Clonal Haematopoiesis of Indeterminate Potential: a Unifying Mechanism Linking Meta-inflammation and Cardiometabolic Diseases.

Abstract

Clonal haematopoiesis of indeterminate potential (CHIP) refers to the age-related expansion of haematopoietic stem cells bearing somatic mutations in the absence of overt haematological malignancy. Emerging evidence suggests that CHIP is not merely a marker of ageing, but an active driver of meta-inflammation, a chronic systemic inflammatory state arising from metabolic dysregulation. Indeed, several studies have linked CHIP with an increased risk of cardiovascular, renal and hepatic diseases, diseases which are known to be driven by inflammation. CHIP also appears to be associated with upstream metabolic precursors such as obesity and type 2 diabetes, suggesting its involvement across the cardiometabolic disease continuum. Importantly, this relationship may be bidirectional: systemic inflammation promotes CHIP expansion, while CHIP mutations further fuel inflammation. Thus, anti-inflammatory agents that mitigate CHIP-driven inflammation may have a future therapeutic role in cardiometabolic diseases. Furthermore, gene-based therapies offer exciting opportunities for precision approaches in CHIP. This review aims to synthesise emerging evidence that links CHIP with cardiovascular, renal and hepatic diseases, emphasising shared inflammatory pathways. Moreover, the review aims to highlight current knowledge gaps, including the need to establish causality between CHIP and cardiometabolic diseases. Furthermore, it emphasizes the need for future research in both human populations and pre-clinical models to elucidate the underlying mechanisms that could ultimately position CHIP at the forefront of cardiometabolic medicine.