ABSTRACT NUMBER: ESOC2026A1574 ASSOCIATIONS OF THE TNF SUPERFAMILY AND RISK OF INCIDENT ISCHEMIC STROKE: A PROTEOMIC ANALYSIS

Abstract Background and aims It is postulated that TNF signaling is involved in the pathogenesis of stroke and cardiovascular disease, but there is limited epidemiological data. We aimed to investigate the association of the TNF superfamily and incident stroke using proteomic analysis. Methods Using data from a large population cohort study (UK Biobank) which included healthy adults without known cardiovascular disease, plasma levels of 34 TNF superfamily proteins (14 ligands, 20 receptors) were measured with Olink Explore. Multivariate Cox regression was used to investigate the association between proteins and incident ischaemic stroke, adjusted for age, sex, ethnicity, cardiovascular risk factors and corrected for multiple comparisons. A secondary analysis was performed for stroke-related cardiovascular endpoints (heart failure, M, AF). Results A total of 48,517 patients (mean age 56.46, 55.40% female) were included in the analysis, with 973 cases of incident ischemic stroke. After adjustment, higher levels (per SD increase) of TNF and its receptors TNFR1 and TNFR2 were associated with incident stroke: TNF (HR 1.31, CI 1.15–1.49), TNFR1 (HR 1.63, 1.35–1.97), and TNFR2 (HR 1.34, 1.18–1.53). An additional 16 members of the TNF superfamily were also associated with incident stroke (Figure 1). Similar associations were identified for stroke-related cardiovascular endpoints (Figure 2). Conclusions These findings implicate TNF signaling in incident ischaemic stroke and stroke-related cardiovascular endpoints. This provides supporting evidence for TNF as a potential target for stroke prevention via the re-purposing of TNF inhibitors in future stroke secondary prevention trials. Conflict of interest Jane Buckley: nothing to disclose. Figure 1 - belongs to Results Figure 2 - belongs to Conclusions