Thread by @brettheimlich

Hey #CHIP folks, ever wondered how clonal cells in the periphery differ from their wildtype counterparts? check out👉biorxiv.org/content/10.110… @AlexBickMDPhD @FerrellLabVUMC @alyssa_c_parker @PBdoingscience

CHIP patient blood is a mixture of normal and mutated cells. Genotyping mutations (@AnnaEnim @landau_lab) is difficult in peripheral blood because DNMT3A and TET2 are not well expressed.

Utilizing mitochondrial DNA SNPs, pioneered by @vangalenlab, @CalebLareau and @bloodgenes, we were able to identify genomic mutational status at the individual cell level

We confirmed the link between CHIP mutation & mitochondrial mutation using two methods: clonal expansion and @MissionBio Tapestri platform

This enabled previously impossible comparisons between mutated and wildtype cells from the same person, solving several riddles:

How does such a small fraction of blood cause significant heart disease? We find that most CD14+ monocytes in patients with large CHIP clones are mutated.

Why do different CHIP genes confer different disease risk? In CD14+ monos, the TET2 mutant cells are highly inflammatory compared to non-mutated cells from the same patient... but not in DNMT3A

Further, macrophage migration inhibitory factor (MIF) was found to be upregulated in TET2 but not DNMT3A, a finding that was supported by human genetics data from the UKB.

Finally, we used phospo-specific flow cytometry to demonstrate the cell-intrinsic nature of TET2 mutated CD14 monocytes in response to IL-6 stimulation.

In summary, we find mutation-specific patterns in RNA expression across CD14 monos in TET2 and DNMT3A patients which could explain divergent risk profiles in CHIP and identify new therapeutic targets in TET2 CHIP.

This paper would not have been possible without excellent co-authors @AlexSilverMSTP @DrFlashHeart and funding from @NIH @nih_nhlbi @BWFUND @pewtrusts @vumccardsfit @VUMCgenetics @VUMChealth @FondationLeducq