Sphingomyelin mediates the association between natural killer cell receptor 2B4 (CD244) and head and neck cancer

Objective: To investigate the causal link between natural killer (NK) cell receptor CD244 and head and neck cancer (HNC), and to evaluate sphingomyelin (SM) as a potential mediator of this relationship. Methods: A two-sample Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) summary statistics from European cohorts (NCD244=14,735; NHNC=2,131; NSM=8,260). Instrumental variables (32 SNPs for CD244, 79 SNPs for HNC) were selected at genome-wide significance (P<5×10⁻⁸/5×10⁻⁶) after rigorous linkage disequilibrium clumping. Causal estimates were generated using inverse variance weighting (IVW), MR-Egger, and weighted median methods. Mediation analysis quantified SM's contribution to CD244-HNC associations. Results: Genetically predicted CD244 levels showed a protective effect against HNC (IVW OR=0.82 per SD, 95% CI:0.71-0.94, P<0.01), while elevated CD244 was associated with reduced SM levels (IVW OR=0.92, 95% CI:0.86-0.98, P<0.05). Conversely, SM demonstrated risk-enhancing effects on HNC (IVW OR=1.20, 95% CI:1.01-1.41, P=0.03). Mediation analysis revealed that SM accounted for 7.3% of the total CD244-associated HNC risk. Conclusion: This study establishes a causal protective role of CD244 in HNC pathogenesis, partially mediated through SM. The findings highlight CD244 and SM metabolism as potential targets for HNC immunomodulatory therapies. Future research should validate these mechanisms in diverse populations and explore additional mediators.