Clonal Hematopoiesis of Indeterminate Potential in Chronic Kidney Disease Patients

摘要 2017年发表了一项里程碑式的《新英格兰医学杂志》研究，该研究将克隆性造血与 动脉粥样硬化性心血管疾病(ASCVD)的不确定潜能(CHIP)迎来了一种新的范式 在血管老化研究中。这项工作强调了与年龄相关的体细胞DNA突变是一种重要的 心血管健康的贡献者，芯片被认为主要通过炎症促进ASCVD 后遗症。尽管慢性肾脏疾病(CKD)具有促炎作用，但CHIP尚未得到评估 对这些患者中终末期肾脏疾病和早产儿ASCVD的贡献。因此，我们的 长期目标是确定CHIP及其相关机制在CKD事件中的作用 慢性肾脏病的进展和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，利用现有的全部外显子组测序 (WES)用于基准芯片测量的数据、纵向确定的生物样本、临床信息和 分子生物标记物与CKD进展和ASCVD事件一起收集的16年随访资料 学习。我们提出了一个由2,126名65岁或以上的CRIC参与者组成的发现阶段队列 基线。选择老年人是为了最大限度地提高研究效率，因为芯片在年轻人中很少见。芯片 将使用基线WES数据和我们最先进的芯片体细胞分析流水线来确定状态 变种叫声。我们还建议对所有老年人进行3年和6年的重复芯片测量。 成人亚队列，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例CRIC CKD中，CHIP与CKD进展(AIM 1)和ASCVD(AIM 2)的相关性 病人。然后，我们将评估上游(目标3a)和下游(目标3b)芯片机制在 使用芯片上的纵向信息和CKD进展和ASCVD的已知风险因素的CKD设置， 包括：临床变量(血压、血糖和血脂)、肾脏损伤的生物标志物、心脏 应激和损伤、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变异体)。为了发现新的分子机制，我们的rna-seq研究将 测试芯片和基因表达之间的关联(目标4a)。差异表达的基因将是 评价与目标3a和3b(目标4b)中确定的芯片机构的联系。为了复制研究结果， 我们将利用现有的芯片、临床、生物标记物、基因表达和结果数据，在多达4,126个Trans- 精准医学组学计划和8,520名英国生物库参与者。芯片效果将准确地 在发现和复制研究的强大元分析中估计。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 CKD中ESKD和ASCVD预防的个性化策略和基于分子的新疗法。

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.