Modeling DNA Diversity in Reverse Cholesterol Transport

描述(由申请人提供)：这项多机构研究项目拨款的长期目标是阐明普通人群中高密度脂蛋白-胆固醇(HDLC)的遗传结构，并评估这种遗传信息对预测发生冠心病(CHD)的附加值，而不是现有的危险因素。将特别强调低频变异以及变异-变异和变异-环境相互作用对高密度脂蛋白-C遗传结构的贡献。在目标1中，我们将对来自青年冠状动脉风险发展(CARDIA)队列的400名个体中的20个高密度脂蛋白相关基因进行重新排序，这些人在多次检查中血浆高密度脂蛋白-C浓度始终高(上四分位数；n=200)或低(下四分位数；n=200)。要研究的基因已经根据三个标准进行了选择和优先排序：i)在该项目的第一个研究资助周期中，关于它们与高密度脂蛋白-C的关联的发现；ii)在复制的链接峰下并导致转基因小鼠的高密度脂蛋白-C水平的变化；以及iii)在高密度脂蛋白-C的全基因组关联研究中被复制。为了找出这些基因的低频变异对高密度脂蛋白-C变异的影响的证据，我们将测试高密度脂蛋白-C分布的一个极端的序列变异是否与另一个极端不同，以及极端分布是否不同于中性预期。无论是全基因组关联研究，还是对高密度脂蛋白-C分布的极端情况进行测序，都不会揭示变异对普通人群遗传结构的贡献。因此，我们将对整个CARDIA队列中以AIM 1中进行的重新测序为特征的遗传变异进行分型，并使用所有的基因型数据(即SNPs和插入/缺失)来量化每个基因变异对一般人群中血浆高密度脂蛋白浓度个体间差异的边缘基因型(AIM 2)和交互作用(AIM 3)的影响。目标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)；与性别、体重、吸烟和饮酒等环境变异指数的相互作用(即变异-环境相互作用)以及与时间的相互作用(即纵向分析)。目标4将评估AIMS 2和AIMS 3中确定的有助于高密度脂蛋白-C遗传结构的变异的能力：i)在大型社区动脉粥样硬化风险(ARIC)研究(n=15,792)中预测一个人是否会有低高密度脂蛋白-C(&lt；40 mg/dl)，以及ii)在ARIC研究中预测CHD事件的发生，超出已确定的危险因素。这项拟议的研究是由来自Boerwinkle、Clark和Sing博士的三个连锁R01实现的。降低的高密度脂蛋白胆固醇(HDLC)是冠心病(CHD)的危险因素。这项研究计划的目标是确定在普通人群中影响高密度脂蛋白-C的基因，并询问这些基因变异是否可以预测传统危险因素以外的冠心病。这项研究不仅考虑了每个基因变异的个体效应，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.