Genetic determinants of triglyceride-rich lipoproteins to disentangle CHD risk

富含甘油三酯脂蛋白的遗传决定因素可解决冠心病风险

• 批准号: 9505042
• 负责人: Gina Marie Peloso
• 金额: $ 9.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505042
• 关键词: Atherosclerosis; Automobile Driving; Biological; Blood; Candidate Disease Gene; Cardiovascular Diseases; Cause of Death; Cholesterol; Clinical; Code; Coronary heart disease; DNA; Data; Data Aggregation; Detection; Evaluation; Event; Framingham Heart Study; Gene Frequency; Gene Proteins; Genetic; Genetic Determinism; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Grain; Human; Individual; Joints; LDL Cholesterol Lipoproteins; Lipids; Lipoprotein (a); Lipoproteins; Location; Measurement; Measures; Mediating; Multi-Ethnic Study of Atherosclerosis; Myocardial Infarction; NMR Spectroscopy; National Heart, Lung, and Blood Institute; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Phenotype; Plasma; Play; Population; Proteins; Public Health; Randomized; Research; Risk; Risk Factors; Role; Sampling; Standardization; Testing; Therapeutic; Time; Trans-Omics for Precision Medicine; Triglycerides; United States; Variant; adjudicate; cardiovascular risk factor; cohort; endophenotype; epidemiological model; follow-up; genetic variant; genome sequencing; genomic variation; heart disease risk; insight; interest; population based; programs; standard of care; targeted treatment; therapeutic development; whole genome

Project Abstract Cardiovascular disease, including coronary heart disease (CHD) and myocardial infarction (MI), is the leading cause of death in the United States. Genetic evidence has accumulated that triglyceride levels are a causal risk factor for CHD, beyond an individual's LDL-C. Triglyceride-rich lipoproteins (TRLs) contain cholesterol as well as triglycerides. An unanswered question is whether the cholesterol or the triglyceride content in TRLs drives the causal relationship of plasma TG levels on CHD risk. This application will leverage two longitudinal population-based cohorts: The Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). These cohorts represent over 7,000 individuals that have (1) nuclear magnetic resonance spectroscopy (NMR) lipoprotein profiling with estimates of cholesterol and triglyceride content of TRLs, (2) adjudicated CHD events and subclinical atherosclerosis measures over time, and (3) whole genome sequencing (WGS) data available through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. WGS provides an avenue for a complete evaluation of all genomic variation (both protein-coding and regulatory) across the allele frequency spectrum, while TRL subspecies provide fine-grained lipoprotein measurements. Aim 1 will harmonize the phenotypic and genotypic data at a central location and predict the joint effect of the cholesterol and triglyceride content of TRLs on CHD risk in FHS and MESA. Aim 2 will identify statistically independent variants associated with TRL subspecies and associate these with risk of CHD. An association analysis will be conducted using standardized lipoprotein profiles to identify genetic variants associated with each TRL subspecies. Measures of significance and annotation will identify the biologically plausible variants in genes (protein-coding) or in regulatory regions of the genome. 95% credible sets of SNPs will be determined to find candidate genes of interest or DNA regulatory regions. The effect of the identified genetic variants on each lipoprotein endo- phenotype will be compared. Finally, the genetic variation associated with lipoprotein subspecies will be associated with risk of CHD. This proposal will dive down a layer of depth in investigating the genetics of lipoproteins, and infer the role of the cholesterol and triglyceride content of the TRLs on risk of CHD. Identifying the genetic markers associated with TRLs subspecies will lead to a better understanding of the atherogenic mechanisms associated with triglyceride-rich lipoproteins in the population. Moreover, understanding the role of the triglyceride and cholesterol content that is driving the relationship with CHD is important to development of therapeutics through identifying better targets for therapy.

项目摘要 心血管疾病，包括冠心病（CHD）和心肌梗死（MI），是导致 美国的死因。遗传学证据已经积累，甘油三酯水平是一个因果风险 CHD的因素，超出个体的LDL-C。富含甘油三酯的脂蛋白（TRL）也含有胆固醇 作为甘油三酯。一个尚未回答的问题是TRL中的胆固醇或甘油三酯含量是否会驱动 血浆TG水平与CHD风险的因果关系。此应用程序将利用两个纵向 基于人群的队列研究：FHS研究和多种族动脉粥样硬化研究 （梅萨）。这些队列代表了7,000多名具有（1）核磁共振光谱的个体 (NMR)脂蛋白谱分析，估计TRL的胆固醇和甘油三酯含量，（2）判定的CHD 事件和亚临床动脉粥样硬化指标随时间的变化，以及（3）全基因组测序（WGS）数据 NHLBI Trans-Omics for Precision Medicine（TOPMed）计划。WGS提供了一种途径， 对于所有基因组变异（包括蛋白质编码和调节）的完整评估， 光谱，而TRL亚种提供细粒度脂蛋白测量。目标1将协调 表型和基因型数据，并预测胆固醇和甘油三酯的联合作用 FHS组和梅萨组的冠心病危险性TRLs含量。目标2将确定统计学上独立的变量， 与TRL亚种相关，并将其与CHD风险相关联。关联分析将使用 标准化的脂蛋白谱，以确定与每个TRL亚种相关的遗传变异。措施 显著性和注释将识别基因（蛋白质编码）或 基因组的调节区域。将确定95%可信的SNP集，以找到候选基因。 感兴趣的区域或DNA调节区域。确定的遗传变异对每种脂蛋白内切酶的影响 将比较表型。最后，与脂蛋白亚种相关的遗传变异将是 与CHD的风险有关。这一建议将深入研究遗传学的一层 脂蛋白，并推断TRLs的胆固醇和甘油三酯含量对CHD风险的作用。识别 与TRL亚种相关的遗传标记将有助于更好地了解动脉粥样硬化的发生， 与人群中富含磷脂酰肌醇的脂蛋白相关的机制。此外，了解 甘油三酯和胆固醇的含量是驱动冠心病的关系是重要的发展， 通过确定更好的治疗靶点来治疗。