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，但了解甚少。该应用旨在阐明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上存在一个血压（BP）位点；(2) bp相关的qtl在小鼠和大鼠中被定位到人1q23-q32的同源区域；(3)在人类中，在多个研究中，三个HTN候选基因的多态性与BP水平相关，这些基因位于1q23-q32、ATP1B1、RGS5和SELE；(4)这些基因的表型效应似乎是累积的，单独造成2-4 mmHg的血压差异，组合时可达10 mmHg。这三个基因编码的蛋白质在血压调节中具有重要的功能。然而，这3个基因的变异究竟是如何扰乱BP稳态的，目前尚不清楚。为了解决这些问题，我们将进行多方面的分析，以确定和表征这三个基因的潜在功能变异。在Aim 1中，我们将描述RGS5和SELE的所有常见变异，以努力识别可能比已知的与BP变异更密切相关的其他snp。在目标2中，我们将选择目标1和目标2中鉴定的潜在功能snp，并在Old Order Amish的独立人群中测试这些基因-环境相互作用，Old Order Amish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Aim 3中，我们将通过评估序列变异对mRNA聚腺苷化的影响，对ATP1B1 3' utr中假设的多态功能U/ gu富元素进行功能测试。了解这3种基因的致病等位基因，以及这些等位基因所破坏的途径，可以发现准确、低成本的HTN症状前诊断和定制治疗。鉴于HTN的高发病率以及HTN导致的高死亡率和发病率，这些进展将对全世界数百万患有HTN相关并发症的人的生活质量产生重大影响。