Genetics of Cardiovascular Disease in Chronic Kidney Disease

摘要 心血管疾病是慢性肾脏疾病(CKD)患者死亡和残疾的主要原因 但对于导致慢性肾脏病心血管疾病负担增加的遗传因素，我们知之甚少。 全基因组关联研究已经确定了几个心血管疾病和亚临床疾病的基因座 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 在复杂性状中的重要作用。我们建议测试基因组的调控区域，这些区域与 使用将基因表达数据与全基因组基因类型相结合的方法获得心血管结果。 我们将使用来自慢性肾功能不全队列的全面的临床和生物标志物数据 (CRIC)，这是一项对慢性肾脏病患者的多种族纵向研究。CRIC已对心血管疾病做出裁决 所有参与者的事件和研究已经记录了动脉粥样硬化和 慢性肾脏病中的心血管疾病。我们将对心血管结果进行全基因组关联研究 使用从Trans-Omics获得的多种族参考小组的密集归因型 精准医学(TOPMed)计划，以确定CKD患者的新基因座(目标1)。确定推定的 CKD中与心血管疾病相关的因果基因，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方法和表达 (目标3)。该项目使用创新的概念和方法，将文字记录和基因分型整合在一起 心血管疾病高危人群的基因发现。该项目与NHLBI的使命相一致 减轻心血管疾病负担。

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.