PT  - JOURNAL ARTICLE
AU  - J. Brett Heimlich
AU  - Pawan Bhat
AU  - Alyssa C. Parker
AU  - Matthew T. Jenkins
AU  - Caitlyn Vlasschaert
AU  - Jessica Ulloa
AU  - Chad R. Potts
AU  - Sydney Olson
AU  - Alexander J. Silver
AU  - Ayesha Ahmad
AU  - Brian Sharber
AU  - Donovan Brown
AU  - Ningning Hu
AU  - Peter van Galen
AU  - Michael R. Savona
AU  - Alexander G. Bick
AU  - P. Brent Ferrell
TI  - Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis
AID  - 10.1101/2022.12.01.518580
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.12.01.518580
4099  - http://biorxiv.org/content/early/2022/12/05/2022.12.01.518580.short
4100  - http://biorxiv.org/content/early/2022/12/05/2022.12.01.518580.full
AB  - 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.Competing Interest StatementAll unrelated to the present work: M.R.S. reports personal fees from AbbVie, BMS, CTI, Sierra Oncology, Novartis, grants from Astex and Incyte, personal fees and other support from Karyopharm, Ryvu, personal fees from Sierra Oncology, grants and personal fees from Takeda, and TG Therapeutics outside the submitted work. P.B.F. reports grants from Incyte. A.G.B. is a scientific co-founder and has equity in TenSixteen Bio. All other authors declare that they have no competing interests.