Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVD), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. CHIP was identified using whole exome sequencing data of blood DNA and modeled both as a composite and for common drivers (DNMT3A, TET2, ASXL1, and JAK2) separately. We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identify 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 risks. We show that CRISPR-induced Asxl1 mutated murine macrophages have a particularly heightened inflammatory response to AIM2 agonism. Our study provides new evidence to support gene-specific strategies to address CHIP-associated CVD risk.

Inflammasomes and Atherosclerosis: a Mixed Picture

“…Strong support for the role of AIM2 in human JAK2 VF CH and ASXL1 CH-associated atherosclerosis has been obtained in a study using data from ~425 000 subjects in the UK Biobank (UKB) published in preprint. 150 The CAD risk of subjects with JAK2 VF and ASXL1 CH was increased in those with higher predicted expression of AIM2 based on expression quantitative trait loci around the AIM2 gene; those without JAK2 VF or ASXL1 CH with higher AIM2 expression scores did not have altered risk and thus the interaction of genotype with predicted AIM2 expression was significant. Moreover, predicted increased expression of IFNGR that mediates interferon-γ signaling increased CAD risk in JAK2 VF CH, consistent with mouse studies showing that interferon-γ increased AIM2 expression in macrophages.…”

“…44 Studies in bone marrow–derived macrophages from Asxl1 CH mice showed increased AIM2 but not NLRP3 inflammasome activation compared with controls. 150 CH subjects collectively who had higher predicted expression of the IL1RAP (IL1 receptor associated protein) that has an essential role in IL-1 signaling, 151 also showed significantly increased CAD risk. These studies point to the broad significance of inflammasome activation in CH-associated CVD risk but suggest distinctive roles for AIM2 and NLRP3 in different forms of CH.…”

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases

“…CH is induced by a gain‐of‐function mutation in one of four genes, TET2 , ASXL1 , DNMT3A or JAK2 , in haematopoietic stem and progenitor cells (HSPCs) (Sánchez‐Cabo & Fuster, 2021). Although CH increased hemopoietic cell expansion and macrophage proliferation, the majority of deaths were caused by atherosclerosis rather than haematological malignancies (Yu et al, 2023). The underlying mechanisms for the increased risk of atherosclerosis and macrophage proliferation remain unclear (Fidler et al, 2021).…”

“…It detects dsDNA in the cytoplasm to carry out its actions (H. Jiang et al, 2023). Due to its specific dsDNA activation mechanism, the AIM2 inflammasome also poses particular cardiovascular risks (Wortmann et al, 2019; Yu et al, 2023). In addition, recent studies have shown that the AIM2 inflammasome promotes metabolic disorders (Hsu et al, 2023; Rossi et al, 2022; Y. Wang et al, 2022).…”

Clonal hematopoiesis of indeterminate potential in persons with HIV

“…IL-1 receptor antagonist (IL-1Ra), because of its longer half-life, represents a practical peripheral marker for inflammasome activity. Moreover, IL-2, which is an inducer of clonal expansion of CD4 þ T cells and of monocyte activation, along with the antiinflammatory marker IL-10, have also been linked to CHIP [15][16][17]. TET2-associated activation of the NLRP3 inflammasome provides a pathophysiological framework, which exemplifies how CHIP might influence inflammation.…”