Project Summary Sickle cell disease (SCD) is associated with chronic hemolysis, systemic endothelial dysfunction, inflammation and vascular occlusion. This complex pathophysiology leads to severe pain, progressive multi-organ damage and premature death with a median lifespan of 48 years in high- income countries. We and others have determined that young adults with progressive heart, lung, and kidney damage, either individually or in combination, are at particularly high risk for premature death. Many individuals with SCD are candidates for high-risk treatments that can potentially eliminate symptoms and arrest organ damage, including allogeneic hematopoietic stem cell (HSC) transplantation and various forms of autologous HSC gene therapy. However, several individuals who received these treatments have developed acute myeloid leukemia or other myeloid neoplasms. In many cases, the blood cancer arose from an autologous, premalignant HSC harboring a somatic “clonal hematopoiesis” (CH) mutation that was present before therapy. We and others have shown in individuals without SCD that CH mutations confer a growth advantage to aging HSCs, predisposing to not only myeloid leukemia, but also endovascular disease affecting the heart, lung and kidney. Additional preliminary data derived from deidentified genomic or exonic sequences indicate that individuals with SCD develop CH at earlier ages than that of the general population. Based on these data, we hypothesize that individuals with SCD have an increased prevalence of CH, which accelerates the development of heart, lung, and kidney disease. We will test this hypothesis by first determining the prevalence and incidence of CH in three well-characterized multi-center cohorts of older children and adults with SCD (n= 2645) and matched controls (n= 7935, Aim 1). We will use a novel, scalable, cost- effective, error-corrected sequencing assay that can detect low-level (0.1%) somatic CH mutations. Next, we will determine whether CH mutations are associated with heart, lung or kidney disease in these cohorts (Aim 2). Our team has already completed whole-genome sequencing of the cohorts through the NIH NHLBI Trans-Omics for Precision Medicine (TOPMed) program, which will allow us to study genetic interactions between CH mutations and germline variants that are known to influence SCD outcomes. Our project will provide novel insights into the importance of CH as a risk factor for heart, lung, and kidney disease in SCD, identify individuals who could benefit from individualized strategies for organ protection administered prospectively, and fuel future studies to determine whether CH predisposes to the development of myeloid leukemia after allogeneic HSC transplantation or gene therapy for SCD.