Clonal hematopoiesis in the Women's Health Initiative

项目摘要 不确定潜能的克隆性造血（CHIP）是一种常见的年龄相关疾病，其中 骨髓中的造血干细胞经历体细胞突变，导致造血干细胞的过度生长（“克隆”）。 遗传上不同的血细胞亚群。越来越多的证据表明，CHIP对 人类健康作为死亡率和慢性疾病（包括血液癌症）的风险因素， 动脉粥样硬化性心血管疾病（CVD）。以前的CHIP研究是横断面的，信息有限 可获得关于行为/生活方式，环境和遗传风险因素的发展，进展， 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）、恶性前血液病和长期痴呆， 术语后续。大型（N~ 161，000），多种族，前瞻性的妇女健康倡议（WHI）， 绝经后妇女在1993-1998年期间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 2012年（WHI入组后14至19年）的后续检查和血液采样， WHI长寿研究（LLS）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）已经接受了深度- 覆盖率（30倍）的全基因组测序的基线基因组DNA，目前正在进行体细胞 需要评估CHIP的变异基因型。通过当前的R 01提案，我们还将执行 在其余6,400例WHI-LLS中进行CHIP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 在目标1中，我们将估计普遍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学， 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TOPM基线CHIP数据（总 N= 17，000），发生临床心血管、血液学、神经认知和死亡结局。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 遗传性种系变异导致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.