Causal Inference and Shared Molecular Pathways in Crohn's Disease, Celiac Disease, and Ankylosing Spondylitis:...

Area of Science:

• Genetics and Immunology
• Gastroenterology and Rheumatology

Background:

• Crohn's disease (CD), celiac disease (CeD), and ankylosing spondylitis (AS) are distinct inflammatory conditions.
• Understanding their shared underlying mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the causal and molecular overlap between CD, CeD, and AS.
• To identify shared genetic factors and immune pathways implicated in these diseases.
• To explore potential cross-disease therapeutic targets.

Main Methods:

• Bidirectional Mendelian randomization was employed to assess causal relationships between disease pairs.
• Transcriptomic analyses identified key upregulated genes across all three conditions.
• Independent datasets and inflammatory cell models were used for validation.
• Functional enrichment, regulatory network, and molecular docking analyses were performed.

Main Results:

• Significant bidirectional causal associations were found between each pair of diseases (CD-CeD, CD-AS, CeD-AS).
• Three hub genes (P2RY8, ITGAL, GPR65) were consistently upregulated across all conditions and validated.
• These genes are implicated in immune signaling and mucosal inflammation.
• Trichostatin A emerged as a potential therapeutic agent through network and docking analyses.

Conclusions:

• Shared genetic and immune-related mechanisms underlie CD, CeD, and AS.
• The identified hub genes represent potential therapeutic targets for cross-disease treatment strategies.
• This research provides a foundation for novel therapeutic approaches targeting common pathways in these inflammatory diseases.