TNFR Pathway-Related Proteins and Recurrent Coronary Artery Disease Events

Abstract

BACKGROUND Despite optimization with lifestyle modifications and medications, complications of coronary artery disease (CAD) remain the leading cause of adult mortality worldwide. OBJECTIVES This study aimed to identify proteins and pathways linked to recurrent CAD events to better understand residual risk. METHODS We used data from 1,009 participants in the UK Biobank with baseline Olink plasma proteomic measures and CAD. Cox proportional hazards regression modeled the association between proteins measured and recurrent CAD events in follow-up. RESULTS Participants had a mean age of 62.51 years (SD 5.94) at enrollment; 183 (18.14%) were females and 656 (65.01%) had recurrent CAD events over 11.40 (IQR: 8.00-14.69) years of follow-up. Among 1,463 proteins tested, 102 proteins were independently associated with recurrent CAD events. Molecular functions were significantly enriched for tumor necrosis factor receptor (TNFR) activity by 100-fold (P = 6.37 & times; 10-10). Of the 16 proteins related to TNF annotated by the Gene Ontology database, tumor necrosis factor-alpha had a risk estimate of 1.36 (95% CI: 1.17-1.57; P = 6.38 & times; 10-5), TNFR1 (TNFRSF1A) had a risk estimate of 1.73 (95% CI: 1.43-2.09; P = 1.23 & times; 10-8), and TNFR2 (TNFRSF1B) had a risk estimate of 1.27 (95% CI: 1.13-1.44; P = 9.15 & times; 10-5) for recurrent CAD events. CONCLUSIONS Although TNFR1 and TNFR2 were initially thought to have opposing roles in cardiac remodeling postmyocardial infarction, this study highlights the complex interaction between these pathways and the need to identify specific inflammation-related targets to therapeutic strategies. (JACC Adv. 2026;5:102687) (c) 2026 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).