Clonal Hematopoiesis of Indeterminate Potential Refines Cardiovascular Risk Stratification in Cardiovascular-Kidney-Metabolic Syndrome Stages 0–3
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Background
Chronic low-grade inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related driver of systemic inflammation, is linked to several cardiometabolic disorders. However, whether CHIP modifies CKM progression and contributes to heterogeneity in cardiovascular disease (CVD) risk within the CKM framework remains uninvestigated.
Methods
This cohort study included 307,025 UK Biobank participants at CKM stages 0–3 free of baseline CVD. CHIP status was identified via whole-exome sequencing (WES). The association between CHIP and baseline CKM severity was examined, along with the independent and joint effects of CHIP and CKM stages on incident CVD risk. The joint effects of CHIP and polygenic risk scores (PRS) were further assessed, and the incremental predictive value of incorporating CHIP into the AHA PREVENT equations was evaluated.
Results
CHIP carriers were more likely to present with advanced CKM stages [OR 1.14 (1.09-1.20), P < 0.001] and exhibited higher incident CVD risk during follow-up [HR 1.13 (1.08-1.18), P < 0.001]. Significant joint effects between CHIP and CKM stages were observed, with the highest risk among CHIP carriers at CKM stage 3 [HR 1.63 (1.50-1.78), P < 0.001]. Large or multiple CHIP mutations conferred greater hazards, with distinct gene-specific effects observed. Moreover, CHIP and high genetic risk also jointly amplified CVD susceptibility. Most importantly, incorporating CHIP into AHA PREVENT significantly improved risk discrimination.
Conclusions
CHIP is a significant risk factor associated with more advanced CKM stages and amplifies incident CVD risk. Integrating CHIP into existing prevention strategies may refine CVD risk stratification.
Graphic Abstract
Clinical Perspective
What Is New?
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This study provides large-scale evidence that clonal hematopoiesis of indeterminate potential (CHIP) is associated with more advanced cardiovascular-kidney-metabolic (CKM) stages and jointly amplifies future cardiovascular disease (CVD) risk within the CKM staging framework.
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Somatic CHIP and germline polygenic susceptibility were jointly associated with CKM severity and CVD risk, with the greatest risk observed among individuals with both high polygenic risk and CHIP.
What Are the Clinical Implications?
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CHIP significantly refines CVD risk stratification across AHA PREVENT risk categories and provides incremental predictive value. Incorporating CHIP into CKM-based prevention strategies may help identify individuals with excess residual cardiovascular risk before the development of clinical CVD.
