Clonal haematopoiesis and cardiovascular-kidney-metabolic syndrome: a cohort study.

BACKGROUND AND AIMS: The cardiovascular-kidney-metabolic (CKM) syndrome framework integrates the shared pathophysiology of cardiovascular disease, excess adiposity, diabetes, and chronic kidney disease into a unified staging framework. Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic stem cells harbouring somatic mutations, has been linked to several CKM components, but its relationship with CKM syndrome is unknown. METHODS: UK Biobank participants without a history of hematologic malignancy were included. Exposures included any CHIP, large CHIP, and major gene-specific CHIP subtypes. Outcomes were CKM stage and progression to stage 4 CKM syndrome during follow-up. Associations of CHIP with CKM stage and progression were tested using multivariable-adjusted logistic and Cox regression, respectively. Proteomic mediation analyses prioritized circulating proteins associated with CKM progression. RESULTS: Among 451,460 participants (mean [SD] age, 56.5 [8.1] years; 245,055 females [54.3%]), 15,486 (3.4%) had CHIP. CHIP was associated with higher CKM stage, driven by associations with non-DNMT3A CHIP, including TET2 (adjusted OR [aOR], 1.10; 95% CI, 1.00-1.20; false discovery rate [FDR]-corrected P = 0.045) and JAK2 CHIP (aOR, 1.68; 95% CI, 1.20-2.35; FDR-corrected P = 0.003). Over a median (IQR) 13.5 (12.6-14.3) years of follow-up, CHIP was independently associated with progression to stage 4 CKM, again driven by associations with non-DNMT3A CHIP subtypes (aHR, 1.24; 95% CI, 1.17-1.31; FDR-corrected P < 0.001). Proteomic mediators of progression to stage 4 CKM in non-DNMT3A CHIP were enriched for immune and inflammatory signalling pathways. CONCLUSION: These findings identify non-DNMT3A CHIP as a marker of CKM progression and support inflammatory mechanisms linking CHIP to CKM syndrome.