Genetically predicted association between immune cells and optic neuritis: evidence from a Mendelian randomization study.

PURPOSE: Optic neuritis (ON) is a common inflammatory disease of the optic nerve that usually precedes serious neurological disorders. The purpose of this study was to explore the causal relationship between immune cells and ON.

METHODS

We adopted a bidirectional Mendelian randomization (MR) approach, analyzing genetic variants associated with 731 immune cells from a Sardinian cohort and ON data from the FinnGen consortium. Instrumental variables (IVs) for each phenotype were stringently selected based on linkage disequilibrium and genome-wide significance levels. Inverse-variance weighted (IVW) served as the primary analysis method, supplemented by sensitivity analyses to assess the robustness of findings.

RESULTS

The study identified 2776 SNPs as IVs for 731 immune cells. The bidirectional MR analysis revealed that 11 immune cells were significantly associated with ON, with 9 positively correlated and 2 negatively correlated with ON risk. Among them, human leukocyte antigen receptor (HLA-DR)++ monocyte proportion showed the strongest association as a risk factor (OR = 1.828, 95% CI = 1.515-2.206, p = 3.13 × 10-10). The robustness of the findings was confirmed through heterogeneity and pleiotropy tests, and the relationship persisted even after adjusting for confounders using multivariate MR analysis. Only the HLA-DR++ monocyte remained a significant risk factor after multiple testing corrections.

CONCLUSIONS

Specific immune cells, notably HLA-DR++ monocytes, critically influence ON pathogenesis, suggesting biomarkers and therapeutic targets. This MR study provides genetic insights into immune-mediated ON mechanisms.