Genetic & Functional Analyses of Chromosome 1 Hypertension Susceptibility Genes

描述(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在人类染色体1q23-q32上存在一个血压(BP)基因座；(2)在小鼠和大鼠中，与BP相关的QTL已被定位到人类1q23-q32的同源区；(3)在人类中，定位于1q23-q32、ATP1B1、RGS5和SELE3个HTN候选基因的多态与血压水平有关；和(4)这些基因的表型效应似乎是累积的，单独解释2-4毫米汞柱的BP差异，当组合时最高可达10毫米汞。这三个基因都编码蛋白质，这些蛋白质在BP调节中具有重要的假定功能。然而，这3个基因中的变异是如何扰乱BP的动态平衡的，目前还不清楚。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。在目标1中，我们将描述RGS5和SELE中所有常见的变异，以努力识别更多与BP变异可能比已知的更强关联的SNP。在目标2中，我们将选择从目标1和2中确定的潜在功能SNPs，并在Old Order Amish的独立群体中测试这些SNP的基因-环境交互作用，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。具体地说，我们将测试这些SNP与血压对冷加压压力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体对mRNA多聚腺化的影响，对ATP1B1的3‘UTR区中一个假想的多态功能元件U/Gu进行功能测试。了解这3个基因的致病等位基因，以及这些等位基因所影响的通路，可以发现准确和低成本的HTN症状前诊断和个性化治疗。鉴于HTN的高发病率和高死亡率和高发病率，这些进展将对全球数百万患有HTN相关并发症的人的生活质量产生重大影响。

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.