Clonal Hematopoiesis and Cardiovascular and Microvascular Outcomes in Type 2 Diabetes: A Retrospective Analysis of the UK Biobank

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease, but its associations across cardiovascular and microvascular complications in type 2 diabetes remain incompletely characterized. METHODS: We retrospectively analyzed 17 893 UK Biobank participants with type 2 diabetes, whole-exome sequencing, and no prevalent cardiovascular or microvascular complications. CHIP was defined from the curated UK Biobank call set by ≥1 driver variant with a variant allele fraction ≥2%. Associations with incident outcomes were evaluated using Fine-Gray models with multiple imputation for missing covariates. Driver-gene, clone-size, proteomic, and metabolomic analyses were exploratory. RESULTS: CHIP was present in 670 participants (3.7%) over a median follow-up of 14.6 years. CHIP was associated with the composite cardiovascular outcome (subdistribution hazard ratio [SHR], 1.19 [95% CI, 1.00-1.42]), with heart failure showing the clearest component association (SHR, 1.43 [95% CI, 1.13-1.81]); acute coronary syndrome and stroke were not significantly associated. CHIP was also associated with the composite microvascular outcome (SHR, 1.34 [95% CI, 1.15-1.56]), broad chronic kidney disease (SHR, 1.28 [95% CI, 1.05-1.57]), and retinopathy (SHR, 1.43 [95% CI, 1.15-1.77]) but not neuropathy or strict diabetes-specific nephropathy. Ten-year adjusted risk differences were 1.94% and 3.46% for the cardiovascular and microvascular composites, respectively. Among 2919 proteins, ZBP1 (Z-DNA-binding protein 1) was the only protein retained after false-discovery-rate correction; no metabolite module was associated with CHIP after correction, whereas selected lipoprotein and amino acid/lactate modules were associated with cardiovascular outcomes, particularly heart failure. CONCLUSIONS: In adults with type 2 diabetes, CHIP was associated with a higher risk of incident microvascular complications and, among cardiovascular outcomes, most consistently with heart failure. Exploratory multiomic findings, including a protein-wide ZBP1 signal and selected metabolic associations with cardiovascular outcomes, provided additional biological context but require independent validation.