Discovery of underlying mechanisms by which clonal hematopoiesis of indeterminate potential (CHIP) provokes coronary artery diseases

Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is an acquired, genetic cardiovascular (CV) risk factor. In order to understand how CHIP mediates CV diseases, we conducted a clinical study to investigate patients undergoing coronary angiography. In our study cohort, CHIP was three times more prevalent than in the general public and was associated with more severe coronary artery disease. Following the clinical findings, we hypothesized that CHIP-mutant monocytes infiltrate better into arterial intima hence accelerate the formation of atheroma lesions. To test our hypothesis, we examined the CHIP mutation frequency of blood monocytes and plaque macrophages from CHIP carriers who underwent carotid endarterectomy. We rejected the hypothesis by showing that plaque macrophages bear the same frequency of CHIP mutation as blood monocytes do. Subsequently, we shifted our focus onto characterizing the CHIP-mutant circulating monocytes.
Recent studies suggest that pro‐inflammatory myeloid cells mediate CHIP‐associated CV risk but have missed to prove a direct linkage between CHIP genotype and phenotype on a single cell level in order to claim causality. To identify an intrinsic effect of CHIP mutation, we applied a single-cell parallel DNA/RNA sequencing technique, by which we discovered that mutant and non‐mutant monocyte gene expression profiles were unexpectedly indistinguishable but collectively more inflammatory in DNMT3A mutation carriers than in non-carriers. The findings inspired the hypothesis: Impacts of CHIP mutation start in the upstream myelopoiesis. We tested our hypothesis applying single-cell parallel sequencing on bone marrow cells from a CHIP carrier (DNMT3A p.R882H) who underwent sternotomy. We found that mutant hematopoietic stem and progenitor cells (HSPC) were more inflammatory as opposed to the non-mutant counterparts. Based on our results, we propose a model that explains how CHIP mutations drive inflammatory myelopoiesis, which ultimately results in overt CV diseases

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2022

Klassifikation und Themen

• Schlagwort: High throughput screening ; Kardiovaskuläre Krankheit ; Mutation ; Entzündung

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Dederichs, Tsai-Sang
• Beteiligte Personen und Organisationen: Hilgendorf, Ingo ; Hilgendorf, Ingo ; Zeiser, Robert ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/232421
• URN: urn:nbn:de:bsz:25-freidok-2324219
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:51 MEZ