Trans-omic Analysis of Alcohol Consumption and its Relation to Cardiovascular Disease

酒精消耗及其与心血管疾病关系的跨组学分析

基本信息

批准号：
10209156
负责人：
Chunyu Liu
金额：
$ 50.08万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209156
关键词：
Address Alcohol consumption Alcohols American Applications Grants Biological Markers Calories Cardiovascular Diseases Complex Computer software Coronary heart disease DNA Methylation Databases Dimensions Disease Outcome Framingham Heart Study Future Gene Expression Genes Genotype-Tissue Expression Project Goals Healthy Eating Human Interdisciplinary Study Investigation Ischemic Stroke Knowledge Life Style Measures Mediating Mediation Medical Mendelian randomization Methods Molecular Molecular Profiling Molecular Target Multiomic Data Neurodegenerative Disorders Participant Pathway Analysis Pathway interactions Pattern Phenotype Plasma Plasma Proteins Prevention Process Proteins Proteome Proteomics Resources Risk Factors Sampling Testing Treatment Cost adjudicate alcohol abuse therapy alcohol effect bioinformatics tool cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor causal variant cohort cost efficient dietary guidelines high throughput technology metabolome metabolomics methylation biomarker methylome modifiable lifestyle factors multidisciplinary multiple omics novel polygenic risk score protein metabolite public health priorities random forest transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Alcohol consumption is an important modifiable lifestyle risk factor for cardiovascular disease (CVD). Advances in high-throughput technologies have made it possible to measure and analyze a variety of ‘omics’, that is, DNA methylation (methylome), gene expression (transcriptome), protein (proteome) and metabolite (metabolome), in relation to alcohol consumption and CVD in a cost-efficient manner. In this grant proposal, we will test the hypothesis that alcohol consumption alters multiple molecular processes across different “omics” dimensions and these molecular intermediates mediate alcohol’s effects on CVD. To test this hypothesis, we will assemble a multidisciplinary team to test five Specific Aims. In Aim 1, we will first identify alcohol-associated transcriptomic markers. We will then examine the associations of alcohol-associated transcriptomic markers with incident CVD (fatal and nonfatal coronary heart disease and ischemic stroke), and test whether these transcriptomic markers mediate the effect of alcohol intake on incident CVD. We will construct polygenic risk scores to examine the potential causal relationships between alcohol intake, transcriptomic markers, and incident CVD. We will also conduct a two-sample Mendelian randomization (MR) analysis to further test and quantify the causal relationships. In Aims 2 and 3, we will identify alcohol-associated proteomic (Aim 2) and metabolomic (Aim 3) markers and will test the relationship between alcohol, omics markers and CVD using similar methods outlined in Aim 1. Many alcohol-associated DNA methylation markers have been identified by our prior study in >13,000 participants. Therefore, in Aim 4, we will examine the relations of alcohol-associated DNA methylation markers with incident CVD using similar methods outlined in Aim 1. In Aim 5, we will integrate alcohol-associated multi-omics markers to identify key pathways and multi-omics modules associated with alcohol intake and CVD. We will perform Random Forest analysis to identify additional alcohol-associated multi- omics markers. We will also perform network analyses to identify modules of alcohol-associated multi-omics markers. We will examine the relationships between these identified multi-omics markers with incident CVD, and will functionally annotate these markers using bioinformatics tools (e.g., ENCODE, GTEx, Human Metabolome Database, and UniProt). With the completion of this project, we will highlight the novel molecular targets for both alcohol-associated CVD risk prevention and treatment. In addition, we will generate a multi-omics biomarker database of alcohol intake with tailored software to facilitate the future investigations of alcohol’s relations with other non-communicable diseases such as neurodegenerative diseases.

项目概要饮酒是心血管疾病（CVD）的一个重要的可改变生活方式的危险因素。高通量技术的发展使得测量和分析各种“组学”（即 DNA）成为可能甲基化（methylome）、基因表达（transcriptome）、蛋白质（proteome）和代谢物（metabolome），在这项拨款提案中，我们将测试以具有成本效益的方式与消费酒精和 CVD 相关的问题。假设饮酒会改变不同“组学”维度的多个分子过程这些分子中间体介导了酒精对 CVD 的影响。为了检验这一假设，我们将组建一个多学科团队来测试五个具体目标，在目标 1 中，我们首先将进行测试。然后我们将鉴定与酒精相关的转录组标记。与CVD事件（致死性和非致死性冠心病以及缺血性中风）相关的转录组标记物，以及我们将构建测试这些转录组标记是否介导酒精摄入对 CVD 的影响。多基因风险评分来检查酒精摄入、转录组学之间的潜在因果关系我们还将进行两个样本孟德尔随机化 (MR) 分析以进一步进行。测试并量化因果关系在目标 2 和 3 中，我们将确定与酒精相关的蛋白质组（目标 2）。和代谢组学（目标 3），并将使用以下方法测试酒精标记物、组学标记物和 CVD 之间的关系目标 1 中概述的类似方法。许多与酒精相关的 DNA 甲基化标记已通过我们之前对超过 13,000 名参与者进行的研究因此，在目标 4 中，我们将研究与酒精相关的关系。使用目标 1 中概述的类似方法对事件 CVD 进行 DNA 甲基化标记。在目标 5 中，我们将整合与酒精相关的多组学标记，以确定与酒精相关的关键途径和多组学模块我们将进行随机森林分析，以确定其他与酒精相关的多种因素。我们还将进行网络分析来识别与酒精相关的多组学模块。我们将检查这些已识别的多组学标记与事件 CVD 之间的关系，以及将使用生物信息学工具（例如 ENCODE、GTEx、人类代谢组）对这些标记进行功能注释随着该项目的完成，我们将重点介绍这两个项目的新分子靶点。此外，我们将生成多组学生物标志物。带有定制软件的酒精摄入量数据库，以促进未来对酒精与酒精的关系的调查其他非传染性疾病，例如神经退行性疾病。