Elevated interleukin-12B is associated with increased seizure susceptibility: insights from two-sample Mendelian randomization and in vivo experiment

TL;DR

High levels of interleukin-12B are linked to a higher risk of generalized epilepsy, confirmed through genetic analysis and mouse experiments.

Contribution

This study establishes a causal link between IL-12B and epilepsy using MR analysis and validates it with in vivo experiments.

Findings

Elevated IL-12B is causally associated with generalized epilepsy (OR = 1.18).

Mice treated with IL-12B showed lower seizure thresholds and higher seizure scores.

Results were validated through multiple sensitivity analyses and in vivo experiments.

Abstract

To evaluate the causality between interleukins (ILs) and epilepsy using Mendelian randomization (MR) analysis. Furthermore, in vivo experiments were conducted to validate the results.

All summary datasets for MR analysis were sourced from publicly available genome-wide association studies. MR analysis was utilized to assess the causal relationship between ILs and generalized epilepsy (GE). Comprehensive sensitivity analyses were carried out to verify the robustness of the findings. Additionally, seizure threshold, seizure score, and video electroencephalography recordings were conducted to evaluate the effect of IL-12B on seizure susceptibility.

The MR results revealed a causal effect of IL-12B on GE (IVW: β = 0.17, OR = 1.18, 95% CI = 1.05–1.34, p = 0.007). Estimated effects derived from supplementary methods were consistent with this finding. The robustness of these results was confirmed by sensitivity tests. Mice pretreated with IL-12B exhibited a significantly decreased seizure threshold, higher seizure scores, shortened latency to SE, and reduced survival probability compared with those pretreated with saline.

Our study demonstrated that elevated serum levels of IL-12B are associated with an increased risk of GE. The results were validated through in vivo experiments. These results underscore the crucial role of targeted anti-inflammatory therapy in the treatment of epilepsy.

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