Plasma EDA2R and Risk of Cardiovascular Diseases and All‐Cause Mortality: Analysis of the UK Biobank Cohort

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Ectodysplasin A2 receptor (EDA2R), a newly identified member of the tumor necrosis factor receptor superfamily, has been implicated in metabolic and inflammatory processes, but its role in CVD is unknown. OBJECTIVE: To examine the associations of plasma EDA2R levels with incident CVD and all-cause mortality. METHODS: A total of 45,305 UK Biobank participants with baseline plasma proteomics measured by Olink were included. EDA2R expression levels in the UKB have been converted to normalized protein expression (NPX). Cox proportional hazards models were used to assess the relationships between EDA2R and CVD, as well as all-cause mortality. Temporal trajectories of EDA2R before events were examined using a nested case-control design with LOESS smoothing. Causal mediation and GO enrichment analyses were performed to identify mediating proteins and underlying pathways. RESULTS: Over a median follow-up of 15 years, 8667 participants (19.1%) developed CVD, and 3988 (8.8%) died. After fully adjusted, each 1 NPX increase in plasma EDA2R was associated with a 74% higher risk of CVD and a 177% higher risk of all-cause mortality, with risks increasing monotonically across the entire distribution. Mediation analysis identified 302 proteins for CVD and 482 for mortality, enriched in death receptor activity, tumor necrosis factor receptor activity, cytokine and growth factor binding, and immune receptor activity. CONCLUSION: Elevated plasma EDA2R is strongly associated with long-term risks of CVD and all-cause mortality, suggesting its potential as a novel prognostic biomarker and therapeutic target.