Copy number loss Of APP cause thoracic aortic dissection

Thoracic aortic dissection (TAD) is a leading cause of sudden cardiovascular death. Although a limited number of copy number variations (CNVs) have been reported in small cohorts of patients with hereditary TAD or sporadic aortic dissection, a comprehensive investigation and functional validation of CNVs in sporadic TAD using large-scale whole genome sequencing (WGS) data remain lacking. To address this gap, we conducted whole genome sequencing in two independent case–control studies, involving 257 patients with sporadic TAD and 132 controls. We generated gene knockout mice to explore the role of the target gene in TAD progression in vivo. Additionally, RNA-seq analysis and molecular biology experiments were performed in vitro to elucidate the underlying mechanisms. In the discovery and validation cohorts, we identified four CNVs genes (DSCAM, APP, LINC00907, PROCR) potentially pivotal in the pathogenesis of TAD. Among these, only APP displayed reduced expression in the aortas of TAD patients compared to controls. Deletion of APP exacerbated elastic fiber fragmentation and promoted TAD formation in both β-aminopropionitrile (BAPN)-induced and PCSK9/AngII-induced TAD models. In vitro, the loss of APP facilitated vascular smooth muscle cells (VSMCs) apoptosis and the switch to a secretory phenotype. Our study is the first to report novel CNVs of APP in TAD, demonstrating that APP deficiency accelerates the initiation and progression of TAD. These findings suggest that APP represents a promising therapeutic target and a potential genetic risk factor for TAD.