Genetics of Cardiovascular Disease in Chronic Kidney Disease

摘要 心血管疾病是慢性肾脏病（CKD）患者死亡和残疾的主要原因 但对CKD患者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。 动脉粥样硬化特征研究还表明，调节基因表达的遗传变异具有 在复杂性状中的重要作用。我们建议测试基因组的调控区域， 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局。 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患者的多种族和纵向研究。CRIC已裁定心血管 所有参与者中的事件，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局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插补基因型， 精准医学（TOPMed）计划，以确定CKD患者的新基因座（目标1）。以鉴定推定 在CKD中，我们将使用预测的基因表达， 方法和表达来自祖先匹配数据集（Aim 2）和多组织的数量性状基因座 (Aim 3）。该项目使用创新的概念和方法，通过整合转录本和基因型， 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的负担。

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.