Integrin-focal adhesion-cytoskeleton signaling axis variations and genetic susceptibility to SCD-CAD

Sudden cardiac death (SCD) is a leading cause of global mortality, with coronary artery disease (CAD) being the primary etiology. Vascular smooth muscle cell (VSMC) migration and proliferation, regulated by actin cytoskeletal dynamics, are pivotal to CAD pathogenesis. The integrin-focal adhesion-cytoskeleton signaling axis modulates these processes; however, its genetic contribution to SCD-CAD remains poorly understood. In this case-control study of a southern Chinese Han population (239 SCD-CAD cases; 594 healthy controls), we investigated 10 insertion-deletion (indel) polymorphisms across eight key genes within this axis. Using multiplex fluorescent PCR and capillary electrophoresis (CE), followed by logistic regression and haplotype analyses, we identified three protective variants: rs10599004 (OR = 0.78, p = 0.018), rs143263543 (OR = 0.70, p = 0.024), and rs58213835 (OR = 0.80, p = 0.046). Additionally, a significant risk haplotype was identified in BCAR1 (ins-rs149617239-ins-rs58213835, p = 0.007). Mendelian randomization (MR) analysis further supported the causal roles of genetically predicted BCAR1, CRK, and DOCK1 expression in cardiovascular risk. These findings underscore the involvement of this signaling axis in SCD-CAD susceptibility and suggest these genetic markers as potential tools for cardiovascular risk assessment as well as forensic molecular autopsy. Further validation through large-scale cohort studies and functional assays is essential to fully elucidate the underlying molecular mechanisms.