Clonal hematopoiesis in humans: determinants of development and progression

人类克隆造血：发育和进展的决定因素

• 批准号: 10448235
• 负责人: CHRISTIE Mitchell BALLANTYNE
• 金额: $ 144.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448235
• 关键词: Accounting; Address; Age; Aging; Atherosclerosis; Atherosclerosis Risk in Communities; Behavioral; Biochemical; Biological Assay; Biological Markers; Blood; Blood Cells; Cardiovascular system; Cell physiology; Clinical; Clonal Expansion; DNA Sequence; Data; Data Aggregation; Development; Disease; Dose; Eating; Event; Exercise; Frequencies; Future; Genes; Genetic; Genetic study; Genome; Genotype; Goals; Growth; Heart; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Human; Hypertension; Individual; Inflammation; Inflammation Mediators; Ischemic Stroke; Leukocytes; Longterm Follow-up; Measures; Mediating; Mendelian randomization; Modeling; Monitor; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Peripheral arterial disease; Persons; Prevalence; Prospective cohort study; Proteins; Proteomics; Risk; Risk Factors; Socioeconomic Status; Somatic Mutation; Stroke; Testing; Time; Variant; Veterans; Visit; aged; aptamer; atherosclerosis risk; biobank; cardiovascular disorder risk; cardiovascular risk factor; chemokine; cigarette smoking; cohort; cytokine; diet and exercise; exome; exome sequencing; follow-up; genetic analysis; genetic manipulation; genetic variant; genome wide association study; genome-wide; good diet; hypercholesterolemia; inflammatory marker; instrument; lifestyle factors; middle age; mouse model; prevent; programs; prospective; response; targeted treatment; variant detection; vascular bed

The goal of this proposal is to understand how acquired (somatic) mutations in hematopoietic stem cells contribute to atherosclerotic cardiovascular disease (ASCVD). We recently analyzed blood exome sequences to describe a new phenomenon—clonal hematopoiesis of indeterminate potential (CHIP)—and connected CHIP to aging, hematologic cancer, and risk for ASCVD. In this proposal, we seek to understand if CHIP relates to future risk for incident ASCVD, why some people develop somatic mutations in hematopoietic stem cells, why these clones expand and cause disease only in some people, whether CHIP is a causal risk factor for ASCVD, and whether inflammatory mediators are associated with CHIP and incident ASCVD events. We will address these questions in two large prospective cohort studies—the Atherosclerosis Risk in Communities Study (n=15,792) and UK Biobank (n=503,317)—in which exome sequences are/will be available in nearly all for the calling of CHIP status, standard ASCVD risk factors have been measured, extensive blood biomarkers have been assayed, common variant genotypes have been determined using genotyping chips, and ASCVD events have been monitored on prospective follow-up. We propose: Aim 1: To perform somatic variant detection in blood exome sequences in ARIC and UK Biobank participants (combined n>500,000 participants) and test the association of CHIP with incident ASCVD events. We will also test the hypothesis that a dose–response relationship exists between the size of the clone and effect on ASCVD. Aim 2: To identify the behavioral and clinical correlates of prevalent CHIP status in both the ARIC and UK Biobank studies. Using regression models, we will test the hypothesis that behavioral and clinical factors promote the development of CHIP. Aim 3: To identify the genetic correlates of prevalent CHIP status in both the ARIC and UK Biobank studies and to utilize the Mendelian randomization approach to test the hypothesis that CHIP causally relates to ASCVD events in humans. We will use extant genotype data to test the hypothesis that common DNA sequence variation in the germline genome predisposes participants to develop CHIP. We will develop a genetic instrument for CHIP exposure and test for association with ASCVD in a large-scale genetic study (the Million Hearts Project and the Million Veteran Program). Aim 4: To identify the determinants of progression of CHIP in the ARIC study through repeat exome sequencing in a subset of 5426 participants at a mean interval of ~20 years. We will determine CHIP status at two time points and test the hypothesis that behavioral, clinical, biochemical, and/or germline genotypes contribute to CHIP progression. Aim 5: To examine the association of CHIP with inflammation and incident ASCVD events. We will examine the association of inflammation with CHIP prevalence in late middle age and in older age using both a candidate chemokine/cytokine panel and an unbiased large-scale aptamer proteomic array. We will then examine if inflammatory markers correlated with CHIP are also associated with incident ASCVD.

该提案的目标是了解造血干细胞的获得性（体细胞）突变是如何发生的 导致动脉粥样硬化性心血管疾病（ASCVD）。我们最近分析了血液外显子组序列 描述一种新现象——不确定潜能克隆造血（CHIP）——并将 CHIP 与衰老、血液癌症和 ASCVD 风险有关。在本提案中，我们试图了解 CHIP 是否 与未来发生 ASCVD 的风险相关，为什么有些人会出现造血干细胞体细胞突变 细胞，为什么这些克隆仅在某些人中扩增并引起疾病，CHIP 是否是一个因果危险因素 ASCVD，以及炎症介质是否与 CHIP 和 ASCVD 事件相关。我们 将在两项大型前瞻性队列研究中解决这些问题——社区动脉粥样硬化风险 研究 (n=15,792) 和英国生物银行 (n=503,317) — 其中外显子组序列在几乎所有疾病中都可用 为了调用 CHIP 状态，已测量标准 ASCVD 危险因素、广泛的血液生物标志物 已进行测定，常见变异基因型已使用基因分型芯片和 ASCVD 确定 已对事件进行前瞻性后续行动监测。我们建议： 目标 1：执行体细胞变异 ARIC 和 UK Biobank 参与者的血液外显子组序列检测（总计 n>500,000 参与者）并测试 CHIP 与 ASCVD 事件的关联。我们还将测试 假设克隆的大小和对 ASCVD 的影响之间存在剂量反应关系。目的 2：确定 ARIC 和英国流行的 CHIP 状态的行为和临床相关性 生物银行研究。使用回归模型，我们将检验行为和临床因素的假设 推动芯片发展。目标 3：确定流行的 CHIP 状态的遗传相关性 ARIC 和英国生物银行研究并利用孟德尔随机化方法来测试 假设 CHIP 与人类 ASCVD 事件存在因果关系。我们将使用现有的基因型数据 检验以下假设：种系基因组中常见的 DNA 序列变异会使参与者倾向于 开发芯片。我们将开发一种用于 CHIP 暴露的遗传仪器，并测试与 ASCVD 的关联 大规模基因研究（百万爱心计划和百万退伍军人计划）。目标 4：识别 ARIC 研究中通过重复外显子组测序确定 CHIP 进展的决定因素 5426 名参与者的子集，平均间隔约为 20 年。我们将分两次确定CHIP状态 点并检验行为、临床、生化和/或种系基因型有助于的假设 芯片进展。目标 5：检查 CHIP 与炎症和 ASCVD 事件的关联 事件。我们将研究中年晚期和老年人中炎症与 CHIP 患病率的关系 使用候选趋化因子/细胞因子组和无偏差的大规模适体蛋白质组阵列来确定年龄。 然后我们将检查与 CHIP 相关的炎症标志物是否也与 ASCVD 事件相关。