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（HDL-C）的遗传结构，并评估该遗传信息对于预测超出既定风险因素的冠心病（CHD）事件的附加价值。将特别强调低频变异、变异体与变异体以及变异体与环境的相互作用对 HDL-C 遗传结构的贡献。在 AIM 1 中，我们将对来自年轻人冠状动脉风险发展 (CARDIA) 队列的 400 名个体样本中的 20 个 HDL 相关基因进行重新测序，这些个体在多次检查中血浆 HDL-C 浓度始终保持高（上四分位数；n=200）或低（下四分位数；n=200）。待研究的基因根据三个标准进行选择和优先排序：i) 在本项目第一轮研究资助中有关其与 HDL-C 关联的发现，ii) 处于复制连锁峰下并导致转基因小鼠中 HDL-C 水平发生变化，以及 iii) 在 HDL-C 全基因组关联研究中得到复制。为了检测这些基因的低频变异对 HDL-C 变异的贡献的证据，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。全基因组关联研究或 HDL-C 分布极端值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 队列进行以 AIM 1 中进行的重测序为特征的遗传变异的基因分型，并使用所有基因型数据（即 SNP 和插入/删除）来量化每个基因变异对整个人群中 HDL-C 血浆浓度个体间变异的边缘基因型 (AIM 2) 和相互作用 (AIM 3) 影响。 AIM 3将考虑每个基因中变异的影响与同一基因和其他基因中变异的影响的相互作用（即变体-变体相互作用）；环境变化指数，如性别、体重、吸烟和饮酒（即变量与环境的相互作用）和时间（即纵向分析）。 AIM 4 将评估 AIMS 2 和 3 中确定的变异对 HDL-C 遗传结构的影响的能力：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出现低 HDL-C（<40 mg/dl），以及 ii) 在 ARIC 研究中预测超出既定风险因素范围的 CHD 事件。拟议的研究是由 Drs. 的三个相连的 R01 实现的。布尔温克尔、克拉克和辛。高密度脂蛋白胆固醇（HDL-C）降低是冠心病（CHD）的危险因素。该研究项目的目标是确定在广大人群中影响 HDL-C 的基因，并探究这些基因变异是否可以预测冠心病（CHD），而不是传统的危险因素。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.