Abstract
Background and aim: Crohn’s Disease (CD) is associated epidemiologically with Atherosclerotic Cardiovascular Disease (ASCVD), but the molecular overlap remains incompletely defined. We asked whether adult CD intestinal biopsy transcriptomes are enriched for genes assigned to the Ingenuity Pathway Analysis (IPA) atherosclerosis signaling pathway. This analysis was designed to evaluate transcriptional overlap, not clinical ASCVD or vascular disease.
Methods: An integrative gene-expression meta-analysis of adult CD versus non-IBD intestinal controls was conducted using the Search Tag Analyze Resource for Gene Expression Omnibus (STARGEO). Seventeen GEO series (594 CD samples, 355 controls) were pooled using inverse-variance fixed- and random-effects models; random-effects estimates were used for the primary analysis. Genes meeting the analysis threshold (false-discovery-rate-adjusted p<0.05 and |experimental log ratio| >0.1) were evaluated with IPA. Clinical metadata were insufficiently harmonized for reliable subgroup analyses.
Results: A total of 464 genes were differentially expressed in CD versus controls (344 upregulated, 120 downregulated). IPA ranked atherosclerosis signaling seventh among enriched canonical pathways (right-tailed Fisher exact p = 1.3×10-7; activation z-score = 3.357). Twenty-four upregulated genes mapped to this knowledge-base pathway, including inflammatory cytokines (IL1B, IL6, IFNG, CXCL8), adhesion molecules (SELE, SELP), chemokines (CCL2, CCL11), and inflammatory effectors (S100A8, MMP1, MMP3, LYZ). IPA also predicted inhibition of IL-10 signaling (z-score = -0.728).
Conclusions: Adult CD intestinal tissue shows an inflammatory transcriptional pattern enriched for genes contained in the IPA atherosclerosis signaling pathway. This finding demonstrates molecular overlap only; it does not establish accelerated atherosclerosis, increased ASCVD events, or a need to alter cardiovascular prophylaxis. Because no independent transcriptomic, qPCR, protein, serum, blood, or vascular-tissue validation was performed, the results should be considered hypothesis-generating.
Keywords
Atherosclerosis, Crohn’s disease, IBD, Genetics, Molecular