Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to increase cardiovascular disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 104,566 single cells from a cohort of 17 CH patients and 6 controls. We discovered that patients harboring DNMT3A and TET2 CH mutations at baseline and in response to IL-6 stimulation confer a pro-inflammatory profile to CD14+ monocytes through previously unrecognized pathways including Macrophage Inhibitory Factor (MIF). A germline genetic variant in MIF modifies TET2 CH cardiovascular disease risk. Using mitochondrial lineage tracing, we used a novel method to compare gene expression between mutated and non-mutated cells within individual CH patients. We found that the mutated CH monocytes, but not non-mutated monocytes are pro-inflammatory, explaining why patients with larger CH clones have increased cardiovascular disease risk.