PCSK9, FES, TMEM106B, and FURIN identified as causal plasma proteins mediating vascular aging

Understanding the molecular drivers of vascular aging is crucial, as it underpins many age-related cardiovascular diseases. Traditional risk factors like high blood pressure and dyslipidemia are well-known, but the specific proteins that causally link these factors to vascular decline remain elusive. This gap hinders the development of targeted interventions. Identifying key plasma proteins with causal roles could provide novel therapeutic targets to mitigate endothelial dysfunction and systemic inflammaging, which are hallmarks of biological aging and contribute significantly to vascular pathology.

Researchers conducted a systematic proteome-wide Mendelian randomization (MR) study to identify plasma proteins with causal roles in vascular aging. They utilized genetic instruments from the UK Biobank Pharma Proteomics Project and the Decode cohort. Genetic colocalization (posterior probability ≥70%) was applied to confirm shared causal variants between protein levels and multiple vascular aging-related phenotypes. Subsequent mediation MR analyses quantified the contributions of blood pressure, lipids, and glucose. Finally, Phenome-wide association studies (PheWAS) validated the broader phenotypic impact of the identified proteins.

Four specific plasma proteins were identified as potential causal mediators of vascular aging: PCSK9, FES, TMEM106B, and FURIN. This identification was strongly supported by robust MR causal effects and compelling genetic colocalization evidence. Mediation MR analyses provided quantitative insights into how these proteins exert their effects. They revealed that a substantial proportion of their impact on vascular aging was mediated through the regulation of low-density lipoprotein cholesterol and systolic blood pressure.