Plasma proteomics reveal key proteins mediating vascular aging

AIMS: To identify plasma proteins with causal roles in vascular aging and to quantify the mediating effects of blood pressure, lipids, and glucose. MATERIALS AND METHODS: We performed a systematic proteome-wide Mendelian randomization (MR) study using genetic instruments from the UK Biobank Pharma Proteomics Project and the Decode cohort. Genetic colocalization (posterior probability ≥70%) was applied to identify shared causal variants between protein levels and multiple vascular aging-related phenotypes. Mediation MR analyses were conducted to quantify the contributions of blood pressure, lipids, and glucose. Phenome-wide association studies (PheWAS) validated the broader phenotypic impact of the identified proteins. KEY FINDINGS: Four plasma proteins (PCSK9, FES, TMEM106B and FURIN) were identified as potential mediators of vascular aging, supported by strong MR causal effects and genetic colocalization evidence. Mediation MR analyses indicated that a substantial proportion (26.7%-75.3%) of their effects on vascular aging was mediated through low-density lipoprotein cholesterol and systolic blood pressure regulation. PheWAS further supported these findings. SIGNIFICANCE: This study identifies four key plasma proteins with potential causal roles in vascular aging, highlighting blood pressure and lipids as major mediators of their effects on vascular aging. These findings provide new insights into the molecular basis of vascular aging and prioritize promising targets for future mechanistic and therapeutic investigation.