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

Area of Science:

• Cardiovascular Research
• Genetics
• Molecular Biology

Background:

• Thoracic aortic aneurysm (TAA) poses a significant public health challenge.
• Understanding TAA's pathogenic mechanisms and identifying drug targets are crucial.

Purpose of the Study:

• To identify novel drug targets for TAA.
• To elucidate the molecular mechanisms underlying TAA pathogenesis.

Main Methods:

• Utilized bidirectional Mendelian randomization with large-scale Icelandic population data (35,559 individuals) and FinnGen data.
• Performed colocalization analysis, plasma transcriptomics, single-cell sequencing, Western blots, and immunofluorescence staining for validation.
• Integrated multi-omics data with in vitro experiments.

Main Results:

• Latent transforming growth factor β-binding protein 4 (LTBP4) was identified as a significant risk factor for TAA.
• Elevated LTBP4 expression was observed in TAA patients and tissues.
• LTBP4 predominantly expressed in fibroblasts, regulating the transforming growth factor β pathway.

Conclusions:

• LTBP4 is a promising therapeutic target for TAA.
• LTBP4's role in the transforming growth factor β pathway is central to TAA pathogenesis, especially in fibroblasts.