{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:01:25Z","timestamp":1784894485063,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteomes"],"abstract":"<jats:p>Background: Autoimmune diseases (AIDs) are associated with increased cardiovascular risk. However, specific protein mediators linking AIDs to major adverse cardiovascular events (MACE) and cardiovascular death (CV death) remain unexplored. This study identifies proteomic mediators linking AIDs to MACE via high-dimensional mediation analysis in the UK Biobank. Methods: We used UK Biobank data with proteomic profiling by Olink platform. Participants with prevalent myocardial infarction (MI), stroke, and heart failure at baseline were excluded. AIDs were categorized into musculoskeletal (MSK), vasculitis, gastrointestinal (GI), neurologic, and rheumatic fever subsets. Fine\u2013Gray models assessed associations between AIDs and MACE and CV death. Proteome-wide association studies identified proteins associated with both AIDs and cardiovascular outcomes. High-dimensional mediation analysis (HIMA) explored protein-mediated pathways. All models adjusted for age, sex, lipids, BMI, smoking, hypertension, diabetes, chronic kidney disease, atrial fibrillation, and coronary artery disease. Results: Among 400,633 participants (median follow-up 14.5 years, 44.8% male), AIDs were present in 28,754 (7.2%). All AID categories were associated with increased MACE (sHR: MSK 1.34, vasculitis 1.67, GI 1.20, neurologic 1.33, rheumatic fever 1.38; all p &lt; 0.001). For CV death, MSK, vasculitis, and rheumatic fever showed increased risk (sHR 1.34, 1.78, 1.51; all p \u2264 0.004), but not GI or neurologic AIDs. In 43,599 participants with proteomic data, HIMA identified 66 and 32 unique potential mediators linking AIDs to MACE and CV death, respectively. Four proteins (Growth Differentiation Factor 15, Interleukin-15, urokinase plasminogen activator receptor, and Tenascin C) mediated the AID-MACE relationship across multiple AID categories. Growth Differentiation Factor 15 and Interleukin-15 were shared mediators for CV death. Conclusions: This proteomic analysis identifies specific proteins that may mediate the association between AIDs and adverse cardiovascular outcomes, offering mechanistic insights into immune-related cardiovascular risk. These findings are hypothesis-generating and require replication and validation before the identified proteins can be considered causal mediators or adopted for clinical risk stratification.<\/jats:p>","DOI":"10.3390\/proteomes14030038","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"38","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomic Mediators Linking Autoimmune Diseases to Major Adverse Cardiovascular Events: Insights from the UK Biobank"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-7381","authenticated-orcid":false,"given":"Jingwen","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8918-7224","authenticated-orcid":false,"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-6370","authenticated-orcid":false,"given":"Laurence S.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8166-679X","authenticated-orcid":false,"given":"Arshed A.","family":"Quyyumi","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2838-1824","authenticated-orcid":false,"given":"Yan V.","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA"},{"name":"Veterans Affairs Atlanta Healthcare System, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5334\/gh.1288","article-title":"The Heart of the World","volume":"19","author":"Perel","year":"2024","journal-title":"Glob. 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