Abstract Body (Do not enter title and authors here): Purpose: Thoracic Aortic Aneurysm (TAA) is a significant public health concern. We aimed to identify drug targets and understand the pathogenic mechanisms of TAA.

Methods: We employed 4,907 circulating proteins as the exposure data from a large-scale protein quantitative trait loci (pQTLs) study involving 35,559 Icelanders. We used the FinnGen study as the outcome data. We conducted bidirectional Mendelian Randomization (MR) analysis and colocalization analysis to pinpoint potential therapeutic targets for TAA and validated the results in the UK Biobank database. We validated findings with plasma transcriptomics and single-cell sequencing (scRNA-seq) to uncover the pathological mechanisms of TAA. Western blots and immunofluorescence staining examined potential drug targets in aortic tissues.

Results: MR results suggest that LTBP4 is significantly associated with the risk of TAA. Plasma transcriptomics revealed a significant upregulation of LTBP4 in TAA patients, with an area under the curve (AUC) of 0.76. The scRNA-seq analysis highlighted the predominant expression of LTBP4 in fibroblasts and the central role of LTBP4 in the functional regulation of the TGF-β pathway. In vitro experiments demonstrate that the expression of LTBP4 protein is significantly increased in TAA tissue. Immunofluorescence staining indicates that LTBP4 is primarily localized in the extracellular matrix of the medial layer of the aorta.

Conclusions: This study presents an innovative integration of MR with multi-omics and in vitro experiments, identifying LTBP4 as a potential therapeutic target for TAA. It also underscores the role of LTBP4 in regulating the TGF-β signaling pathway within the pathogenic mechanism of TAA, particularly within fibroblast cells.