CD39+ CD4+ T cells influence cluster headache risk via ADP/N-acetylneuraminate and choline metabolic pathways: evidence from Mendelian Randomization

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CD39+ CD4+ T cells influence cluster headache risk via ADP/N-acetylneuraminate and choline metabolic pathways: evidence from Mendelian Randomization
Jingshan Zeng, Ying Yi, Hu Xie & Yun Zhu

Published in International Journal of Neuroscience on October 30, 2025
Link: https://doi.org/10.1080/00207454.2025.2580332

Abstract:
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. Using genome-wide association study (GWAS) data, MR analyses were conducted on 731 immune cell phenotypes, 1400 serum metabolites, and CH. The inverse variance weighted (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.
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.
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.

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