HYPERGEN: GENETICS OF LEFT VENTRICULAR HYPERTROPHY

HYPERGEN：左心室肥大的遗传学

• 批准号: 6650357
• 负责人: Donna K Arnett
• 金额: $ 46.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-10 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650357
• 关键词: cardiovascular disorder epidemiology; clinical research; disease /disorder proneness /risk; echocardiography; family genetics; gene environment interaction; genetic markers; genetic screening; genetic susceptibility; human genetic material tag; human population genetics; human subject; hypertension; linkage mapping; quantitative trait loci; ventricular hypertrophy

DESCRIPTION: (Adapted from the Investigator's Abstract) Left ventricular (LV) hypertrophy is a common condition that profoundly affects morbidity and mortality from cardiovascular diseases. The long-term objective of this study, the HyperGEN (Genetics of LV Hypertrophy) study is to identify genetic predictors influencing susceptibility to LV hypertrophy and cardiac dysfunction. During the initial project period, echocardiography was performed on 3,000 black and white participants in the parent HyperGEN study, a multicenter study designed to determine the genetics of hypertension. As a result, most study participants were family members ascertained on hypertension. The investigators carried out genome-wide linkage analyses, and identified chromosomal regions with a high probability of harboring genetic loci contributing the interindividual variation in LV and myocardial contractility. In this renewal application, the investigators propose to extend this work with three complementary specific aims to further understanding of the genetics of echocardiography phenotypes. Specific Aim 1 proposes to further characterize genomic regions contributing to interindividual variation in LV mass and related cardiographic phenotypes among 1,900 hypertensive sibs, 400 of their normotensive offspring, and an additional 720 offspring to be recruited by the parent HyperGEN study beginning in Summer, 2000. To enhance statistical power to detect genetic linkage and association for narrowing genomic regions, the investigators will conduct echocardiography on 480 of these offspring who are not being phenotyped by HyperGEN. Specific Aim 2 will consist of identifying positional candidate genes within the implicated genomic regions based on their known function and chromosomal location. To facilitate this aim, the investigators will use results from rat models to identify regions of homology in humans with know gene locations in the rat. Specific Aim 3 will investigate whether genes contributing to LV mass in hypertensives also contribute to the phenotype in normotensives, and thereby characterize the full spectrum of LV mass and related cardiac phenotypes. This will require using the randomly ascertained sample from the HyperGEN study to recruit and examine sibling and offspring of normotensive individuals who have LV mass in the upper 75th percentile of the LV mass distribution. The investigators will examine allelic variation in the candidate genes identified in specific Aim 2 in this normotensive sample ascertained on increased LV mass. Finally, the investigators will replicate these findings in a second population-based sample of normotensive with LV hypertrophy and their age and sex matched controls. Overall, the study represents a complementary approach, from animal to human, to further understanding of the genetic architecture of LV hypertrophy.

描述：（改编自研究者摘要）左心室（LV） 肥大是一种常见的疾病，严重影响发病率， 心血管疾病的死亡率。这项研究的长期目标是， HyperGEN（左心室肥大遗传学）研究是为了确定遗传 影响左室肥厚和心脏病易感性的预测因子 功能障碍在项目初期，进行了超声心动图检查， 在父母HyperGEN研究的3,000名黑人和白色参与者中， 一项旨在确定高血压遗传学的多中心研究。作为 结果，大多数研究参与者是家庭成员， 高血压研究人员进行了全基因组连锁分析， 确定染色体区域具有高概率的遗传性， 导致LV和心肌细胞中个体间变异的基因座 收缩性 在这份更新申请中，研究人员建议将这项工作扩展到 三个互补的具体目标，以进一步了解遗传学的 超声心动图表型具体目标1建议进一步描述 导致LV质量个体间变异的基因组区域， 在1,900名高血压同胞中， 血压正常的后代，另外720名后代将被招募 2000年夏季开始的母公司HyperGEN研究。为了增强统计能力 为了检测缩小基因组区域的遗传连锁和关联， 研究人员将对其中480名后代进行超声心动图检查， 没有被HyperGEN分型 具体目标2将包括识别位置候选基因， 基于其已知功能和染色体特征， 位置.为了实现这一目标，研究人员将使用大鼠的结果， 模型来识别人类中具有已知基因位置的同源区域， 老鼠具体目标3将研究是否有基因导致LV质量 在高血压患者中也有助于正常血压患者的表型，从而 表征LV质量和相关心脏表型的全谱。这 将需要使用HyperGEN研究中随机确定的样本， 招募并检查血压正常个体的同胞和后代， LV质量分布的上75百分位数中的LV质量。的 研究人员将检查候选基因中的等位基因变异， 在特定目标2中，在该血压正常的样品中确定LV质量增加。 最后，研究人员将在一秒钟内复制这些发现， 基于人群的血压正常伴LV肥大的样本及其年龄， 性别匹配的对照组。总的来说，这项研究是一种补充办法， 从动物到人类，以进一步了解遗传结构， 左心室肥大。