Circulating inflammatory proteins as pathogenic mediators and potential therapeutic targets in myasthenia gravis

Myasthenia gravis (MG) is a neurological immune-mediated disorder affecting approximately three million people worldwide. While specific circulating inflammatory proteins (CIPs), including cytokines and chemokines, have been strongly implicated in the pathogenesis of MG, their causal roles remain poorly understood.

A cis-Mendelian randomization (MR) framework was utilized to assess the genetically inferred causal associations between 91 CIPs, as proxied by protein quantitative trait loci, and the risk of MG. The inverse-variance weighted method served as the primary analytical approach, supplemented by sensitivity analyses to ensure the robustness of our findings and compliance with key MR assumptions. Furthermore, enrichment and protein-protein interaction (PPI) analyses were conducted to determine the functional associations among the significant CIPs.

Positive associations were observed between plasma TNFSF12 levels and both MG and late-onset MG. Additionally, elevated plasma levels of CD244 and CXCL6 were associated with an increased risk of late-onset MG. In contrast, early-onset MG exhibited significant negative associations with plasma levels of GDNF, IL12B, and IL18R1, but a positive association with CX3CL1 levels. These key findings were further validated through sensitivity analyses. Gene Ontology enrichment analysis indicated that the identified CIPs are primarily involved in biological processes related to natural killer and T cell immune responses, whereas PPI analysis revealed their interactions with other mainstay drug targets for MG.

Our study genetically established several CIPs as culprits contributing to disease causation and potential therapeutic druggable targets for MG. Further research is warranted to decipher the underlying molecular mechanisms in greater depth.