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Yu Z, Fidler TP, Ruan Y, Vlasschaert C, Nakao T, Uddin MM, Mack T, Niroula A, Heimlich JB, Zekavat SM, Gibson CJ, Griffin GK, Wang Y, Peloso GM, Heard-Costa N, Levy D, Vasan RS, Aguet F, Ardlie KG, Taylor KD, Rich SS, Rotter JI, Libby P, Jaiswal S, Ebert BL, Bick AG, Tall AR, Natarajan P
J. Clin. Invest. 133 (18) - [2023-09-15; online 2023-09-15]
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD-protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.
PubMed 37498674
DOI 10.1172/JCI168597
Crossref 10.1172/JCI168597
pmc: PMC10503804
pii: 168597