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 (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 CVDprotective 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.

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).…”

“…But in TET2-regulated CH, the NLRP3 inflammasome reduced atherosclerosis and HF symptoms. To some extent, different genetically mutated CHs are correspondingly controlled by distinct inflammasomes (Yu et al, 2023). Nevertheless, additional research is required to investigate the precise mechanism by which the gene mutation is linked to particular inflammasomes.…”

“…Despite its recognition as a critical DNA sensor, the specific pathogenic mechanism of the AIM2 inflammasome in cardiocerebrovascular and metabolic diseases remains unclear. Current research, mostly based on population studies and phenotypic validation, does not fully elucidate this mechanism (Wortmann et al, 2019;Yu et al, 2023). Further research is warranted to better understand the upstream regulators and downstream signalling pathways involved in AIM2 inflammasomes.…”

“…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).…”

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 + T cells and of monocyte activation, along with the anti-inflammatory marker IL-10, have also been linked to CHIP [15–17]. TET2 -associated activation of the NLRP3 inflammasome provides a pathophysiological framework, which exemplifies how CHIP might influence inflammation.…”