Cytokines and oral cancer risk: Genetic evidence from a bidirectional Mendelian randomization study

This study aimed to elucidate the causal relationship between cytokines and oral cancer using Mendelian randomization (MR) analysis. Utilizing genetic data from genome-wide association studies (GWAS) and publicly available datasets, we conducted a bidirectional 2-sample MR analysis. The study design employed single nucleotide polymorphisms as genetic instruments to investigate the link between cytokines and oral cancer. The analysis was based on data from 2 cohorts with total 132 cytokines: 41 cytokines from comprehensive GWAS meta-analysis data, 91 cytokines from GWAS summary statistics for circulating inflammatory cytokines. Oral cancer genetic association data was sourced from the FinGen R10 datasets. To discern the causal relationship between cytokines and oral cancer, 5 MR methodologies, including inverse variance weighted and MR-Egger regression, weighted median, weighted mode, and simple mode were applied. The MR analysis revealed nominal associations between certain cytokines and the risk of oral cancer. Specifically, increased levels of C-X-C motif chemokine ligand 9 (odd ratios [OR] = 0.760, 0.600-0.962, 95% confidence interval [CI] 0.600-0.962, P = .023), monocyte chemoattractant protein 1 (OR = 0.78, 95% CI 0.32-0.99, P = .046), and TNF related activation induced cytokine (OR = 0.792, 95% CI 0.630-0.994, P = .044) were associated with a reduced risk of oral cancer, while higher levels of monocyte chemoattractant protein 2 (OR = 1.164, 95% CI 1.001-1.353, P = .048) and CC motif chemokine 25 (OR = 1.434, 95% CI 1.106-1.858, P = .006) were linked to an increased risk. The reverse analysis suggested a possible effect of oral cancer on the level of circulating cytokines, particularly Fractalkine (OR = 0.942, 95% CI 0.897-0.990, P = .019). No evidence of heterogeneity or significant pleiotropy was detected, validating the instrumental variables used. The findings support a causal relationship between specific cytokines and the risk of oral cancer, highlighting the complex interplay between inflammatory mediators and cancer development. These results underscore the importance of individualized immune profiling in treating oral cancer patients and pave the way for future research into targeted therapies based on cytokine profiles.