Clonal hematopoiesis in humans: determinants of development and progression

这项提议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序列 描述一种新现象--不确定电位的克隆性造血(CHIP)--并与 芯片与衰老、血液病和ASCVD风险有关。在这个提案中，我们试图了解芯片是否 与未来发生ASCVD的风险有关，为什么有些人会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，芯片是否是一个因果风险因素 对于ASCVD，以及炎症介质是否与CHIP和事件ASCVD相关。我们 将在两项大型前瞻性队列研究中解决这些问题--社区中的动脉粥样硬化风险 研究(n=15,792)和英国生物库(n=503,317)-其中外显子组序列几乎在所有 对于芯片状态的调用，已经测量了标准的ASCVD危险因素，广泛的血液生物标记物 已经进行了检测，使用基因分型芯片和ASCVD确定了常见的变异基因类型 已经对事件进行了监测，以进行预期的后续行动。我们建议：目标1：进行体细胞变异 检测ARIC和UK生物库参与者的血液外显子序列(合并n&gt；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 假设克隆的大小和对ASCVD的影响之间存在剂量-反应关系。目标 2：确定ARIC和英国流行的芯片状态的行为和临床相关性 生物库研究。使用回归模型，我们将检验行为和临床因素的假设 推动芯片产业发展。目的3：确定CHIP流行状态的遗传相关因素 ARIC和UK Biobank的研究，并利用孟德尔随机化方法来测试 假设CHIP与人类的ASCVD事件有因果关系。我们将使用现有的基因数据来 检验这样一种假设，即生殖系基因组中常见的DNA序列变异使参与者容易患上 开发芯片。我们将开发一种芯片暴露的基因仪器，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老兵计划)。目标4：确定 重复外显子测序在ARIC研究中进展的决定因素 5426名参与者的子集，平均间隔约20年。我们将分两次确定芯片状态 指出并检验以下假设：行为、临床、生化和/或生殖系基因对 芯片进度。目的5：研究CHIP与炎症和ASCVD的关系 事件。我们将研究炎症与中年晚期和老年患者芯片患病率之间的关系。 使用候选趋化因子/细胞因子小组和无偏见的大规模适体蛋白质组阵列进行AGE。 然后，我们将检查与CHIP相关的炎症标志物是否也与ASCVD事件有关。

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.