{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:21:12Z","timestamp":1792264872043,"version":"4.4.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2023J01176"],"award-info":[{"award-number":["2023J01176"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Cardiology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To examine the associations of plasma EDA2R levels with incident CVD and all\u2010cause mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010cause mortality. Temporal trajectories of EDA2R before events were examined using a nested case\u2013control design with LOESS smoothing. Causal mediation and GO enrichment analyses were performed to identify mediating proteins and underlying pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Over a median follow\u2010up of 15 years, 8667\u00a0participants (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\u2010cause 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Elevated plasma EDA2R is strongly associated with long\u2010term risks of CVD and all\u2010cause mortality, suggesting its potential as a novel prognostic biomarker and therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/clc.70314","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:17:17Z","timestamp":1777371437000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma EDA2R and Risk of Cardiovascular Diseases and All\u2010Cause Mortality: Analysis of the UK Biobank Cohort"],"prefix":"10.1002","volume":"49","author":[{"given":"Ziqing","family":"Ruan","sequence":"first","affiliation":[{"name":"Department of Cardiology Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital Fuzhou China"},{"name":"Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases Fuzhou China"},{"name":"Fujian Heart Failure Center Alliance Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabin","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital Fuzhou China"},{"name":"Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases Fuzhou China"},{"name":"Fujian Heart Failure Center Alliance Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongli","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital Fuzhou China"},{"name":"Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases Fuzhou China"},{"name":"Fujian Heart Failure Center Alliance Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Zhi","sequence":"additional","affiliation":[{"name":"Fujian Medical University School of Pharmacy Fuzhou Fujian 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