Journal Article

Genetic modification of inflammation- and clonal hematopoiesis–associated cardiovascular risk

Vasan, Ramachandran S., Yu, Zhi, Nakao, Tetsushi, Ebert, Benjamin L., Natarajan, Pradeep, Taylor, Kent D., Zekavat, Seyedeh M., Ruan, Yunfeng, Heard-Costa, Nancy, Fidler, Trevor P., Tall, Alan R., Bick, Alexander G., Vlasschaert, Caitlyn, Uddin, Md Mesbah, Mack, Taralynn, Heimlich, J. Brett, Wang, Yuxuan, Niroula, Abhishek, Gibson, Christopher J., Rotter, Jerome I., Aguet, François, Jaiswal, Siddhartha, Libby, Peter, Griffin, Gabriel K., Rich, Stephen S., Levy, Daniel, Peloso, Gina M., Ardlie, Kristin G.

2023

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Atherosclerosis / Basic Medicine / Biobanks / Biomedical research / Cardiology / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - genetics / Clonal Hematopoiesis - genetics / Cloning / CRISPR / Diabetes / DNA damage / DNA repair / DNA sequencing / Gene expression / Genes / Genetic aspects / Genetically modified organisms / Genetics / Genomics / Health aspects / Heart Disease Risk Factors / Hematopoiesis / Hematopoiesis - genetics / Hemopoiesis / Humans / Inflammasomes / Inflammasomes - genetics / Inflammation / Inflammation - complications / Inflammation - genetics / Janus kinase 2 / Macrophages / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Methyltransferases / Mice / Mutation / Pharmaceutical industry / Risk Factors / Scientific equipment and supplies industry / Type 2 diabetes