Associations between T-cell traits and narcolepsy type 1: new insights from a Mendelian randomization study.

Background: Narcolepsy type 1 (NT1) is primarily caused by a malfunctioning immune system in which T-cells damage the hypothalamus. To elucidate the causal relationships between biomarkers in T-cells and NT1, we employed Mendelian randomization (MR) analysis.

Methods: We conducted a two-sample MR analysis utilizing genetically predicted T-cell traits to examine their effects on NT1. Genome-wide association study summary data were extracted from studies by Valeria (3,757 participants) for 211 T-cell traits, Ollila (6,073 cases and 84,856 controls) for NT1. The MR analysis was executed at two threshold levels. Inverse variance weighted, Wald ratio, weighted median, and MR-Egger regression methods were used for the MR analysis. Odds ratios (ORs) were calculated, and heterogeneity tests, as well as pleiotropy tests, were conducted.

Results: After Bonferroni correction at the significant level (p < 1.18 × 10^-4), a higher ratio of naive CD4^- CD8^- T-cells was identified as a risk factor for NT1 (OR = 10.50; 95% CI: 6.98, 15.90, p = 3.89 ×10^-29). Conversely, CD4 on HLA DR⁺ CD4⁺ T cells (mean fluorescence intensity, MFI) exhibited a negative correlation with NT1. At nominally significant levels (p < 0.05) for both threshold levels, HVEM (herpesvirus entry mediator) on naive CD8⁺ T cells (MFI) was suggested as a protective factor for NT1. Additionally, a higher ratio of CD25⁺⁺ CD45RA^- CD4 not regulatory T cells, CD127 on CD45RA^- CD4 not regulatory T cells (MFI), CD127 on CD28⁺ CD4⁺ T cells (MFI), CD3 on HLA DR⁺ T cells (MFI), and CD3 on HLA DR⁺ CD4⁺ T cells (MFI) were suggested as risk factors for NT1.

Conclusion: This study confirmed the causal effects of CD4⁺ and CD8⁺ T-cells on NT1 and found several novel T-cell-related characteristics.