Causal relationship between inflammatory cytokines, metabolites, and ulcers of lower limb: A Mendelian randomization study

Abstract Inflammatory cytokines are key indicators affecting the development of ulcers of lower limb. The causal role of inflammatory cytokines in ulcers of lower limb and whether this can be mediated by metabolites remain unknown. We conducted a two‐step, two‐sample Mendelian randomization (MR) study to investigate the causal effect of inflammatory cytokines on ulcers of lower limb and the mediating role of metabolites in the association between inflammatory cytokines and ulcers of lower limb. MR analysis identified seven inflammatory cytokines (CCL19, IL‐12β, MCP4, MIP1a, SCF, sirtuin2, and TNFSF9) that promote ulcers of lower limb. Additionally, 56 metabolites were found to be associated with ulcers of lower limb. Mediation MR indicated that the causal effect of sirtuin2 on ulcers of lower limb (total effect Inverse Variance Weighted [IVW]: odds ratio [OR] = 1.162, 95% confidence interval [CI] [1.051, 1.285], p = 0.003) is largely mediated by 4‐hydroxyphenylacetate (0.0185, 95% CI [−0.00278, 0.0397], accounting for 11.1% of the total effect).