ABSTRACT NUMBER: ESOC2026A1550 CIRCULATING AND GENETICALLY DETERMINED TUMOR NECROSIS FACTOR ALPHA (TNF-Α) TO REVEAL ETIOLOGIES OF ISCHEMIC STROKE: INSIGHTS FROM THE PHEGAESUS STUDY

Abstract Background and aims The TNF-α promoter variant rs1800629 and TNF-α serum levels could indicate inflammatory pathways across stroke subtypes, aiding precise etiology assignment. In this phenotype-genotype association study investigating embolic stroke of undetermined source (ESUS) (PHEGAESUS), we performed targeted analyses to elucidate the role of TNF-α and its genetic variants in stroke etiologies. Methods Within the PHEGAESUS study, ischemic stroke patients were consecutively recruited at Hannover Medical School between December 2020 and July 2023. Genotyping was performed using Axiom myDesign Custom Genotyping Array. TNF-α serum concentrations were measured by chemiluminescence immunoassay in samples obtained >24h after stroke onset. We performed explorative analyses between rs1800629 and ESUS, and between rs1800629 and TNF-α serum concentration. Results After quality control, data from 1,001 patients with both SNP and clinical information were available. Comparing 288 ESUS patients to 713 patients assigned to another defined etiology, rs1800629 carriers in a dominant model (GA+AA) showed a higher prevalence in ESUS than in other stroke etiologies (35.8% vs. 29.2%, p-chi2: 0.042, OR 1.35, 95%CI 1.01-1.8). No difference across genotypes was observed for TNF-α serum concentration in ESUS (median (IQR) GA+AA (n=46) vs. GG (n=96): 10.7 (4.4)pg/ml vs. 9.8 (5.3)pg/ml, p Mann-Whitney-U: 0.36). Conclusions TNF-α promoter variant rs1800629 is enriched in ESUS patients but does not appear to influence TNF-α serum levels. These findings suggest a complex relationship between biomarker and genetic variation. Further investigation of the genomic region of TNF-α is warranted to clarify the potential pathophysiological role of inflammatory pathways in ESUS. Conflict of interest Ricarda Siegel: nothing to disclose, Johannes Teller: nothing to disclose, Gerrit M. Grosse: nothing to disclose, Ramona Schuppner: nothing to disclose, Johanna Ernst: nothing to disclose, Ralf Lichtinghagen: nothing to disclose, Karin Weissenborn: nothing to disclose, Gesa Wilde: nothing to disclose, Hannelore Ehrenreich: nothing to disclose, Anika Grosshennig: nothing to disclose