MOLECULAR GENETICS OF LIPID VARIATION IN OUTBRED POPULATIONS

该项目的总体目标是在近亲繁殖的人群中确定导致冠状动脉疾病(CAD)的遗传决定因素及其风险因素，特别是甘油三酯和相关的脂代谢。我们建议通过识别易患动脉粥样硬化-家族性混合性高脂血症(FCHL)的主要血脂异常疾病的脂和脂蛋白变异基因来完成这一点，利用系统基因组扫描的力量，并通过鼠-人联会和相关人类研究的发现，最终分析位置候选基因。我们将使用这些方法来识别负责任的基因和致病变异。这项研究利用了马斯垂赫特大学(荷兰)的Tierk de Bruin博士及其同事确定的大量深入研究FCHL家庭的集合。在当前的周期中，我们对一些候选基因进行了连锁研究。此外，我们完成了对这个FCHL家族材料中的240个个体的10 cM基因组扫描。这项工作导致了FCHL及其相关数量性状可能的区域的识别。这个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55个具有良好特征的FCHL家系的研究样本，包括1012个个体，测试与FCHL的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正在对更多的家庭和个人进行表型鉴定)。第二个目标是精细定位支持连锁的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(芬兰的Project V和/或鼠-人同时性)，以及数量性状的共生作图。为了选择具有最好的连锁证据的基因座，第三个目标是测试在AIM 2中确定的5个样本中的基因座：芬兰FCHL样本(项目V)和4个CAD家庭人口，这些样本已经由合作研究人员Leslie Raffel博士(洛杉矶)、Jonathan Cohen(达拉斯)、Ron Krauss(Berkeley)和他们的同事收集。四是在目标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的变体，通过在表型的极端处对选定的个体进行测序，以及在有和没有连锁标记的情况下进行。这些变异将通过传递不平衡检验和基因关联方法在表现出连锁的样本中测试它们对脂类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血脂变异和易患冠心病的方式，最终导致新的治疗和预防性干预。

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.