To investigate the causal relationship between plasma lipidome and Crohn’s disease (CD), and further reveal the potential mediating role of inflammatory factors in the lipid-CD pathogenesis mechanism by integrating genome-wide association study (GWAS) data of inflammatory factors.

Based on GWAS summary statistics from GeneRISK (n=7 174), SCALLOP (n=14 824), and FinnGen (n=395 179), a two-sample Mendelian randomization (MR) study design was adopted. Using single nucleotide polymorphisms (SNPs) as instrumental variables, the total causal effects of 179 plasma lipid metabolites on CD were first evaluated. Subsequently, a stepwise MR and intersection screening strategy was employed to explore the regulatory pathways involving 91 circulating inflammatory factors. The main statistical method used was the inverse variance weighting (IVW) method, supplemented by sensitivity analyses and multiple testing correction.

The initial MR screening identified 19 lipid phenotypes significantly associated with CD risk. Further analysis pinpointed Phosphatidylcholine (PC 18:1_20:4) as a significant protective factor against CD, with elevated levels robustly causally associated with reduced CD risk. In exploring the mechanism, it was found that this lipid significantly downregulated the expression level of the T-cell surface glycoprotein CD6 (β=-0.054, P<0.05), while genetically elevated CD6 levels significantly increased CD risk (β=0.179, P<0.05). Mediation effect analysis indicated that the CD6-mediated effect direction was consistent with the total effect, accounting for approximately 6.9% of the effect (indirect effect β indirect=-0.010, P=0.396). Reverse MR analysis did not support a reverse causal effect of CD on this lipid.

This study provides genetic evidence confirming the significant protective effect of Phosphatidylcholine (PC 18:1_20:4) against Crohn’s disease. CD6 is identified as a key downstream responder molecule that is negatively regulated by this lipid and promotes CD risk. The results suggest that “phosphatidylcholine—CD6—CD” may be a potential biological pathogenic axis, offering new theoretical foundations for in-depth analysis of the immunometabolic mechanisms of CD and the exploration of intervention targets.