Clonal hematopoiesis in the Women's Health Initiative

项目概要 不确定潜能克隆造血 (CHIP) 是一种常见的、与年龄相关的疾病，其中 骨髓中的造血干细胞发生体细胞突变，导致造血干细胞过度生长（“克隆”） 遗传上不同的血细胞亚群。越来越多的证据表明 CHIP 对以下领域具有重大影响： 人类健康是死亡和慢性疾病（包括血液癌症和 动脉粥样硬化性心血管疾病（CVD）。先前的 CHIP 研究是横断面的且信息有限 提供关于发育、进展的行为/生活方式、环境和遗传风险因素， CHIP 的发生以及 CHIP 与特定 CVD 亚型（冠心病）风险的关系 疾病、中风和静脉血栓栓塞性疾病）、癌前血液疾病和长期痴呆症 期限跟进。大型（N~161,000）、多种族、前瞻性的女性健康倡议（WHI）， 1993年至1998年期间的绝经后妇女特别适合解决这些限制，因为其 纵向设计、广泛暴露和表型数据的可用性以及对事件的持续监测 老年妇女的疾病/死亡率。特别是，原始 WHI 队列中约 7,800 人的子集接受了 作为 2012 年后续检查和血液采样（WHI 注册后 14 至 19 年）的一部分 WHI 长寿研究 (LLS) 的一部分。通过 NHLBI 精准医学跨组学 (TOPMed) 项目， 11,000 名原始 WHI 参与者（包括约 1,400 名 WHI-LLS 参与者）经历了深度学习 对其基线基因组 DNA 进行覆盖 (30x) 全基因组测序，目前正在进行体细胞测序 需要进行 CHIP 评估的变异基因型。通过当前的 R01 提案，我们将额外执行 对剩余 6,400 个 WHI-LLS 进行 CHIP 基因分型和靶向造血基因测序检测 使用外周血基因组 DNA 的样本（基线）和全套 7,800 名 WHI-LLS 参与者 在 LLS 考试中提取。在目标 1 中，我们将估计流行的 CHIP（基线）、 CHIP 的发生率或进展（基线和 LLS 之间）以及假定的社会人口统计数据， CHIP 的心脏代谢、行为、药理学、环境、遗传和衰老相关风险因素。在 目标 2，我们将使用 LLS 队列和 TOPMed 基线 CHIP 数据（总计 N=17,000）与临床心血管、血液学、神经认知和死亡率结局相关。在目标 3 中， 根据目标 1 和 2 的结果，我们将使用孟德尔随机化方法、中介分析、 和多基因风险评分，以评估 CHIP 和 可遗传种系变异促成 CHIP 的机制。

PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related condition in which hematopoietic stem cells in the bone marrow undergo somatic mutations that lead to overgrowth (“clones”) of a genetically distinct subpopulation of blood cells. Evidence is mounting that CHIP has major implications for human health as a risk factor for mortality and chronic diseases including hematologic cancers and atherosclerotic cardiovascular disease (CVD). Prior studies of CHIP were cross-sectional and limited information is available on behavioral/lifestyle, environmental, and heritable risk factors for the development, progression, and the occurrence of CHIP and also the relationship of CHIP to risk of specific CVD subtypes (coronary heart disease, stroke, and venous thromboembolic disease), pre-malignant blood diseases, and dementia over long- term follow up. The large (N~161,000), multi-ethnic, prospective Women’s Health Initiative (WHI), which enrolled post-menopausal women during 1993-1998 is particularly well-suited to address these limitations because of its longitudinal design, availability of extensive exposure and phenotype data, and ongoing surveillance of incident disease/mortality among aging women. In particular, a subset of ~7,800 of the original WHI cohort underwent a subsequent examination and blood sampling in 2012 (ranging from 14 to 19 years after WHI enrollment) as part of the WHI Long Life Study (LLS). Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) Project, 11,000 original WHI participants (including approximately 1,400 WHI-LLS participants) have undergone deep- coverage (30x) whole genome sequencing of their baseline genomic DNA and are currently undergoing somatic variant genotype calling for assessment of CHIP. Through the current R01 proposal, we will additionally perform CHIP genotyping and detection by targeted hematopoiesis gene sequencing in the remaining 6,400 WHI-LLS samples (at baseline) and the full set of 7,800 WHI-LLS participants using peripheral blood genomic DNA extracted at the LLS exam. In Aim 1, we will estimate associations between prevalent CHIP (at baseline), incidence or progression of CHIP (between baseline and LLS), and putative socio-demographic, cardiometabolic, behavioral, pharmacologic, environmental, genetic, and aging-related risk factors for CHIP. In Aim 2, we will estimate CHIP-outcome associations using the LLS cohort and TOPMed baseline CHIP data (total N=17,000) with incident clinical cardiovascular, hematologic, neurocognitive, and mortality outcomes. In Aim 3, informed by results from Aims 1 and 2, we will use Mendelian randomization approaches, mediation analyses, and polygenic risk scores to assess causal mediation of exposure-outcome associations by CHIP and the mechanisms by which heritable germline variants contribute to CHIP.