Genetic relationship between Sjögren's syndrome and abdominal aortic aneurysm: insights from a European population's genome-wide association analysis

Background Abdominal aortic aneurysm (AAA) and Sjögren's syndrome (SS) frequently coexist, suggesting shared pathogenesis, but their genetic-immunological links are unclear. Objective Investigate the shared genetic architecture and immune pathways between SS and AAA. Methods Using European GWAS summary statistics (SS: 585 cases/1,546 controls; AAA: 4,083 cases/420,324 controls), we applied complementary genomics approaches: LDSC (genetic correlation), S-LDSC (tissue heritability), PLACO/FUMA (pleiotropic loci), MAGMA/Metascape (pathways), SMR (druggable targets), and HyPrColoc (immune cells). Key results A significant positive genetic correlation exists (rg = 0.32, PFDR = 0.021). We identified 8 shared risk SNPs and 6 pleiotropic genes (e.g., HLA-B, HLA-DQB2, LSM2) within loci 6p22.2-21.32. Pathway analyses revealed significant enrichment for MHC class II antigen presentation ( P = 3.1 × 10 −12 ) and U6 snRNA binding/spliceosome ( P = 2.8 × 10 −7 ). Tissue-specific heritability enrichment occurred in artery/aorta, kidney, and secretory tissues (all pS-LDSC < 9.3 × 10 −4 ). Immune co-localization implicated myeloid dendritic cells expressing HLA-DR (rs9272318) in convergent dysregulation. HLA-B emerged as a prioritised druggable target (pSMR = 1.65 × 10 −8 ). Conclusion This study establishes a shared genetic and immunological basis for SS and AAA, driven primarily by dysregulated HLA-mediated antigen presentation (HLA-B/HLA-DR), spliceosome dysfunction, and NK cell impairment. These findings provide mechanistic insights for early AAA detection in SS patients and support developing immunotherapies targeting HLA pathways.