Bidirectional mendelian randomization identifies plasma proteins associated with cervical cancer risk

Cervical cancer continues to pose a considerable challenge to global health, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Prior investigations have suggested that plasma proteins may play a role in the pathogenesis of cervical cancer; however, these studies do not confirm a causal relationship. To address this gap, conducted a large-scale Mendelian randomization (MR) study of the plasma proteome.

We performed a two-sample bidirectional Mendelian randomization analysis involving 4,907 plasma proteins, utilizing publicly accessible genome-wide association study (GWAS) summary statistics, to examine the causal association between the plasma proteome and the risk of cervical cancer. Analytical methods included inverse variance weighting (IVW), weighted median, MR-Egger regression, and simple and weighted models. Additionally, we performed sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy through Cochran's Q test, MR-Egger intercept, MR-PRESSO test, and leave-one-out analysis. We also applied false discovery rate (FDR) correction to the results of all IVW methods to identify the plasma proteins most strongly associated with cervical cancer. Finally, we enriched the most relevant plasma protein genes using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses and GeneMANIA to identify disease-related pathways.

According to the IVW method, seven plasma proteins are significantly associated with cervical cancer risk (P < 0.05). Specifically, six proteins demonstrated protective factors: DEFB135 (OR = 0.201, 95% CI = 0.082-0.492, P < 0.001), FGL2 (OR = 0.104, 95% CI = 0.032-0.338, P < 0.001), FTMT (OR = 0.612, 95% CI = 0.465-0.804, P < 0.001), PDIA4 (OR = 0.088, 95% CI = 0.026-0.295, P < 0.001), SPHK2 (OR = 0.102, 95% CI = 0.030-0.350, P < 0.001), and TMED2 (OR = 0.045, 95% CI = 0.008-0.246, P < 0.001). In contrast, RACGAP1 (OR = 1.755, 95% CI = 1.286-2.395, P < 0.001) was identified as a risk factor. Reverse MR analysis revealed no significant evidence of reverse causation (P > 0.05) between cervical cancer and these plasma proteins. Functional enrichment analysis identified several biologically relevant pathways potentially involved in cervical cancer pathogenesis, including the establishment of organelle localization, regulation of oxidoreductase activity, Ferroptosis, and Porphyrin metabolism.

These findings suggest that DEFB135, FGL2, FTMT, PDIA4, SPHK2, and TMED2 may protect against cervical cancer, while RACGAP1 may represent a potential risk factor. The identified tumor markers provide mechanistic insights into the molecular basis of cervical cancer and warrant further investigation in functional studies.