Exploring the Role of Inflammatory Cytokines in Cervical cancer Pathogenesis: Evidence from Mendelian Randomization Analysis

Abstract

Background: Cervical cancer (CC) is a prevalent malignancy worldwide, which seriously threatens women's quality of life and health. Although CC etiology remains uncertain, mounting evidence suggests that inflammatory cytokines (CKs) contribute to CC pathogenesis. Nonetheless, more research is required to determine if there is a causal connection between them. Therefore, our study performed a Mendelian randomized (MR) study to investigate the causal link between inflammatory CKs and CC. Methods: The inflammatory CK data are derived from two European population databases: one containing 41 inflammatory CKs and the other containing 91 inflammatory CKs. The CC data came from the UK Biobank (n ≤ 408961), including 1659 cases of CC and 381902 controls of European ancestry. Our study employed the inverse variance weighted, MR-Egger, weighted median, and weighted mode to analyze the causal relation between inflammatory CKs and CC. Additionally, multiple sensitivity analyses, including MRE intercept test, MR-PRESSO and Leave One Out, were deployed to further validate the robustness of the results. Eventually, a reverse MR analysis was carried out. RESULTS: The MR results showed that the increase of the Monokine triggered by gamma interferon )INF-γ( level was negatively correlated with CC (odds ratio (OR) = 0.84, 95% confidence interval (95% CI): 0.72–0.99, P = 0.044). Elevated cystatin D (CysD), Interleukin-8 (IL-8), Leukemia Inhibitory Factor (LIF), and Monocyte chemoattractant protein 2 (MCP-2) levels were positively correlated with CC occurrence (OR = 1.18, 95% CI:1.02–1.36, P = 0.025; OR = 1.41, 95% CI:1.02–1.95, P = 0.035; OR = 1.39, 95% CI:1.00–1.94, P = 0.044; OR = 1.76, 95% CI:1.25–2.47, P = 9×10–4), which aligned with sensitivity analyses results. Reverse MR Results showed that CC had no effect on 132 inflammatory CKs. Conclusion: Herein, the MR analysis demonstrated a potential causal connection between INF-γ, CysD, IL-8, LIF, and MCP-2 levels and CC risk. The role of inflammatory CKs in CC occurrence and development needs further investigation.