Causal inference of the effect of inflammatory cytokines on the risk of oral cancer：two-sample Mendelian randomization

Abstract Objective: This study aimed to investigate the causal relationship between inflammatory cytokines and oral cavity cancer risk using Mendelian randomization analysis. Methods: Two-sample Mendelian randomization was conducted using summary-level genome-wide association study data on 41 inflammatory cytokines and oral cavity cancer risk in Europeans. Single nucleotide polymorphisms associated with cytokines (p<5x10-6) and oral cancer were selected as instrumental variables, excluding those in linkage disequilibrium. Inverse-variance weighted analysis was used as the primary method, supplemented by MR Egger, weighted median, simple and weighted mode methods. Sensitivity analyses included heterogeneity, horizontal pleiotropy, leave-one-out, and funnel plot assessments. Multivariable MR analysis adjusted for smoking, alcohol, periodontitis and malnutrition was performed. Results: In univariate MR analysis, increased beta-nerve growth factor (OR: 1.53, 95% CI: 1.06–2.20), and decreased macrophage colony stimulating factor (OR: 0.87, 95% CI: 0.78–0.98) and interleukin-18 (OR: 0.80, 95% CI: 0.65–0.98) were causally associated with higher oral cancer risk. In multivariable MR analysis, the effects of beta-nerve growth factor (OR: 1.63, 95% CI: 1.24–2.13) ,macrophage colony stimulating factor(OR:0.87, 95% CI:0.75–1.00)and interleukin-18 (OR: 0.82, 95% CI: 0.67–0.99) remained significant after adjusting for exposures. No reverse causation was found. Conclusions: This MR study provides evidence for causal effects of increased beta-nerve growth factor along with decreased macrophage colony stimulating factor and interleukin-18 on higher oral cavity cancer risk, independent of known risk factors. These inflammatory cytokines may represent etiologic targets for oral cancer prevention.