Modeling DNA Diversity in Reverse Cholesterol Transport

胆固醇反向转运中 DNA 多样性的建模

• 批准号: 8044111
• 负责人: ERIC A. BOERWINKLE
• 金额: $ 114.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044111
• 关键词: Address; Alcohol consumption; Alleles; Architecture; Atherosclerosis; Back; Candidate Disease Gene; Cholesterol; Communities; Complement; Coronary artery; Coronary heart disease; DNA; DNA Resequencing; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Environment; Evaluation; Excretory function; Exons; Family; Frequencies; Funding; Gender; Gene Frequency; Gene Targeting; Genealogy; General Population; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hypertension; Individual; LDL Cholesterol Lipoproteins; Link; Liver; Measures; Methodology; Methods; Modeling; Mus; Peripheral; Persons; Phenotype; Plasma; Population; Population Genetics; Process; Proteins; RNA Splicing; Relative (related person); Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Sampling; Scanning; Single Nucleotide Polymorphism; Site; Smoking; Tail; Testing; Time; Tissues; Translating; Variant; Weight; base; clinical practice; clinically relevant; cohort; disorder risk; empowered; expectation; genetic linkage analysis; genetic variant; genome wide association study; high risk; indexing; insertion/deletion mutation; particle; programs; research clinical testing; reverse cholesterol transport; young adult

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.

描述（由申请人提供）：该多机构研究项目的长期目标是阐明一般人群中高密度脂蛋白 - 胆固醇（HDL-C）的遗传结构，并评估该遗传信息的附加值价值，以预测超出既定风险因素以外的预测冠心病（CHD）。将特别强调低频变化的贡献，以及变体变化和变体环境对HDL-C的遗传结构的贡献。在AIM 1中，我们将在年轻人（Cardia）同类中的400个个体的样本中，将20个与HDL相关的基因重新配置，他们在多个检查中始终具有较高的（顶级四分位数； n = 200）或低（底部四分位数； n = 200）plasma hdl-c浓度。根据三个标准选择并确定了要研究的基因：i）关于该项目研究资金的第一个研究周期中与HDL-C相关的发现，ii）ii）被复制的链接峰值，并导致HDL-C水平的变化在基因范围内的小鼠中，以及III）在基因组范围内的HDL-C研究中被复制。为了检测这些基因中低频变异对HDL-C变化的贡献的证据，我们将测试HDL-C分布的一个极端序列变化是否与另一极端的序列变化是否不同，并且在极端的分布是否与中性期望不同。全基因组的关联研究或测序HDL-C分布的极端都不会揭示变体对大量人群中遗传结构的贡献。 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（即变体变体相互作用）的相互作用；随着环境变化的指标，例如性别，体重，吸烟和饮酒（即变体环境相互作用）以及时间（即纵向分析）。 AIM 4将评估目标2和3中确定的变化的能力，这是有助于HDL-C的遗传结构：i）预测在社区中大动脉粥样硬化风险（ARIC）研究（ARIC）研究（ARIC）研究（n = 15,792）的大动脉粥样硬化风险（n = 15,792），以及在AriC中的危险中预测，在ARIC的研究中，在大型动脉粥样硬化风险中是否具有较低的HDL-C（<40 mg/dl）。拟议的研究是由DRS的三个链接的R01进行的。 Boerwinkle，Clark和Sing。降低的高密度脂蛋白胆固醇（HDL-C）是冠心病（CHD）的危险因素。该研究计划的目的是确定影响大量人口中HDL-C的基因，并询问这些遗传变异是否预测了冠心病的传统危险因素超出了冠心病。这项研究不仅考虑了每个基因变异的个体影响，而且还考虑了它们与其他基因以及与环境的相互作用。