane; Messenger RNA; Metabolism; Minor; Mus; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Population; Postoperative Period; Precipitating Factors; Prevalence; Property; Protein Engineering; Proteins; RNA Splicing; Relative (related person); Reporter Genes; Research; Risk; Role; Serum; Single Nucleotide Polymorphism; Sodium; Stress; Testing; Translations; Water; base; cohort; human subject; in vitro Assay; in vitro testing; indexing; interest; mRNA Stability; male; men; mortality; osteoporosis with pathological fracture; promoter; protein expression; protein function; response; sensor; thiazide

DESCRIPTION (provided by applicant): Disorders of systemic water balance (i.e., hypo- and hypernatremia) are extremely common among the elderly, chronically ill, and hospitalized patients. Hyponatremia, particularly if severe, is associated with markedly increased mortality, even in the absence of evident comorbidity. The cation channel TRPV4 is believed to be the long-sought central sensor of systemic hypotonicity: it is activated by relative water excess (i.e., hyponatremia/hypotonicity); it is expressed in the osmoregulatory nuclei of the brain; and mice deleted for the gene exhibit abnormal water metabolism. We have identified two non-synonymous single nucleotide polymorphisms in the human TRPV4 gene (i.e., resulting in an amino acid change). When expressed in cultured cells, TRPV4 protein encoded by either of these minor alleles is less responsive to hypotonicity than is the wild-type channel. Furthermore, we show in preliminary fashion that one minor allele is significantly over-represented among human subjects with aberrant water metabolism. In 209 healthy elderly subjects, this TRPV4 allele was approximately five-fold more prevalent among subjects with a serum sodium concentration of < 135 mEq/liter than in normonatremic subjects. We propose to investigate this functionally significant TRPV4 minor allele on two levels. In Aim I, we will phase, in preliminary fashion, the haplotype(s) that includes this minor allele of interest, to exclude the possibility that a tightly linked polymorphism contributes to the hyponatremic phenotype. Any newly identified polymorphisms in the haplotype will be tested for functional significance using in vitro assays addressing transcription, mRNA stability and splicing, and protein function. In Aim II, we will test for an association between the TRPV4 minor allele and the presence of clinical hyponatremia in a second, much larger, data set. Banked serum and DNA from 6000 healthy elderly subjects in the Osteoporotic Fractures in Men (MrOS) study will be analyzed for serum sodium concentration (as an index of water balance) and TRPV4 genotype, respectively. With this combined approach, we will address the physiological significance of the TRPV4 alleles at the cellular level, and at the human population level. The over-all objective is to prospectively identify patients at increased risk for potentially life-threatening retention of free water, for example when treated with hypotonic fluids in the post-operative setting, or when treated with a thiazide-type diuretic. Many chronic disease states and several widely prescribed medications can cause dangerous abnormalities in water balance in an unpredictable fashion; perturbed water balance can generally only be detected through measurement of the serum sodium concentration . This proposal aims to increase our understanding of disorders of water balance among the elderly, and to genetically identify patients who may be at increased risk for potentially life-threatening retention of water.

描述（由申请人提供）：全身水平衡紊乱（即，低钠血症和高钠血症）在老年人、慢性病患者和住院患者中极为常见。低钠血症，特别是严重的低钠血症，即使没有明显的合并症，也与死亡率显著增加相关。阳离子通道TRPV 4被认为是长期寻找的全身性低渗的中枢传感器：它被相对过量的水激活（即，低钠血症/低渗）;它在大脑的神经调节核中表达;缺失该基因的小鼠表现出异常的水代谢。我们已经鉴定了人TRPV 4基因中的两种非同义单核苷酸多态性（即，导致氨基酸变化）。当在培养的细胞中表达时，由这些次要等位基因中的任一个编码的TRPV 4蛋白对低渗的响应比野生型通道低。此外，我们表明，在初步的方式，一个次要等位基因是显着过度的水代谢异常的人类受试者。在209名健康老年受试者中，TRPV 4等位基因在血清钠浓度< 135 mEq/L的受试者中的流行率约为正常钠血症受试者的5倍。 我们建议在两个水平上研究这个功能显著的TRPV 4次要等位基因。在目的I中，我们将以初步的方式对包括该次要等位基因的单倍型进行分相，以排除紧密连锁的多态性导致低钠血症表型的可能性。将使用涉及转录、mRNA稳定性和剪接以及蛋白质功能的体外试验检测单倍型中任何新鉴定的多态性的功能意义。在目标II中，我们将在第二个更大的数据集中测试TRPV 4次要等位基因与临床低钠血症之间的关联。将分别分析来自男性骨质疏松性骨折（MrOS）研究中6000例健康老年受试者的库存血清和DNA的血清钠浓度（作为水平衡指标）和TRPV 4基因型。通过这种结合的方法，我们将在细胞水平和人群水平上解决TRPV 4等位基因的生理意义。总体目标是前瞻性识别潜在危及生命的游离水潴留风险增加的患者，例如在术后环境中接受低渗液体治疗或接受噻嗪类利尿剂治疗时。 许多慢性疾病状态和几种广泛使用的处方药可以以不可预测的方式导致水平衡的危险异常;水平衡紊乱通常只能通过测量血清钠浓度来检测。该提案旨在增加我们对老年人水平衡紊乱的理解，并从遗传学上确定可能存在潜在危及生命的水潴留风险增加的患者。