AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Leukocyte Telomere Length Polygenic Risk Score for Coronary Artery Disease Across the Spectrum of Atherosclerotic Disease: An Analysis of 59,905 Patients from 6 TIMI Randomized Trials
By Lai YP, Kamanu F, Melloni G et al.
Background: Leukocyte telomere length (LTL), a marker of biological aging, has been associated with the risk of coronary artery disease (CAD) in epidemiological studies, and Mendelian randomization studies have supported a causal effect of genetically predicted shorter LTL with the development of CAD. However, whether an LTL polygenic risk score (PRS) predicts incident events across the spectrum of atherosclerotic cardiovascular disease (ASCVD), independent of traditional risk factors, remains uncertain. Purpose: To evaluate the association of an LTL PRS with cardiovascular events among patients without overt ASCVD and in patients with ASCVD with and without a prior event. Methods: Genotyped data from six TIMI trials (ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, DECLARE-TIMI 58, FOURIER (TIMI 59)) spanning populations with diabetes mellitus, atrial fibrillation, recent ACS, stable ASCVD, and prior MI were pooled for analysis. An LTL PRS derived from a UK Biobank LTL GWAS ( Nat Genet, 2021 ) was evaluated alongside a restricted CAD PRS ( Nat Med, 2023 ), from which variants overlapping LTL-associated loci were excluded to account for shared genetic architecture. PRS was analyzed continuously (per 1-SD) and categorically as high (top decile), intermediate, and low risk (bottom decile). The primary endpoint was major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. Associations were assessed using Cox proportional hazards models adjusted for age, sex, ancestry, trial, and traditional risk factors. Results: A total of 59,905 patients were included (median f/u 3.2 yrs; mean age 66 yrs; 71% male; 79% with prior ASCVD), of whom 5,557 (9.3%) patients experienced MACE during follow-up. A higher LTL PRS (genetically predicted shorter LTL) was independently associated with an increased risk of MACE among participants without overt ASCVD (adjusted HR per 1-SD: 1.08 [1.01-1.16]; P =0.019). Compared to the bottom decile, those in the top decile had a nearly 40% higher risk of events (8.1% vs 6.2% at 3.2 yrs; adjusted HR 1.39 [1.03-1.87]; P =0.032). In contrast, no significant association was observed among patients with established ASCVD. The corresponding P -interaction between numerical LTL PRS and the ASCVD status was 0.068 (Figure1A). Among patients without overt ASCVD, the association remained consistent after further adjustment for the restricted CAD PRS, with the increased risk associated with high LTL PRS comparable to that of conventional risk factors ( P- trend=0.019; Figure1B). No significant treatment interaction with LTL PRS was observed across the six individual trials. Conclusion: An LTL PRS was associated with MACE among patients without overt ASCVD, independent of clinical risk factors and CAD PRS, and may provide an ability to improve cardiovascular risk stratification in these individuals.