CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL IN CHRONIC KIDNEY DISEASE PATIENTS

慢性肾病患者的克隆性造血潜力不确定

基本信息

批准号：
10220344
负责人：
Tanika Nicole Kelly
金额：
$ 71.86万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-13 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220344
关键词：
Age-Years Aging Atherosclerosis Biological Biological Markers Blood Cells Blood Pressure Blood Vessels CDKN2A gene Cardiac Cardiovascular Diseases Chronic Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Clonal Expansion Cohort Studies Cox Proportional Hazards Models DNA Sequence Alteration Data Development Dialysis procedure Disease Disease Progression Elderly End stage renal failure Event Fibrosis Follow-Up Studies Gene Expression Genes Genetic Heart Injuries Hematopoiesis High Prevalence Inflammation Inflammatory Injury Injury to Kidney Ischemic Stroke Journals Kidney Diseases Kidney Failure Kidney Transplantation Knowledge Linear Regressions Link Lipids Measurement Measures Mediating Medicine Meta-Analysis Modeling Molecular Myocardial Infarction New England Outcome Participant Pathway interactions Patients Phase Phenotype Precision Health Public Health Publications Recurrence Renal function Renin-Angiotensin-Aldosterone System Research Resources Risk Factors Role Sample Size Somatic Mutation Stress Structural Models Testing Time Trans-Omics for Precision Medicine Variant Work age related base biobank cardiovascular disorder prevention cardiovascular health clinical biomarkers cohort differential expression exome sequencing follow-up genomic data hazard high risk human old age (65+)inhibitor/antagonist insight interest longitudinal analysis molecular marker nephrogenesis novel personalized strategies premature prevent programs prospective test recruit risk stratification stroke event trait transcriptome sequencing young adult

项目摘要

ABSTRACT The 2017 publication of a landmark New England Journal of Medicine study linking clonal hematopoiesis of indeterminate potential (CHIP) to atherosclerotic cardiovascular disease (ASCVD) ushered in a new paradigm in vascular aging research. This work highlighted age-related somatic DNA mutation as an important contributor to cardiovascular health, with CHIP thought to promote ASCVD primarily through inflammatory sequelae. Despite the pro-inflammatory setting of chronic kidney disease (CKD), CHIP has not been assessed for its contribution to end stage kidney disease and premature ASCVD among these patients. Hence, our long-term objective is to characterize the role of CHIP and its related mechanisms in incident CKD progression and ASCVD in a CKD setting. To achieve this overall objective, we will leverage the rich resources of the Chronic Renal Insufficiency Cohort (CRIC) study, utilizing available whole exome sequencing (WES) data for baseline CHIP measurement, longitudinally ascertained biospecimens, clinical information, and molecular biomarkers, along with CKD progression and ASCVD events collected over 16 years of follow-up study. We propose a discovery stage cohort of 2,126 CRIC participants who were 65 years of age or older at baseline. Older adults are selected to maximize study efficiency, since CHIP is rare in younger adults. CHIP status will be determined using baseline WES data and our state-of-the-art analytic pipeline for CHIP somatic variant calling. We also propose repeated CHIP measurements at 3- and 6-years follow-up in the entire older adult sub-cohort, along with RNA sequencing (RNA-seq) in 400 CRIC participants, half with CHIP. We will test CHIP associations with incident CKD progression (Aim 1) and ASCVD (Aim 2) among the 2,126 CRIC CKD patients. We will then evaluate upstream (Aim 3a) and downstream (Aim 3b) CHIP mechanisms in the unique CKD setting using longitudinal information on CHIP and known risk factors for CKD progression and ASCVD, including: clinical variables (blood pressure, glycemic traits, and lipids), biomarkers of kidney injury, cardiac stress and injury, inflammation, and fibrosis, use of renin angiotensin aldosterone system inhibitors, and aging related genetic factors (CDKN2A variants). To discover novel molecular mechanisms, our RNA-seq study will test associations between CHIP and gene expression (Aim 4a). Differentially expressed genes will be evaluated for association with CHIP mechanisms identified in Aims 3a and 3b (Aim 4b). To replicate findings, we will leverage existing CHIP, clinical, biomarker, gene expression and outcome data in up to 4,126 Trans- omics for Precision Medicine program and 8,520 UK Biobank participants. CHIP effects will be precisely estimated in powerful meta-analyses of discovery and replication studies. Findings of the proposed research could have broad implications, ranging from the improvement of risk stratification efforts to the development of personalized strategies and novel molecular-based therapies for ESKD and ASCVD prevention in CKD.

抽象的 2017 年《新英格兰医学杂志》发表了一项具有里程碑意义的研究，该研究将克隆造血作用联系起来动脉粥样硬化性心血管疾病（ASCVD）的不确定电位（CHIP）开创了新范例从事血管老化研究。这项工作强调了与年龄相关的体细胞 DNA 突变是一个重要的心血管健康的贡献者，CHIP 主要通过炎症促进 ASCVD 后遗症。尽管慢性肾病 (CKD) 具有促炎作用，但 CHIP 尚未得到评估表彰其对这些患者的终末期肾病和过早 ASCVD 的贡献。因此，我们的长期目标是描述 CHIP 及其相关机制在 CKD 事件中的作用 CKD 环境中的进展和 ASCVD。为了实现这一总体目标，我们将利用富人的力量慢性肾功能不全队列 (CRIC) 研究资源，利用可用的全外显子组测序 (WES) 基线 CHIP 测量数据、纵向确定的生物样本、临床信息和分子生物标志物，以及 16 年随访期间收集的 CKD 进展和 ASCVD 事件学习。我们提出了一个由 2,126 名 CRIC 参与者组成的发现阶段队列，他们的年龄在 65 岁或以上。基线。选择老年人是为了最大限度地提高研究效率，因为 CHIP 在年轻人中很少见。芯片将使用基线 WES 数据和我们最先进的 CHIP 体细胞分析流程来确定状态变体调用。我们还建议在整个老年患者的 3 年和 6 年随访中重复进行 CHIP 测量。成人子队列，以及 400 名 CRIC 参与者的 RNA 测序 (RNA-seq)，其中一半使用 CHIP。我们将测试在 2,126 名 CRIC CKD 患者中，CHIP 与 CKD 进展（目标 1）和 ASCVD（目标 2）相关患者。然后，我们将以独特的方式评估上游（目标 3a）和下游（目标 3b）CHIP 机制使用 CHIP 的纵向信息以及 CKD 进展和 ASCVD 的已知危险因素进行 CKD 设置，包括：临床变量（血压、血糖特征和血脂）、肾损伤、心脏损伤的生物标志物压力和损伤、炎症和纤维化、肾素血管紧张素醛固酮系统抑制剂的使用以及衰老相关遗传因素（CDKN2A 变异）。为了发现新的分子机制，我们的 RNA-seq 研究将测试 CHIP 和基因表达之间的关联（目标 4a）。差异表达基因将评估与目标 3a 和 3b（目标 4b）中确定的 CHIP 机制的关联。为了复制研究结果，我们将利用现有的芯片、临床、生物标志物、基因表达和结果数据，最多 4,126 个 Trans- 精准医学组学计划和 8,520 名英国生物银行参与者。 CHIP效果将精确在对发现和复制研究的强大荟萃分析中进行了估计。拟议研究的结果可能产生广泛的影响，从改进风险分层工作到制定针对 CKD 中 ESKD 和 ASCVD 预防的个性化策略和新型分子疗法。