Proteomic signatures associated with inflammation and immune response are enriched in patients with CH mutation vs without CH mutations and increased more in patients with concurrent CH mutations and anemia. Baseline proteomic profile from SomaScan and individual cytokines ELISA characterized biological changes mediated by CH mutations and anemia. (A-C) Baseline levels of IL-6 (A), hepcidin (B), and TNF-α (C) in patients with and without CH mutations, showing mean values at the top of each plot. (D-E) Volcano plots of multiplexed proteomic data comparing patients with CH mutations vs without CH mutations. Highlighted are (D) proteins associated with immune response and defense response to inflammation and infection (GO terms in defense response, response to bacterium and regulation of immune system), and (E) high-risk CV biomarkers (red), inhibitory immune molecules (purple), BMP-signaling ligands (blue; antagonists and agonist, BMP1), and proteins associated with erythropoiesis (pink) among significant proteins. (F-G) Volcano plots of multiplexed proteomic data in patients with CH mutations comparing patients with baseline anemia (CCUS) vs without baseline anemia (CHIP). Highlighted are (F) proteins associated with immune response and defense response to inflammation and infection, and (G) high-risk CV biomarkers (red), inhibitory immune molecules (purple), BMP-signaling ligands (blue; antagonists and agonist, BMP1), and proteins associated with erythropoiesis (pink) among significant proteins. FDR, false discovery rate; RFU, relative fluorescence unit.