Exploring the Causal Role of Circulating Inflammatory Proteins in Multiple Sclerosis: A Mendelian Randomization Study and Druggability Analysis

Introduction: To evaluate the causal effects of circulating inflammatory proteins on the development of Multiple Sclerosis (MS) and to discover potential therapeutic targets for the disease. Methods: Two-sample Mendelian randomization analysis was used to evaluate causal relationships between levels of 91 inflammatory proteins in serum and the risk of MS. For each circulating protein, genetic variation data were from a genome-wide association study of 14,736 individuals of European ancestry. The MS dataset included 47,429 cases and 68,374 controls. Additional sensitivity, colocalization, functional enrichment, and protein-protein interaction analyses were performed to assess the robustness and biological relevance of the findings. Soluble proteins causally associated with MS were assessed for their therapeutic target potentials using the Drug-Gene Interaction Database. Results: The analysis identified 9 circulating inflammatory proteins with nominal evidence of association with MS risk. Among them, CD40 (Odds Ratio [OR]: 0.907) and VEGFA (OR: 0.971) appear protective, while IL1A (OR: 1.139), CD6 (OR: 1.047), TNF (OR: 1.058), LIF-R (OR: 1.052), CCL25 (OR: 1.032), CD244 (OR: 1.057) and CXCL10 (OR: 1.061) were associated with higher risks of MS. After correcting for multiple testing, associations with MS risks remained significant only for CD40. Supportive analyses highlighted immune- and inflammation-related pathways, particularly cytokine signaling, as mediators of the risks of MS. Six circulating proteins were identified as candidates in an exploratory assessment of druggability. Discussion: These results offered new insight into the inflammatory landscape of MS, reinforcing the pathogenic relevance of immune signaling pathways. The robust statistical significance of CD40 highlighted it as a primary candidate for further investigation, while the additional eight proteins provided a foundation for future hypothesis-generating studies. While the findings strengthened the biological plausibility of inflammation-driven disease mechanisms, the presence of nominal significance and potential pleiotropy for certain markers necessitated a cautious interpretation. Conclusion: Genetic evidence linking inflammatory proteins to MS pathogenesis was uncovered, offering clues for novel therapeutic targets for this condition.