Genetic modification of inflammation and clonal hematopoiesis-associated coronary artery disease
Yu, Z.; Fidler, T. P.; Ruan, Y.; Vlasschaert, C.; Nakao, T.; Uddin, M. M.; Mack, T.; Niroula, A.; Heimlich, J. B.; Zekavat, S. M.; Gibson, C. J.; Griffin, G. K.; Wang, Y.; Peloso, G. M.; Heard-Costa, N.; Levy, D.; Vasan, R. S.; Aguet, F.; Ardlie, K.; Taylor, K. D.; Rich, S. S.; Rotter, J. I.; Libby, P.; Jaiswal, S.; Ebert, B. L.; Bick, A. G.; Tall, A. R.; Natarajan, P.
Show 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, 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 new evidence to support gene-specific strategies to address CHIP-associated CVD risk.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Human Plasma Proteomic Profile of Clonal Hematopoiesis 96%
- Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistanis and Bangladeshis 96%
- Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease 96%
Similar papers in this journal
- Ox-LDL induces a non-inflammatory response enriched for coronary artery disease risk in human endothelial cells 96%
- Elucidating the genetic architecture of DNA methylation to identify promising molecular mechanisms of disease 95%
- Whole-genome sequencing identifies variants in ANK1 , LRRN1 , HAS1, and other genes and regulatory regions for stroke in type 1 diabetes 94%
Similar papers in this journal
- Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease 96%
- Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension 96%
- Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.