Plasma Proteome Signature for Leukocyte Telomere Length and Its Link to Abdominal Aortic Aneurysm

ABSTRACT Shorter leukocyte telomere length (LTL) is an aging biomarker and risk factor for aging‐related diseases, including abdominal aortic aneurysm (AAA). This study aimed to identify plasma proteins causally associated with LTL and investigate their roles in linking LTL to AAA. A proteomics analysis was conducted for LTL and a polygenic risk score (PRS) for LTL using 4955 plasma proteins by SomaScan in self‐identified White participants ( N = 7587–8055) from the Atherosclerosis Risk in Communities (ARIC) study. Replications were evaluated in self‐identified Black participants ( N = 1668–2094) from ARIC and White participants ( N = 2333–2431) from the Cardiovascular Health Study (CHS). Mendelian randomization (MR) analysis assessed causality between LTL and proteins. Survival and mediation analyses explored protein‐mediated associations between LTL and AAA risk. In ARIC White participants, 15 unique proteins were identified for LTL or LTL PRS. Three LTL‐associated proteins (MZB1, PLOD3, COL28A1) replicated in ARIC Black participants, and six (TNFRSF17, MZB1, CHL1, GDF15, THPO and PLOD3) in CHS White participants. Three proteins associated with LTL PRS (THPO, GP1Bα, PEAR1) replicated in CHS White participants. MR analysis supported causal associations between LTL and five proteins (KDR, TNFRSF17, GDF15, ST3GAL6, CHL1) with all except GDF15 being novel to LTL. LTL was associated with AAA risk (HR = 0.873, 95% CI: 0.803–0.950), with GDF15 mediating 12.4% of this association ( p = 0.028). We identified five proteins causally influenced by LTL and highlighted GDF15 as a mediator linking LTL to AAA risk, offering novel insights into aging biology and AAA pathogenesis.