Genetic determinants of triglyceride-rich lipoproteins to disentangle CHD risk

项目摘要 心血管疾病，包括冠心病和心肌梗死，是主要的 在美国的死因。遗传证据已经积累，甘油三酯水平是一种致病风险 除了个人的低密度脂蛋白-C外，还有冠心病的危险因素。富含甘油三酯的脂蛋白(TRL)也含有胆固醇 作为甘油三酯。一个悬而未决的问题是，TRL中的胆固醇或甘油三酯含量是否会推动 血浆甘油三酯水平与冠心病风险的因果关系。此应用程序将利用两个纵向 基于人群的队列：弗雷明翰心脏研究(FHS)和动脉粥样硬化的多种族研究 (梅萨)。这些队列代表了超过7,000名具有(1)核磁共振波谱的个体 (核磁共振)脂蛋白图谱和TRL中胆固醇和甘油三酯含量的估计，(2)判定冠心病 随时间推移的事件和亚临床动脉粥样硬化测量，以及(3)全基因组测序(WGS)数据 可通过NHLBI Trans-Omics for Precision Medicine(TOPMed)计划获得。WGS提供了一条途径 对于等位基因频率上的所有基因组变异(包括蛋白质编码和调节)的完整评估 而TRL亚种则提供细粒脂蛋白测量。目标1将协调 中心位置的表型和基因数据，并预测胆固醇和甘油三酯的联合作用 FHS和MESA对冠心病风险的TRLS含量。AIM 2将确定相关的统计独立变量 与TRL亚型相关，并将其与冠心病风险相关联。将使用以下工具进行关联分析 标准化的脂蛋白图谱，以确定与每个TRL亚种相关的遗传变异。衡量标准 重要性和注解将识别基因(蛋白质编码)或 基因组的调控区域。将确定95%可信的SNPs集合来寻找候选基因 兴趣或DNA监管区域。已确定的遗传变异对每个脂蛋白内切的影响。 表型将进行比较。最后，与脂蛋白亚种相关的遗传变异将是 与冠心病的风险相关。这一提议将深入研究人类的遗传学。 脂蛋白，并推断TRL的胆固醇和甘油三酯含量对冠心病风险的作用。识别 与TRLS亚种相关的遗传标记将有助于更好地理解动脉粥样硬化的形成。 人群中与富含甘油三酯的脂蛋白相关的机制。更重要的是，理解 推动与CHD关系的甘油三酯和胆固醇含量对 通过确定更好的治疗靶点进行治疗。

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.