Int J Neurosci. 2025 Oct 26:1-14. doi: 10.1080/00207454.2025.2580332. Online ahead of print.
ABSTRACT
Objective This study employs the Mendelian randomization (MR) approach to investigate the causal relationships among immune cells, cluster headache (CH), and potential mediation by serum metabolites. Methods Using genome-wide association study (GWAS) data, MR analyses were conducted on 731 immune cell phenotypes, 1400 serum metabolites, and CH. The inverse variance weighting (IVW) method was employed as the primary analytical approach, supplemented by MR-Egger and weighted median analyses. Stability of results was assessed using Cochran’s Q and other statistical tests. Results The analysis identified a negative causal relationship between CD39+ CD4+ %T cells and CH, supported by sensitivity analyses. Reverse MR analysis showed no effect of CH on CD39+ CD4+ T cells, suggesting a unidirectional role of these cells in reducing CH risk. Further mediation MR analysis indicated that CD39+ CD4+ T cells may influence CH risk through the regulation of either the adenosine 5′-diphosphate (ADP) to N-acetylneuraminate ratio or the choline phosphate to phosphoethanolamine ratio, with mediation effect ratios of 12.4% and 12.5%, respectively. Conclusion CD39+ CD4+ T cells may reduce CH risk by increasing the adenosine 5′-diphosphate (ADP) to N-acetylneuraminate ratio or the choline phosphate to phosphoethanolamine ratio. These findings provide novel insights into potential targets for the prevention and treatment of CH.
PMID:41139232 | DOI:10.1080/00207454.2025.2580332
