Genetic & Functional Analyses of Chromosome 1 Hypertension Susceptibility Genes

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• 批准号: 7880821
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880821
• 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风险因素。其病因是多因素和知之甚少。本申请的目的是阐明3个新发现的HTN易感基因中的变异的分子机制，并受到以下几条证据的启发：（1）HTN相关表型的多重连锁研究表明，人类染色体1 q23-q32上存在血压（BP）位点;（2）在小鼠和大鼠中，BP相关的QTL定位在人类1 q23-q32的同源区域;（3）在人类中，定位于1 q23-q32、ATP 1B 1、RGS 5和SELE的三个HTN候选基因的多态性在多项研究中与血压水平相关;（4）这些基因的表型效应似乎是累积的，单独解释2-4 mmHg BP差异，当组合时高达10 mmHg。所有这三个基因编码的蛋白质在血压调节中具有重要的推定功能。然而，这3个基因中的变异体究竟如何扰乱BP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，以确定和表征这三个基因中的潜在功能变体。在目标1中，我们将描述RGS 5和SELE中的所有常见变体，以努力识别可能比已知的SNP与BP变异更密切相关的其他SNP。在目标2中，我们将选择从目标1和2中鉴定的潜在功能性SNP，并在一个独立的旧秩序阿米什人群体中测试这些SNP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与冷加压应激和饮食盐干预的BP反应的关联，以深入了解这些基因可能影响BP调节的机制。在目标3中，我们将通过评估序列变体对mRNA多聚腺苷酸化的影响，对ATP 1B 1的3 'UTR中的一个假设的多态性功能U/GU丰富元件进行功能测试。了解这3个基因的致病等位基因以及这些等位基因损害的途径可以导致发现HTN的准确和低成本的症状前诊断和定制治疗。鉴于HTN的高发病率以及归因于HTN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。