MOLECULAR GENETICS OF LIPID VARIATION IN OUTBRED POPULATIONS

远交群体脂质变异的分子遗传学

• 批准号: 6564846
• 负责人: Jerome I Rotter
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564846
• 关键词: atherosclerosis; blood lipoprotein metabolism; clinical research; coronary disorder; familial hyperlipoproteinemia; family genetics; genetic mapping; genetic polymorphism; genetic susceptibility; human population genetics; human subject; molecular pathology; quantitative trait loci; restriction fragment length polymorphism

The overall goal of this Project is to identify genetic determinants contributing to coronary artery disease (CAD) and its risk factors in outbred populations, with a particular emphasis on triglyceride and associated lipid metabolism. We propose to accomplish this by identifying the genes for lipid and lipoprotein variation in the major dyslipidemic disorder predisposing to atherosclerosis-familial combined hyperlipidemia (FCHL), by using the power of a systematic genome scan, augmented by findings from mouse-human synteny and allied human studies and culminating in the analyses of positional candidate genes. We will use these approaches to identify responsible genes and causative variations. This study capitalizes on a large and intensively studied collection of FCHL families, ascertained by Dr. Tierk de Bruin and colleagues, of the University of Maasstricht (The Netherlands). In the current cycle, we conducted linkage studies of a number of candidate genes. In addition we completed a 10 cM genome scan on 240 individuals in this FCHL family material. This work has led to the identification of possible regions for FCHL and its associated quantitative traits. The first Aim of this project is to extend the systematic 10 cM scan to our currently available study sample of 55 well characterized FCHL families comprising 1012 individuals, testing for linkage to both the quantitative trait of FCHL and its associated quantitative traits. (In parallel, additional families and individuals are being phenotyped by our collaborator, D. de Bruin). The second Aim is to fine map the 12 chromosomal regions have the best support for linkage, base don a multiple criteria: the lod scores, evidence for linkage in other studies (Project V in the Finns and/or mouse-human synteny), and co-incident mapping of quantitative traits. In order to select the loci having the best evidence for linkage, the third Aim is to test the loci identified in Aim 2 in 5 samples: the Finnish FCHL sample (Project V), and 4 CAD family populations, already collected by collaborating investigators Drs. Leslie Raffel (Los Angeles, Jonathan Cohen (Dallas), Ron Krauss (Berkeley) and their colleagues. The fourth is to test positional candidate genes in the areas with the best evidence for linkage as determined by Aims 1-3. This will be done by delineating the variants of the positional candidates, by sequencing selected individuals at the extremes of the phenotypes and with and without the linked markers. The variants will be tested for their effects on lipid and lipoprotein variations in the samples exhibiting linkage by the transmission disequilibrium test and genotype association approaches. Our long term goal for future cycles is to understand the manner in which these variations affect lipid variation and predispose to CAD, leading eventually to new therapies and preventive interventions.

该项目的总体目标是确定远交人群中导致冠状动脉疾病（CAD）及其危险因素的遗传决定因素，特别强调甘油三酯和相关脂质代谢。我们建议通过识别易患动脉粥样硬化-家族性混合型高脂血症（FCHL）的主要血脂异常疾病中的脂质和脂蛋白变异基因来实现这一目标，通过使用系统基因组扫描的力量，通过小鼠-人类同线性和人类相关研究的发现来增强，并最终分析位置候选基因。我们将使用这些方法来确定责任基因和致病变异。这项研究利用了大量深入研究的FCHL家族，由马斯特里赫特大学（荷兰）的Tierk de Bruin博士及其同事确定。在本周期中，我们对一些候选基因进行了连锁研究。此外，我们对该FCHL家族材料中的240名个体完成了10 cM基因组扫描。这项工作导致FCHL及其相关的数量性状的可能区域的识别。该项目的第一个目的是将系统的10 cM扫描扩展到我们目前可用的研究样本55个良好的特征FCHL家族，包括1012个个体，测试FCHL的数量性状及其相关的数量性状的连锁。(In与此同时，我们的合作者D. de Bruin）。第二个目标是精细绘制对连锁有最佳支持的12个染色体区域，基于多个标准：lod评分、其他研究中的连锁证据（芬兰人的项目V和/或小鼠-人同线性），以及数量性状的同时作图。为了选择具有最佳连锁证据的基因座，第三个目标是在5个样本中测试目标2中鉴定的基因座：芬兰FCHL样本（项目V）和4个CAD家族群体，这些样本已经由合作研究者Leslie Raffel博士（洛杉矶）、Jonathan Cohen博士（达拉斯）、罗恩克劳斯（伯克利）及其同事收集。第四个是在目标1-3确定的具有最佳连锁证据的区域中测试位置候选基因。这将通过描绘位置候选物的变体，通过在表型的极端处以及在有和没有连锁标记物的情况下对所选择的个体进行测序来完成。将通过传递不平衡检验和基因型关联方法检测变异体对显示连锁的样本中脂质和脂蛋白变异的影响。我们对未来周期的长期目标是了解这些变化影响脂质变化和易患CAD的方式，最终导致新的治疗和预防干预。