Accelerated hematopoietic aging in type 1 diabetes links telomere attrition to myocardial infarction

Type 1 diabetes (T1D) is associated with early-onset and increased risk of coronary artery disease (CAD), particularly myocardial infarction (MI), that is not fully explained by traditional cardiovascular risk factors. Hematopoietic aging, marked by clonal hematopoiesis of indeterminate potential (CHIP) and leukocyte telomere length (LTL) attrition, has been linked to CAD risk in the general population. We investigated whether T1D is associated with increased prevalence and earlier onset of CHIP and accelerated LTL attrition, and whether these processes contribute to CAD risk.

We analyzed 416,565 UK Biobank participants (1,342 T1D cases) with harmonized CHIP calls and qPCR-derived LTL measurements. T1D was defined using ICD-10 codes, diagnosis before age 40 years, and insulin initiation within one year. CHIP was defined as variant allele fraction >=2%, with higher thresholds evaluated in sensitivity analyses. Multivariable regression compared CHIP prevalence, age-specific CHIP probability, and LTL between T1D and controls. Associations of CHIP and LTL with prevalent and incident (median follow-up approximately 13.5 years) MI and CAD were evaluated within T1D. Mendelian randomization, conjFDR, and integrated single-cell genomic analyses assessed genetic relationships.

CHIP prevalence was higher in T1D than in controls (4.40% vs 3.00%; absolute risk difference 1.39%, 95% CI 0.29 to 2.49; p=3.7×10-3), with higher adjusted odds (OR 1.71, 95% CI 1.31 to 2.23; p=6.9×10-5). Age modeling indicated an approximately 7-year earlier shift in CHIP risk in T1D (3% prevalence at age 52.2 vs 59.0 years). Mean LTL did not differ significantly between T1D and controls (beta −0.040 SD; p=0.13); however, T1D disease duration was associated with shorter LTL independent of covariates (beta −0.0082 SD per year; p=0.002). Within T1D, shorter LTL was associated with higher risk of both prevalent and incident MI (OR 0.77, 95% CI 0.65 to 0.91; p=0.003; HR 0.63, 95% CI 0.44 to 0.91; p=0.012). CHIP was not significantly associated with MI or CAD in this cohort. Genetic analyses supported a bidirectional relationship between T1D and LTL, but not CHIP, and identified 47 T1D-LTL loci enriched for hematopoietic stem and progenitor cell pathways.

In conclusion, T1D is associated with accelerated hematopoietic aging, reflected by earlier and more prevalent CHIP and disease duration-dependent LTL attrition. LTL attrition, but not CHIP, was associated with MI risk, implicating telomere dynamics as a contributor to excess cardiovascular risk in T1D.