Clonal hematopoiesis in humans: determinants of development and progression

这项提案的目的是了解造血干细胞中的获得性（体细胞）突变如何 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序列 描述了一种新的现象-不确定潜能的克隆造血（CHIP）-和连接 CHIP与衰老、血液学癌症和ASCVD风险的关系在这项建议中，我们试图了解，如果芯片 与ASCVD事件的未来风险有关，为什么有些人在造血干细胞中发生体细胞突变 细胞，为什么这些克隆只在某些人中扩张并导致疾病，CHIP是否是一个因果风险因素 以及炎症介质是否与CHIP和ASCVD事件相关。我们 我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）和英国生物样本库（n= 503，317）-其中外显子组序列可用于/将用于几乎所有 对于CHIP状态的调用，已经测量了标准ASCVD风险因素，广泛的血液生物标志物 已经进行了分析，使用基因分型芯片确定了常见的变异基因型，ASCVD 在前瞻性随访中监测事件。我们提出：目的1：进行体细胞变异 在ARIC和UK生物库参与者（组合n> 500，000）中检测血液外显子组序列 参与者），并测试CHIP与ASCVD事件的相关性。我们还将测试 假设克隆大小与对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CHIP状态的行为和临床相关性 生物样本库研究。使用回归模型，我们将检验行为和临床因素 促进CHIP的发展。目的3：确定CHIP流行状态的遗传相关性， ARIC和英国生物库研究，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。我们将使用现存的基因型数据， 测试假设，即生殖细胞基因组中常见的DNA序列变异使参与者倾向于 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的相关性。 一项大规模的基因研究（百万心脏计划和百万退伍军人计划）。目标4：查明 在ARIC研究中，通过重复外显子组测序， 5426名参与者的子集，平均间隔约20年。我们将在两个时间确定CHIP状态 点和测试的假设，行为，临床，生化，和/或生殖基因型有助于 CHIP进展。目的5：研究CHIP与炎症和ASCVD事件的相关性 事件我们将研究炎症与中年晚期和老年人CHIP患病率的关系 年龄使用候选趋化因子/细胞因子面板和无偏的大规模适体蛋白质组阵列。 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。

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.