HYPERGEN: GENETICS OF LEFT VENTRICULAR HYPERTROPHY

HYPERGEN：左心室肥大的遗传学

• 批准号: 6200180
• 负责人: Donna K Arnett
• 金额: $ 100.02万
• 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/6200180
• 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《调查者摘要》)左心室(LV) 肥大是一种常见的疾病，它深刻地影响着发病率和 心血管疾病的死亡率。这项研究的长期目标是 HyperGEN(左心室肥厚遗传学)研究是为了确定遗传 影响左室肥厚和心肌肥厚易感性的预测因素 功能障碍。在最初的项目阶段，进行了超声心动图检查。 在父母HyperGEN研究中的3000名黑人和白人参与者中， 旨在确定高血压遗传学的多中心研究。作为一名 结果，大多数研究参与者是被确定的家庭成员。 高血压。研究人员进行了全基因组的连锁分析，并 识别出高概率携带遗传基因的染色体区域 左心室和心肌的个体间变异的基因座 伸缩性。 在这份续签申请中，调查人员提议将这项工作扩展到 三个相辅相成的具体目标，以进一步了解人类的遗传学 超声心动图表型。具体目标1建议进一步描述 导致左心室重量和左心室重量个体间差异的基因组区域 1900名高血压同胞中400人的相关心动图表型 血压正常的后代，以及额外的720名后代将由 家长HyperGEN研究于2000年夏季开始。增强统计力量 为了检测缩小基因组区域的遗传连锁和关联， 调查人员将对其中480名子女进行超声心动图检查，他们是 没有被HyperGEN表型。 具体目标2将包括识别 基于已知功能和染色体的隐含基因组区域 地点。为了促进这一目标，调查人员将使用来自老鼠的结果 识别具有已知基因位置的人类同源区域的模型 那只老鼠。特定目标3将调查是否有导致左心室重量的基因 高血压患者的表型也有助于正常血压患者的表型，因此 描述左心室肿块的全谱和相关的心脏表型。这 将要求使用从HyperGEN研究中随机确定的样本来 招募和检查血压正常的人的兄弟姐妹和后代 左心室质量分布的上75%百分位数。这个 研究人员将检查已确定的候选基因中的等位基因变异 在特定的目标2中，在这个血压正常的样本中，确定了左心室质量的增加。 最后，调查人员将在一秒钟内复制这些发现 正常血压伴左室肥厚的人群样本及其年龄和 性别匹配的对照组。总体而言，这项研究代表了一种补充方法， 从动物到人类，以进一步了解生物的遗传结构 左心室肥厚。