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.

该提案的目的是了解造血干细胞中获得的（体细胞）突变 有助于动脉粥样硬化心血管疾病（ASCVD）。我们最近分析了血液外显子组序列 描述一种新现象 - 不确定潜力（芯片）的克隆造血 - 并连接 CHIP至衰老，血液学癌和ASCVD风险。在此提案中，我们试图了解Chip是否 与未来发生ASCVD的未来风险有关，为什么有些人会在造血茎中形成躯体突变 细胞，为什么这些克隆仅在某些人中扩展并引起疾病，CHIP是否是因果风险因素 对于ASCVD，以及炎症介质是否与芯片和事件ASCVD事件有关。我们 将在两项大型的前瞻性队列研究中解决这些问题：社区的动脉粥样硬化风险 研究（n = 15,792）和英国生物银行（n = 503,317） - 在哪个外显子组序列中，几乎全部可用 为了呼叫芯片状态，已经测量了标准的ASCVD风险因素，广泛的血液生物标志物 已经分配了，已经使用基因分芯片确定了常见的变体基因型，而ASCVD已确定 已经监视了有关预期随访的事件。我们建议：目标1：执行躯体变体 在ARIC和UK Biobank参与者中的血液外显子组序列中检测（合并n> 500,000 参与者）并测试芯片与事件ASCVD事件的关联。我们还将测试 假设克隆的大小与对ASCVD的影响之间存在剂量反应关系。目的 2：确定ARIC和英国普遍芯片状态的行为和临床相关性 生物库研究。使用回归模型，我们将测试行为和临床因素的假设 促进芯片的发展。目标3：确定在 ARIC和英国生物库研究，并利用Mendelian随机化方法来测试 CHIP偶尔与人类ASCVD事件有关的假设。我们将使用额外的基因型数据 检验了种系基因组中常见的DNA序列变化的假设使参与者易于 开发芯片。我们将开发一种基因仪器，以进行芯片暴露并与ASCVD相关的测试 一项大规模的遗传研究（百万心项目和百万退伍军人计划）。目标4：确定 ARIC研究中CHIP进展的决定剂通过A中的重复外显子组测序 5426名参与者的子集的平均间隔约为20年。我们将两次确定芯片状态 点并检验了行为，临床，生化和/或种系基因型的假设有助于 芯片进展。目标5：检查芯片与感染和事件ASCVD的关联 事件。我们将检查中期晚期炎症与CHIP患病率的关联 使用候选趋化因子/细胞因子面板和无偏的大规模纠纷蛋白质组学阵列的年龄。 然后，我们将检查是否与芯片相关的炎症标记也与入射ASCVD相关。