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: 6450038
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450038
• 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种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。我们建议通过使用系统基因组扫描的力量，通过小鼠-人类合成和相关人类研究的发现以及最终的位置候选基因分析，鉴定易导致动脉粥样硬化-家族性合并高脂血症（FCHL）的主要血脂异常疾病的脂质和脂蛋白变异基因来实现这一目标。我们将使用这些方法来识别负责基因和致病变异。这项研究利用了马斯特里赫特大学（荷兰）的Tierk de Bruin博士及其同事对FCHL家族的大量深入研究。在当前周期中，我们对一些候选基因进行了连锁研究。此外，我们完成了240个FCHL家族材料个体的10 cM基因组扫描。这项工作已经确定了FCHL的可能区域及其相关的数量性状。该项目的第一个目标是将系统的10厘米扫描扩展到我们目前可用的研究样本，包括55个特征明确的FCHL家族，包括1012个个体，测试与FCHL数量性状及其相关数量性状的联系。（与此同时，我们的合作者D. de Bruin正在对其他家庭和个人进行表型分析）。第二个目标是根据多种标准，精确绘制出对连锁支持最好的12个染色体区域，这些标准包括：lod分数、其他研究（芬兰人和/或小鼠-人类同质性的V项目）中连锁的证据，以及数量性状的重合图谱。为了选择具有最佳关联证据的基因座，第三个目标是在5个样本中测试目标2中确定的基因座：芬兰FCHL样本（项目V）和4个CAD家庭人群，这些样本已经由合作研究者博士收集。莱斯利·拉斐尔（洛杉矶），乔纳森·科恩（达拉斯），罗恩·克劳斯（伯克利）和他们的同事。第四步是在目标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。这将通过描述候选位置的变异，通过在表型的极端和有或没有连锁标记的情况下对选定的个体进行测序来完成。变体将通过传递不平衡测试和基因型关联方法测试其对样品中显示连锁的脂质和脂蛋白变异的影响。我们未来周期的长期目标是了解这些变异影响脂质变异和CAD易感性的方式，最终导致新的治疗和预防性干预。