Multi-Omics Analysis for Pathogenesis and Candidate Therapeutic Target in Thoracic Aortic Aneurysms

Thoracic aortic aneurysm (TAA) is a significant public health concern. We aimed to identify drug targets and understand the pathogenic mechanisms of TAA.

We employed 4907 circulating proteins as exposure data from a large-scale protein quantitative trait loci study involving 35 559 Icelanders. We used findings from the FinnGen study as the outcome data. We conducted bidirectional Mendelian randomization 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 to uncover the pathological mechanisms of TAA. Western blots and immunofluorescence staining examined potential drug targets in aortic tissues.

Mendelian randomization results suggest that LTBP4 (latent transforming growth factor β-binding protein 4) is significantly associated with the risk of TAA. Plasma transcriptomics showed significantly increased LTBP4 expression in patients with TAA (log fold change=0.69, adjusted P=7.04×10^-4), with an area under the curve of 0.76. The single-cell sequencing analysis highlighted the predominant expression of LTBP4 in fibroblasts and the central role of LTBP4 in the functional regulation of the transforming growth factor 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.

This study presents an innovative integration of Mendelian randomization with multi-omics and in vitro experiments, identifying LTBP4 as a candidate therapeutic target for TAA. It also underscores the role of LTBP4 in regulating the transforming growth factor β signaling pathway within the pathogenic mechanism of TAA, particularly within fibroblast cells.