Mechanisms by which clonal haematopoiesis of indeterminate potential (CHIP)-driver mutations confer cardiovascular risk

• Applicant: Professor Dr. Ingo Hilgendorf
• Subject Area: Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464669100

Clonal haematopoiesis of indeterminate potential (CHIP) is characterized by the presence of an expanded blood cell clone carrying somatic mutations, most commonly in epigenetic modifier genes DNMT3A or TET2, which are associated with a ten times higher risk for developing haematological malignancies. Yet, increased mortality in carriers of CHIP-driver mutations is largely determined by cardiovascular disease rather than leukaemia. Our preliminary data show that in patients undergoing coronary angiography in our hospital, CHIP is three times more prevalent compared to the general population. The molecular and cellular mechanisms by which CHIP increases cardiovascular risk are ill-defined, and mainly rely on experimental models in transgenic mice. We hypothesize that genomic mutation in CHIP-driver genes reprograms the monocyte/macrophage machinery via epigenetic modification that regulates gene transcription and translation, leading to an altered cell fate triggering chronic inflammation in the cardiovascular system. To close the knowledge gap, we established a protocol to sequence genomic DNA and messenger RNA in parallel from the same cell, and will model CHIP clones in vitro by base-editing human iPSC-derived monocytes and macrophages for multi-omic analysis. Taken together, our proposed work will unveil mechanistic links between CHIP-driver mutation induced DNA methylation changes, transcriptional dysregulation and altered cell function, laying the foundation for identifying specific therapeutic targets in CHIP-driven cardiovascular disease.

• DFG Programme: Research Grants