Clonal hematopoiesis in the Women's Health Initiative

项目总结 克隆性造血不确定电位(CHIP)是一种常见的与年龄相关的疾病 骨髓中的造血干细胞经历体细胞突变，导致骨髓细胞过度生长(克隆) 在遗传上不同的血细胞亚群。越来越多的证据表明，芯片对 人类健康是死亡和包括血液病和癌症在内的慢性疾病的风险因素 动脉粥样硬化性心血管疾病(CVD)。以往对芯片的研究是横断面的，信息量有限。 有关于行为/生活方式、环境和可遗传的风险因素的信息， 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症)、恶性前血液疾病和长期痴呆。 学期跟踪调查。大型(N~161,000)、多族裔、预期妇女健康倡议(WHI)，该倡议已加入 1993-1998年的绝经后妇女特别适合于解决这些限制，因为它 纵向设计、广泛暴露和表型数据的可用性，以及事件的持续监控 老年妇女的疾病/死亡率。特别是，原始WHI队列中的~7800人的子集经历了 2012年(加入WHI后14至19年)进行后续检查和采血，作为部分 WHI长寿研究(LLS)。通过NHLBI Transans-Omics for Precision Medicine(TOPMed)项目， 11,000名原始WHI参与者(包括大约1,400名WHI-LLS参与者)经历了深度- 覆盖(30倍)其基线基因组DNA的全基因组测序，目前正在进行体细胞分析 需要对芯片进行评估的变异基因。通过目前的R01提案，我们将额外执行 其余6400例WHI-LLS的芯片基因分型和靶向造血基因测序检测 样本(基线)和全套7,800名WHI-LLS参与者使用外周血基因组DNA 是在法律系考试中摘录的。在目标1中，我们将评估流行芯片之间的联系(基线)， CHIP的发病率或进展(在基线和LLS之间)，以及推定的社会人口统计， CHIP的心脏代谢、行为、药理、环境、遗传和衰老相关危险因素。在……里面 目标2，我们将使用LLS队列和TOPMed基线芯片数据来估计芯片-结果关联(总计 N=17,000)与临床心血管、血液学、神经认知和死亡结局有关。在《目标3》中， 根据目标1和目标2的结果，我们将使用孟德尔随机化方法、调解分析、 和多基因风险评分，以评估芯片和 可遗传生殖系变异对CHIP的作用机制。

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.