Genetic & Functional Analyses of Chromosome 1 Hypertension Susceptibility Genes

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• 批准号: 7645874
• 负责人: YEN PEI CHRISTY CHANG
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645874
• 关键词: 1q23; 3' Untranslated Regions; ATP phosphohydrolase; Accounting; Address; Adult; Affect; Alleles; Amish; Arteries; Be++ element; Beryllium; Blood Pressure; Blood Vessels; Candidate Disease Gene; Cell Adhesion Molecules; Cell membrane; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1; Complex; Coronary heart disease; DNA Sequence; Development; Diagnosis; E-Selectin; Endothelium; Enzymes; Essential Hypertension; Etiology; Event; Founder Generation; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; Gene Expression; Gene Expression Regulation; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Guanosine Triphosphate Phosphohydrolases; Heart; Heredity; Heritability; Heterogeneity; Human; Human Chromosomes; Hypertension; Incidence; Indium; Inheritance Patterns; Inherited; Intervention; Kidney; Kidney Diseases; Lead; Life Style; Link; Linkage Disequilibrium; Maps; Measures; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Muscle Tonus; Mutation; Na(+)-K(+)-Exchanging ATPase; Older Population; Pathogenesis; Pathway interactions; Pattern; Peripheral Resistance; Pharmaceutical Preparations; Phenotype; Plasma; Play; Polyadenylation; Polyadenylation Pathway; Predisposition; Protein Family; Proteins; Public Health; Publishing; Quality of life; Rattus; Renal function; Research Personnel; Risk; Risk Factors; Role; SELE gene; Signal Transduction; Smooth Muscle; Sodium Chloride; Stress; Stroke; Susceptibility Gene; Testing; Variant; Vasoconstrictor Agents; Work; absorption; base; blood pressure regulation; cardiovascular risk factor; cost; enzyme activity; gain of function; gene environment interaction; genome-wide linkage; hypertension treatment; insight; mRNA Precursor; microbial alkaline proteinase inhibitor; mortality; programs; protein structure; response; salt sensitive; trait

DESCRIPTION (provided by applicant): Hypertension (HTN) is a major risk factor for cardiovascular events. Its etiology is multifactorial and poorly understood. This application aims to elucidate the molecular mechanisms that link variants in 3 newly identified HTN susceptibility genes and is motivated by several lines of evidence: (1) Multiple linkage studies of HTN- related phenotypes suggest the presence of a blood pressure (BP) locus on human chromosome 1q23-q32; (2) BP-related QTLs have been mapped to the homologous region of human 1q23-q32 in mouse and rat; (3) In humans, polymorphisms in three HTN candidate genes that map to 1q23-q32, ATP1B1, RGS5, and SELE, have been associated with BP levels in multiple studies; and (4) The phenotypic effects of these genes appear to be cumulative, accounting for 2-4 mmHg BP difference individually and up to 10 mmHg when combined. All three genes encode proteins that have putative functions important in BP regulation. However, exactly how variants in these 3 genes perturb BP homeostasis, are not known. To address these issues, we will carry out a multifaceted analysis to identify and characterize potentially functional variants in these three genes. In Aim 1, we will characterize all common variants in RGS5 and SELE in effort to identify additional SNPs that may be more strongly associated with BP variation than those already known. In Aim 2, we will select the potentially functional SNPs identified from Aims 1 and 2, and test these for gene- environment interactions in an independent population of Old Order Amish, a unique closed founder population that is relatively homogeneous with respect to genetic background and lifestyle. Specifically, we will test for associations of these SNPs with BP responses to cold pressor stress and dietary salt interventions to gain insights into the mechanisms by which these genes may influence BP regulation. In Aim 3, we will perform functional testing of an hypothesized polymorphic functional U/GU-rich element in the 3'UTR of ATP1B1 by assessing the impact of the sequence variants on polyadenylation of the mRNA. Knowing the causative alleles of these 3 genes, and the pathways compromised by such alleles can lead to discovery of accurate and low-cost pre-symptomatic diagnosis and customized treatment for HTN. Given the high incidence of HTN and the high mortality and morbidity attributed to HTN, these advances will impact substantially on the quality of life of millions of people worldwide suffering from HTN-related complications.

描述（由申请人提供）：高血压（HTN）是心血管事件的主要危险因素。其病因是多因素的且知之甚少。本申请旨在阐明连接 3 个新发现的 HTN 易感基因变异的分子机制，并受到以下几方面证据的推动：(1) HTN 相关表型的多重连锁研究表明，人类染色体 1q23-q32 上存在血压 (BP) 基因座； (2) BP相关QTL已在小鼠和大鼠中定位到人类1q23-q32的同源区域； (3) 在人类中，多项研究表明，映射到 1q23-q32、ATP1B1、RGS5 和 SELE 的三个 HTN 候选基因的多态性与血压水平相关； (4) 这些基因的表型效应似乎是累积的，单独造成 2-4 mmHg 血压差异，组合起来可达 10 mmHg。所有这三个基因都编码在血压调节中具有重要推定功能的蛋白质。然而，这 3 个基因的变异究竟如何扰乱血压稳态尚不清楚。为了解决这些问题，我们将进行多方面的分析，以识别和表征这三个基因的潜在功能变异。在目标 1 中，我们将描述 RGS5 和 SELE 中所有常见变异的特征，以努力识别与 BP 变异相关性比已知的 SNP 更紧密的其他 SNP。在目标 2 中，我们将选择从目标 1 和 2 中识别出的潜在功能性 SNP，并测试这些在旧秩序阿米什人的独立群体中的基因-环境相互作用，这是一个独特的封闭创始人群体，在遗传背景和生活方式方面相对同质。具体来说，我们将测试这些 SNP 与血压对冷加压应激和饮食盐干预的反应之间的关联，以深入了解这些基因可能影响血压调节的机制。在目标 3 中，我们将通过评估序列变异对 mRNA 多腺苷酸化的影响，对 ATP1B1 3'UTR 中假设的富含 U/GU 的多态性功能元件进行功能测试。了解这 3 个基因的致病等位基因以及受这些等位基因影响的途径可以发现准确且低成本的症状前诊断和针对 HTN 的定制治疗。鉴于高血压的高发病率以及高血压引起的高死亡率和发病率，这些进展将对全世界数百万患有高血压相关并发症的人的生活质量产生重大影响。