Genetics of Cardiovascular Disease in Chronic Kidney Disease

慢性肾脏病心血管疾病的遗传学

基本信息

批准号：
10593089
负责人：
Nora Franceschini
金额：
$ 44.82万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593089
关键词：
Acceleration Accounting Address Adult African American African American population Age Aorta Atherosclerosis Biological Biological Markers Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Chromosome Mapping Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Cohort Studies Collaborations Complex Coronary artery Coronary heart disease Data Data Set Disease Disease susceptibility Eligibility Determination European ancestry Event Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genome Genomic Segment Genotype Genotype-Tissue Expression Project Goals Heart Heart failure Individual Ischemic Stroke Kidney Knowledge Linkage Disequilibrium Longitudinal Studies Medicare Mental Depression Methods Mission Modeling Multi-Ethnic Study of Atherosclerosis Myocardial Infarction National Heart, Lung, and Blood Institute Nucleic Acid Regulatory Sequences Outcome Participant Pathway interactions Patients Peripheral arterial disease Persons Predisposition Publishing Quantitative Trait Loci Risk Factors Role Stroke Susceptibility Gene Testing Tissues Trans-Omics for Precision Medicine Transcript Untranslated RNA Variant Veterans Whole Blood adjudication biomarker identification brain tissue burden of illness cardiovascular disorder risk cardiovascular risk factor causal variant clinical center cohort coronary artery calcification disability disease prognosis disorder prevention gene discovery genetic risk factor genetic variant genome sequencing genome wide association study genome-wide health difference high risk high risk population innovation insight monocyte multi-ethnic novel pleiotropism population health precision medicine programs recruit secondary outcome targeted treatment trait transcriptome whole genome

项目摘要

ABSTRACT Cardiovascular disease is a main cause of death and disability in individuals with chronic kidney disease (CKD) but little is known on the genetic factors accounting for the increased cardiovascular disease burden in CKD. Genome-wide association studies have identified several loci for cardiovascular disease and subclinical atherosclerosis traits. Studies have also shown that genetic variants that regulate gene expression have important roles in complex traits. We propose to test regulatory regions of the genome associated with cardiovascular outcomes using approaches that integrate gene expression data to genome-wide genotypes. We will use the comprehensive clinical and biomarker data from the Chronic Renal Insufficiency Cohort (CRIC), a multi-ethnic and longitudinal study of individuals with CKD. CRIC has adjudicated cardiovascular events in all participants and the study has already documented a high burden of atherosclerosis and cardiovascular disease in CKD. We will perform genome-wide association studies of cardiovascular outcomes using dense imputed genotypes from multi-ethnic reference panels obtained from the Trans-Omics for Precision Medicine (TOPMed) Program to identify new loci in individuals with CKD (Aim 1). To identify putative causal genes associated with cardiovascular disease in CKD, we will use predicted gene expression approaches and expression quantitative trait loci from ancestry-matched datasets (Aim 2) and multi-tissues (Aim 3). This project uses innovative concepts and approaches by integrating transcripts and genotypes for gene discovery in a high-risk population for cardiovascular disease. This project aligns with NHLBI mission to reduce the burden of CVD.

抽象的心血管疾病是慢性肾病 (CKD) 患者死亡和残疾的主要原因但对于导致 CKD 心血管疾病负担增加的遗传因素知之甚少。全基因组关联研究已经确定了心血管疾病和亚临床疾病的几个位点动脉粥样硬化的特征。研究还表明，调节基因表达的遗传变异在复杂性状中发挥重要作用。我们建议测试与相关的基因组调控区域使用将基因表达数据整合到全基因组基因型的方法来评估心血管结果。我们将使用来自慢性肾功能不全队列的综合临床和生物标志物数据（CRIC），一项针对 CKD 患者的多种族纵向研究。 CRIC已裁定心血管所有参与者都发生了事件，并且该研究已经记录了动脉粥样硬化的高负担 CKD 中的心血管疾病。我们将进行心血管结果的全基因组关联研究使用从 Trans-Omics 获得的多种族参考组的密集估算基因型精准医学 (TOPMed) 计划旨在识别 CKD 患者的新基因座（目标 1）。识别假定的 CKD 中与心血管疾病相关的致病基因，我们将使用预测的基因表达来自祖先匹配数据集（目标 2）和多组织的数量性状基因座的表达方法和表达（目标 3）。该项目通过整合转录本和基因型来使用创新的概念和方法心血管疾病高危人群的基因发现。该项目符合 NHLBI 的使命：减轻CVD负担。