UK Biobank Study Links CKM Syndrome Stages to Stepwise Cancer Risk via Distinct Immune-Metabolic Pathways
核心洞察
Analysis of 448,323 UK Biobank participants found overall cancer (搜索) risk rose incrementally from cardiovascular-kidney-metabolic (CKM) syndrome stage I through stage III, with persistent elevation at stage IV.
Stage-specific mediators were identified, from leukocyte activation in stage I to dominant natural killer cell tolerance induction and tissue-resident chronic pathology in stage IV.
Metabolomic mediation shifted from high-density and triglyceride-rich lipoproteins (搜索) in early stages toward low-density lipoproteins in later stages, alongside stage-specific protein-metabolite interaction networks.
Cardiovascular-kidney-metabolic (CKM) syndrome is associated with incremental cancer (搜索) risk and stage-specific immune-metabolic pathways, according to a UK Biobank study published by Xiao et al in JACC: CardioOncology. The authors report that the findings elucidate biological pathways linking CKM stages to oncogenesis and highlight stage-specific immune-metabolic pathways as potential targets for integrated cardiometabolic and cancer prevention.
Cohort Design and Follow-Up
In the large, prospective cohort study, researchers categorized more than 500,000 UK Biobank participants recruited between 2006 and 2010 into CKM stages 0 to IV. After excluding participants with a cancer (搜索) history at recruitment or who developed cancer within 1 year of recruitment, 448,323 participants were eligible for analysis.
Associations between CKM staging and overall cancer (搜索) incidence were evaluated using Cox regression. Proteomic and metabolomic mediators linking adjacent stages and cancer underwent Gene Ontology enrichment and interaction network analyses, and were identified using Cox regression, logistic regression, and mediation analysis.
Over a median follow-up of 4.3 years, 27,251 participants developed cancer (搜索).
Cancer Risk Rises Across CKM Stages
Results showed that overall cancer (搜索) risk increased from CKM stages I to III, with a slight attenuation and persistent elevation in stage IV.
The study further identified stage-specific mediators and mechanisms across the CKM continuum. These comprised leukocyte/lymphocyte activation and cell-cell adhesion in stage I; T cell–related immunity and emerging immune tolerance induction in stage II; emerging natural killer (NK) cell tolerance induction and respiratory burst involved in the inflammatory response in stage III; and dominant NK cell tolerance induction and tissue-resident chronic pathology in stage IV.
Metabolomic and Proteomic Shifts
Dominant metabolomic mediation evolved from high-density lipoproteins (HDLs) and triglyceride-rich lipoproteins (搜索) (TRLs) to low-density lipoproteins (LDLs), according to the investigators.
Protein-metabolite interaction networks revealed stage-specific profiles, including angiopoietin-like protein 1 (搜索)/HDL and asialoglycoprotein receptor 1 (搜索)/TRL interactions in early stages, and phospholipid transfer protein (搜索)/HDL, apolipoprotein M (搜索)/LDL, and fibroblast growth factor–binding protein 1/intermediate-density lipoprotein/LDL correlations in the later stages.
Validation Still Required
The authors framed the work as a mechanistic map rather than a validated interventional strategy. "These findings elucidate biological pathways linking CKM stages to oncogenesis and highlight stage-specific immune-metabolic pathways as potential targets for integrated cardiometabolic and cancer (搜索) prevention," they wrote, adding that "the mediating mechanisms require further validation in experimental and interventional studies."
Parallel Evidence on Biological Age and Mortality in CKM
Separate evidence published in Medicine (Baltimore) by Chen et al examined biological age acceleration as a prognostic marker in CKM syndrome. That analysis included 16,837 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999–2010 and 2015–2018, with mortality data linked through 2019. Biological age was estimated using Klemera-Doubal Method Biological Age (KDM-BA) and Phenotypic Age algorithms, with residuals used to define biological age acceleration.
Over a median follow-up of 11.33 years, 10.8% of the weighted population, equivalent to 9.75 million adults, died. After full adjustment for confounding factors, positive KDM-BAA was associated with a 41% higher risk of all-cause mortality, a 74% higher risk of cardiovascular disease (搜索) mortality, and a 31% higher risk of non-cardiovascular disease mortality. Positive phenotypic age acceleration (PAA) showed stronger associations, with respective risk increases of 103%, 79%, and 112% for all-cause, cardiovascular disease, and non-cardiovascular disease mortality.
Both measures demonstrated consistent positive associations across multiple subgroups and sensitivity analyses. The researchers also developed LASSO-Cox nomograms to predict mortality, with training area under the curve values of 0.776 and 0.775 at 10 and 20 years, respectively, and corresponding validation values of 0.765 and 0.757, with good calibration reported. PAA demonstrated greater prognostic value than KDM-BAA in the analysis.
The researchers concluded that biological age acceleration independently predicted long-term mortality among adults at CKM syndrome stages 0–3 and suggested that monitoring biological ageing could potentially support earlier intervention and improve long-term outcomes.