Clonal Hematopoiesis of Indeterminate Potential in Chronic Kidney Disease Patients

慢性肾病患者的克隆造血潜力不确定

• 批准号: 10620348
• 负责人: Tanika Nicole Kelly
• 金额: $ 62.84万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-02 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620348
• 关键词: Age Years; Aging; Articulation; 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; Journals; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Linear Regressions; Link; Lipids; Measurement; Measures; Mediating; Medicine; Meta-Analysis; Modeling; Molecular; Myocardial Infarction; Myocardial Ischemia; 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; biobank; cardiovascular disorder prevention; cardiovascular health; cohort; differential expression; exome sequencing; follow-up; genomic data; hazard; high risk; human old age (65+); improved; inhibitor; 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

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年的地标新英格兰医学研究杂志的2017年出版 对动脉粥样硬化心血管疾病（ASCVD）的不确定潜力（芯片）引入了新的范式 在血管衰老研究中。这项工作强调了与年龄有关的体细胞DNA突变作为重要的 心血管健康的贡献者，认为CHIP主要通过炎症促进ASCVD 后遗症。尽管慢性肾脏疾病（CKD）的促炎性设置，但尚未评估CHIP 在这些患者中对末期肾脏疾病和早产ASCVD的贡献。因此，我们的 长期目标是表征芯片及其相关机制在事件中的作用 CKD设置中的进度和ASCVD。为了实现这一总体目标，我们将利用富人 慢性肾功能不全队列（CRIC）研究的资源，利用可用的整个外显子组测序 （WES）基线芯片测量，纵向确定的生物测量，临床信息和 分子生物标志物，以及CKD的进展和ASCVD事件，在16年的随访中收集了 学习。我们提出了一个65岁或以上的2126名CRIC参与者的发现阶段队列 基线。选择老年人以最大程度地提高研究效率，因为芯片在年轻人中很少见。芯片 状态将使用基线WES数据和我们的最先进的芯片分析管道确定 变体通话。我们还建议在整个较老的3年和6年的随访中重复进行芯片测量 成人亚果园，以及400名Cric参与者的RNA测序（RNA-Seq），一半带有芯片。我们将测试 在2,126个CRIC CKD之间 患者。然后，我们将评估独特的上游（AIM 3A）和下游（AIM 3B）芯片机制 CKD使用有关芯片和已知风险因素的CKD进展和ASCVD的纵向信息设置， 包括：临床变量（血压，血糖性状和脂质），肾脏损伤的生物标志物，心脏 压力和损伤，炎症和纤维化，使用肾素血管紧张素醛固酮系统抑制剂和衰老 相关的遗传因素（CDKN2A变体）。为了发现新的分子机制，我们的RNA-seq研究将 芯片和基因表达之间的测试关联（AIM 4A）。差异表达的基因将是 评估与目标3A和3B中确定的芯片机制相关（AIM 4B）。复制发现， 我们将利用现有的芯片，临床，生物标志物，基因表达和最多4​​,126次的结果数据 精确医学计划的OMICS和8,520名英国生物银行参与者。芯片效果将精确 在强大的发现和复制研究中估计。拟议研究的结果 可能具有广泛的影响，从改善风险分层工作到发展 CKD中针对ESKD和ASCVD预防的个性化策略和新型基于分子的疗法。

项目成果

An atlas of associations between 14 micronutrients and 22 cancer outcomes: Mendelian randomization analyses.

• DOI: 10.1186/s12916-023-03018-y
• 发表时间: 2023-08-21
• 期刊: BMC MEDICINE
• 影响因子: 9.3
• 作者: Kim, Jong Yeob;Song, Minku;Kim, Min Seo;Natarajan, Pradeep;Do, Ron;Myung, Woojae;Won, Hong-Hee
• 通讯作者: Won, Hong-Hee