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 strategi...