Modeling DNA Diversity in Reverse Cholesterol Transport

描述（由申请人提供）：这项多机构研究项目的长期目标是阐明普通人群中高密度脂蛋白-胆固醇（HDL-C）的遗传结构，并评估该遗传信息在预测冠心病（CHD）事件方面的附加价值。将特别强调低频变异、变异-变异和变异-环境相互作用对HDL-C遗传结构的贡献。在AIM 1中，我们将对400名来自年轻人冠状动脉风险发展（CARDIA）队列的样本中的20个hdl相关基因进行重测序，这些个体在多次检查中始终具有高（前四分位数，n=200）或低（后四分位数，n=200）血浆HDL-C浓度。待研究基因的选择和优先顺序基于三个标准：i)在本项目研究资助的第一个周期中发现它们与HDL-C的关联，ii)在复制的连锁峰下并导致转基因小鼠中HDL-C水平的变化，以及iii)在HDL-C的全基因组关联研究中被复制。为了检测这些基因的低频变异对HDL-C变异的贡献证据，我们将测试HDL-C分布的一个极端的序列变异是否与另一个极端不同，以及极端的分布是否与中性预期不同。无论是全基因组关联研究还是高密度脂蛋白- c分布的极端测序，都无法揭示变异对整个人群遗传结构的贡献。因此，我们将对整个CARDIA队列进行基因分型，以确定AIM 1中进行的重测序所表征的遗传变异，并使用所有基因型数据（即snp和插入/缺失）来量化每个基因变异的边际基因型（AIM 2）和相互作用（AIM 3）对整个人群血浆中HDL-C浓度的个体间差异的影响。AIM 3将考虑每个基因变异的影响与同一基因和其他基因变异的影响之间的相互作用（即变异-变异相互作用）；具有环境变化指数，如性别、体重、吸烟和饮酒（即变量-环境相互作用）和时间（即纵向分析）。AIM 4将评估AIMS 2和AIMS 3中确定的变异对HDL-C遗传结构的影响能力：1)在社区动脉粥样硬化风险研究（n=15,792）中预测一个人是否会有低HDL-C (<40 mg/dl)，以及ii)在ARIC研究中预测冠心病的发生，超出既定风险因素的范围。这项拟议的研究是由三位博士的r01组成的。Boerwinkle， Clark和Sing。高密度脂蛋白胆固醇（HDL-C）降低是冠心病（CHD）的危险因素。这项研究计划的目标是确定影响人群中HDL-C的基因，并询问这些基因变异是否能预测冠心病，而不是传统的风险因素。这项研究不仅考虑了每个基因变异的个体影响，还考虑了它们与其他基因和环境的相互作用。

DESCRIPTION (provided by applicant): The long-term goal of this Multi-Institutional Research Project grant is to elucidate the genetic architecture of high density lipoprotein-cholesterol (HDL-C) in the general population and to evaluate the added value of this genetic information for predicting incident coronary heart disease (CHD) beyond the established risk factors. Special emphasis will be given to the contribution of low frequency variation, and variant-variant and variant-environment interactions to the genetic architecture of HDL-C. In AIM 1 we will resequence 20 HDL-related genes in a sample of 400 individuals from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort who consistently have high (top quartile; n=200) or low (bottom quartile; n=200) plasma HDL-C concentrations across multiple examinations. The genes to be studied have been selected and prioritized based on three criteria: i) findings about their association with HDL-C in the first cycle of research funding of this project, ii) as being under replicated linkage peaks and resulting in changes in HDL-C levels in genetically modified mice, and iii) as being replicated in genome-wide association studies of HDL-C. To detect evidence for the contribution of low frequency variations in these genes to HDL-C variation we will test whether the sequence variation in one extreme of the HDL-C distribution differs from the other extreme and whether the distributions in the extremes differ from neutral expectations. Neither genome-wide association studies or sequencing the extremes of the HDL-C distribution will reveal the contribution of variants to the genetic architecture in the population-at-large. Therefore, we will genotype the entire CARDIA cohort for the genetic variations characterized by the resequencing carried out in AIM 1, and use all of the genotype data (i.e. SNPs and insertion/deletions) to quantify the marginal genotypic (AIM 2) and interaction (AIM 3) effects of each gene variant on inter-individual variation in plasma concentrations of HDL-C in the population-at-large. AIM 3 will consider interactions of the effects of variations in each gene with the effects of variations in the same gene and in other genes (i.e. variant-variant interactions); with indices of environmental variations such as gender, weight, smoking and alcohol consumption (i.e. variant-environment interaction) and with time (i.e. longitudinal analyses). AIM 4 will evaluate the ability of the variations identified in AIMS 2 and 3 as contributing to the genetic architecture of HDL-C: i) to predict whether a person will have low HDL-C (<40 mg/dl) in the large Atherosclerosis Risk in Communities (ARIC) study (n=15,792), and ii) to predict incident CHD in the ARIC study beyond that afforded by the established risk factors. The proposed research is made possible by three linked R01s from Drs. Boerwinkle, Clark and Sing. Reduced high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary heart disease (CHD). The goal of this research program is to identify the genes influencing HDL-C in the population-at-large, and to ask if these genetic variations predict CHD beyond the traditional risk factors. This research not only considers the individual effects of variation in each gene, but their interactions with other genes and with the environment.