Levels of 91 circulating inflammatory proteins and risk of non-melanoma skin cancer:A two-sample Mendelian randomization study

Background Non-Melanoma Skin Cancer (NMSC) is one of the most common human malignancies with a high incidence rate, posing a heavy economic burden on the global healthcare system. Methods We utilized single nucleotide polymorphisms (SNPs) that exhibited significant associations with circulating inflammatory proteins as genetic instruments, obtained non-melanoma skin cancer (NMSC) data from pooled sources of independent genome-wide association studies (GWAS), and subsequently conducted two-sample Mendelian randomization (MR) analyses. In the MR analysis, we employed methods such as inverse variance weighting, weighted median, MR-Egger regression, MR Multi-effect residuals, and outlier tests to assess the potential causal relationship between 91 distinct circulating inflammatory proteins and non-melanoma skin cancer. Results We found that higher levels of CCL23 (OR 1.07, 95% CI 1.00-1.13), CCL25 (OR 1.04, 95% CI 1.01–1.07), EN-RAGE (OR 1.08, 95% CI 1.01–1.15), IL-15RA (OR 2.03, 95% CI 1.15–3.61), IL-1α (OR 1.21, 95% CI 1.08–1.35), and IL-8 (OR 1.61, 95% CI 1.06–2.43) were significantly positively associated with the risk of NMSC. Conversely, higher levels of CCL4 (OR 0.95, 95% CI 0.91–0.98), FIt3L (OR 0.92, 95% CI 0.86–0.98), MMP-1 (OR 0.63, 95% CI 0.41–0.98), OPG (OR 0.65, 95% CI 0.43–0.98), and TRANCE (OR 0.94, 95% CI 0.89–0.99) were significantly associated with a reduced risk of NMSC. Sensitivity analysis validated the robustness of the findings for CCL23, CCL25, EN-RAGE, IL-15RA, IL-8, and IL-1α. Conclusion This innovative two-sample MR analysis reveals an intrinsic causal relationship between inflammation and the risk of non-melanoma skin cancer, providing new insights into the molecular mechanisms of the disease and potentially identifying potential therapeutic targets.