Dissecting the impact of clonal hematopoiesis on atherosclerosis using multiscale 'omics

使用多尺度组学剖析克隆造血对动脉粥样硬化的影响

• 批准号: 10242879
• 负责人: Seyedeh Maryam Zekavat
• 金额: $ 3.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242879
• 关键词: Address; Adhesions; Affect; Age; Aging; Animal Model; Antibodies; Arterial Fatty Streak; Atherosclerosis; Bioinformatics; Biological; Blood Cells; Bone Marrow; CD14 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Carrier State; Cause of Death; Clinical; Clinical Data; Clonal Expansion; Coronary Arteriosclerosis; DNA; Data; Development; Event; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Human; Human Genetics; Individual; Inflammatory; Influentials; JAK2 gene; Knock-out; Knowledge; Lead; Learning; Link; Measures; Medicine; Mendelian randomization; Multi-Ethnic Study of Atherosclerosis; Mus; Mutation; Myocardial; Myocardial Infarction; National Heart, Lung, and Blood Institute; Participant; Pathway interactions; Phagocytes; Phagocytosis; Physicians; Prevalence; Prevention; Risk; Risk Factors; Scientist; Signal Transduction; Somatic Mutation; Therapeutic; Training; Trans-Omics for Precision Medicine; Variant; age related; atherosclerosis risk; cardiovascular risk factor; causal variant; chemokine; cohort; coronary artery calcification; coronary artery calcium; cytokine; disorder risk; early onset; exome sequencing; genetic risk factor; genetic variant; genome sequencing; genome wide association study; heart imaging; improved; macrophage; monocyte; novel; programs; receptor; risk prediction; therapeutic target; transcriptome sequencing; transcriptomics; whole genome

Title: Dissecting the impact of clonal hematopoiesis on atherosclerosis using multi-scale ‘omics Description: Despite current risk prediction, prevention, and therapeutic strategies, coronary artery disease (CAD) continues to remain the leading cause of death in the US and worldwide. I aim to investigate a novel mechanism contributing towards CAD: age-related somatic mutations in bone marrow hematopoietic stem cells predisposing to clonal hematopoiesis (clonal hematopoiesis of indeterminate potential, CHIP). CHIP-related somatic mutations in peripheral blood cells, typically in DNMT3A, TET2, JAK2, and ASXL1, increase risk of CAD by 2-4 fold, independent of other cardiovascular risk factors and similar in magnitude to risk conferred from traditional risk factors. Hematologic knock-out of one of these CHIP driver genes, Tet2, in mice causes larger atherosclerotic lesions. Transcriptomics of cultured bone-marrow-derived macrophages from these mice show significant changes in expression among genes in inflammatory pathways (ex: cytokines/chemokines and phagocytic lysosomal function). CHIP carriers with somatic variants in TET2 have significantly reduced major adverse cardiovascular events when treated with canakinumab, an IL-1B antibody, suggesting that specific therapeutic strategies may be especially influential in CHIP carriers. My overall hypothesis is that whole genome sequencing (WGS) will identify germline genetic variants influencing CHIP carrier state that causally affect atherosclerosis, that transcriptomic analyses in human monocytes will discover biological pathways influenced by CHIP, and that combining germline and somatic data will uncover protective germline genetic variants that may be leveraged towards future therapeutic targets. Specific aims: By integrating germline whole genome sequencing data with somatic variant calls, transcriptomics, cardiac imaging, and clinical data from over 107,000 individuals from the NHLBI Trans-Omics for Precision Medicine consortium, I aim to improve understanding of the mechanistic link between CHIP and atherosclerosis. In aim 1, I will associate germline genetic predisposition to CHIP with coronary artery calcium levels from cardiac CT, and with CAD. This will assess whether CHIP carrier state causally influences subclinical atherosclerosis and clinical atherosclerosis. In aim 2, I will discover the biological networks influenced by CHIP using transcriptomics from human monocytes. In aim 3, I will characterize how germline genetic factors interact with CHIP somatic variants to influence the progression of CHIP to CAD.

标题：使用多尺度的'Omics剖析克隆造血对动脉粥样硬化的影响 描述：尽管当前的风险预测，预防和治疗策略，冠状动脉疾病 （CAD）继续在美国和全球造成死亡的主要原因。我的目的是调查小说 有助于CAD的机制：骨髓造血干细胞中与年龄相关的体细胞突变 易感克隆造血（不确定电势的克隆造血，芯片）。芯片有关 外周血细胞中的体细胞突变通常在DNMT3A，TET2，JAK2和ASXL1中增加 CAD乘以2-4倍，与其他心血管危险因素无关，幅度相似 来自传统的风险因素。这些芯片驱动器基因TET2的血液学敲除鼠标的原因 较大的动脉粥样硬化病变。来自这些小鼠的培养骨衍生巨噬细胞的转录组学 在炎症途径中显示基因表达显着变化（例如：细胞因子/趋化因子 和吞噬细胞溶酶体功能）。 TET2中具有躯体变异的芯片载体显着降低了主要 不良心血管事件用canakinumab（一种IL-1B抗体处理），表明特定于 治疗策略可能在芯片载体中尤其具有影响力。我的总体假设是整个 基因组测序（WGS）将识别种系遗传变异，影响芯片载体状态 影响动脉粥样硬化，人类单核细胞中的转录组分析会发现生物学途径 受芯片的影响，结合种系和躯体数据将发现受保护的种系遗传 可能利用未来治疗靶标的变体。具体目的：通过整合种系 基因组测序数据具有体细胞变异呼叫，转录组学，心脏成像和临床数据 我旨在改善NHLBI Trans-Omics的107,000人 了解芯片与动脉粥样硬化之间的机械联系。在AIM 1中，我将使种系关联 从心脏CT和CAD中与冠状动脉钙水平和CAD的遗传易感性。这会 评估芯片载体状态是否导致影响亚临床动脉粥样硬化和临床动脉粥样硬化。 在AIM 2中，我将发现使用人类的转录组学影响受芯片影响的生物网络 单核细胞。在AIM 3中，我将表征种系遗传因素如何与CHIP体细胞变体相互作用 影响芯片到CAD的进展。