Tsai-sang Dederichs (Germany)
University Heart Center Freiburg- Bad Krozingen Cardiology and Angiology 1, AG HilgendorfAuthor Of 1 Presentation
O033 - CHIP mutations mediate human atherosclerosis by activating monocyte pro-inflammatory pathways without evidently promoting monocyte chemotaxis (ID 713)
Abstract
Background and Aims
Clonal hematopoiesis of indeterminate potential (CHIP) is an age‑associated expansion of blood cells that carry specific somatic mutations. CHIP mutations double the risk of CAD and are associated with worse overall survival. Our research aims to understand how CHIP mutations change the myeloid cell biology and contribute to atherosclerosis.
Methods
We screened 812 patients admitted for left heart coronary angiography in University Heart Center Freiburg and conducted targeted genomic sequencing to identify CHIP carriers. We applied single‑cell gDNA/mRNA parallel sequencing to perform intra‑individual comparison of gene expression in monocytes carrying DNMT3A H882 hotspot mutation and that in non‑mutated monocytes.
Results
The prevalence of CHIP mutation was at least two times higher in all age groups of our cohort than that of general population. Middle‑aged (age of 40 to 69) patients with mutations in the two most common CHIP genes, DNMT3A and TET2, had significantly higher burden of CAD than those without CHIP mutations. Single‑cell RNA profiling revealed that monocytes with DNMT3A H882C mutation formed separate clusters and distinctively increased the expression of genes that regulate IFNγ, IL‑6, IL‑12, and TNF production or response. Genes regulating monocyte chemotaxis was not differentially expressed in mutated monocytes.
Conclusions
We confirmed the enhanced risk of CAD associated with CHIP mutations. With single‑cell gDNA/RNA parallel sequencing, we demonstrated the direct effect of CHIP mutation on monocyte biology, avoiding inter‑individual variation. DNMT3A H882C mutation altered gene expression of monocytes and activated pro‑inflammatory pathways without noticeable influences on monocyte chemotaxis.
Presenter of 1 Presentation
O033 - CHIP mutations mediate human atherosclerosis by activating monocyte pro-inflammatory pathways without evidently promoting monocyte chemotaxis (ID 713)
Abstract
Background and Aims
Clonal hematopoiesis of indeterminate potential (CHIP) is an age‑associated expansion of blood cells that carry specific somatic mutations. CHIP mutations double the risk of CAD and are associated with worse overall survival. Our research aims to understand how CHIP mutations change the myeloid cell biology and contribute to atherosclerosis.
Methods
We screened 812 patients admitted for left heart coronary angiography in University Heart Center Freiburg and conducted targeted genomic sequencing to identify CHIP carriers. We applied single‑cell gDNA/mRNA parallel sequencing to perform intra‑individual comparison of gene expression in monocytes carrying DNMT3A H882 hotspot mutation and that in non‑mutated monocytes.
Results
The prevalence of CHIP mutation was at least two times higher in all age groups of our cohort than that of general population. Middle‑aged (age of 40 to 69) patients with mutations in the two most common CHIP genes, DNMT3A and TET2, had significantly higher burden of CAD than those without CHIP mutations. Single‑cell RNA profiling revealed that monocytes with DNMT3A H882C mutation formed separate clusters and distinctively increased the expression of genes that regulate IFNγ, IL‑6, IL‑12, and TNF production or response. Genes regulating monocyte chemotaxis was not differentially expressed in mutated monocytes.
Conclusions
We confirmed the enhanced risk of CAD associated with CHIP mutations. With single‑cell gDNA/RNA parallel sequencing, we demonstrated the direct effect of CHIP mutation on monocyte biology, avoiding inter‑individual variation. DNMT3A H882C mutation altered gene expression of monocytes and activated pro‑inflammatory pathways without noticeable influences on monocyte chemotaxis.