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Introduction Abdominal aortic aneurysms (AAAs) are often identified incidentally or through screening, underscoring the need for specific biomarkers and insight into AAA-associated systemic changes. Building on previous research, we aimed to identify AAA-specific gene expression signatures in whole blood, using comorbidity matched controls to isolate signals beyond general cardiovascular disease.Methods Ethical approval was obtained (REC reference: 22/PR/1487, EA-92482). Whole blood was collected from 12 patients undergoing elective AAA repair and 12 age-, sex-, and comorbidity-matched patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis. RNA was extracted, followed by globin transcript depletion and polyA-selected RNA sequencing. Differential gene expression (DEG) analysis was performed using DESeq2. Functional enrichment was assessed via Gene Ontology (GO) and KEGG pathway analysis. Clinical and biochemical data were recorded for all participants.Results A total of 221 genes were significantly differentially expressed in AAA whole blood compared to controls. Enriched GO terms included immune response, haemostasis, and platelet activation. KEGG pathways enriched among DEGs included NOD-like receptor and Toll-like receptor signalling, complement activation, and coagulation cascades. Key immune-related pathways were predominantly downregulated in AAA patients. Dysregulated genes included AIM2(p=0.003), C1QB(p=0.0001), VWF(p=0.02), SERPING1(p=0.002), CCL3(p=0.02), PAK6(p=0.04), and SLPI(p=0.002).Conclusion This pilot study reveals a distinct transcriptomic signature in AAA whole blood, highlighting dysregulation of innate immune and haemostatic pathways when compared to matched aortic stenosis controls. These findings offer novel insights into AAA pathogenesis and systemic immune dysregulation, with potential implications for biomarker discovery.