Plasma proteomics reveal key proteins mediating vascular aging

Area of Science:

• Genetics
• Proteomics
• Cardiovascular Science

Background:

• Vascular aging is a complex process influenced by multiple molecular factors.
• Identifying causal proteins and their mediating pathways is crucial for understanding vascular aging.
• Existing research lacks comprehensive proteome-wide analyses linking plasma proteins to vascular aging.

Purpose of the Study:

• To identify plasma proteins with causal roles in vascular aging.
• To quantify the mediating effects of blood pressure, lipids, and glucose on these protein-mediated pathways.
• To explore the broader phenotypic impact of identified proteins.

Main Methods:

• Systematic proteome-wide Mendelian randomization (MR) study using UK Biobank and Decode cohort genetic data.
• Genetic colocalization to identify shared causal variants between protein levels and vascular aging phenotypes.
• Mediation MR analyses and Phenome-wide association studies (PheWAS) for validation.

Main Results:

• Four plasma proteins (PCSK9, FES, TMEM106B, FURIN) were identified as potential mediators of vascular aging.
• Mediation MR revealed 26.7%-75.3% of effects were mediated by low-density lipoprotein cholesterol and systolic blood pressure.
• PheWAS confirmed the significant phenotypic impact of these proteins.

Conclusions:

• Identified four key plasma proteins with potential causal roles in vascular aging.
• Blood pressure and lipids are major mediators in the effects of these proteins on vascular aging.
• Findings prioritize novel targets for future mechanistic and therapeutic research in vascular aging.