TNFR Pathway-Related Proteins are Associated with Recurrent Coronary Artery Disease Events

Background: Despite optimization of coronary artery disease (CAD) related factors with lifestyle modifications and medications, complications of CAD are the leading cause of death worldwide among adults. The objective of this study was to characterize the proteomic profile and enriched pathways associated with recurrent CAD events to better understand drivers and mechanisms underlying residual CAD risk. Methods: This retrospective analysis included 1,256 participants from the prospective UK Biobank (UKB) with baseline Olink plasma proteomic measures and CAD at enrollment. Cox proportional hazards regression modeled the association between proteins measured and recurrent CAD events in follow-up. Results: Participants had a mean age of 62.46 years (SD 5.86) at enrollment; 236 (18.79%) were female, and 817 (65.05%) had recurrent CAD over 11.40 [interquartile range 8.00-14.69] years of follow-up. Among the 1,463 proteins tested, 102 proteins at experiment-wide significance (Bonferroni p-value < 3.42×10 ⁻⁵ ) were independently associated with recurrent CAD events. Molecular functions were significantly enriched for tumor necrosis factor receptor (TNFR) activity by 100-fold (p-value = 6.37×10 ⁻¹⁰ ) (Figure 1). Of the 8 proteins related to TNF annotated by the Gene Ontology database, TNF-alpha had a risk estimate of 1.36 (95% CI 1.17-1.57, p-value = 6.38×10 ⁻⁵ ), a superfamily of TNFR1 (TNFRSF1A) had a risk estimate of 1.73 (95% CI 1.43-2.09, p-value = 1.23×10 ⁻⁸ ), and a superfamily of TNFR2 (TNFRSF1B) had a risk estimate of 1.27 (95% CI 1.13-1.44, p-value = 9.15×10 ⁻⁵ ) for recurrent CAD (Figure 2). When stratified by clinical subgroups, there was a significant attenuation of the risk estimate for recurrent CAD in older compared to younger patients for TNF-alpha (1.25 vs 1.74, p-interaction = 0.027) and TNFR2 (1.19 vs 1.64, p-interaction = 0.030). There was also a higher risk of recurrent CAD in males compared to females for TNF-alpha (1.78 vs 1.17, p-interaction = 0.010) and TNFR2 (1.71 vs 1.07, p-interaction = 0.002). Conclusion: Recurrent CAD event rates are high and associated with several plasma proteins. Pathway enrichment analyses prioritized TNFR-related proteins. Further research should explore their role in reducing CAD risk.