Association between total testosterone and cervical cancer: A bidirectional Mendelian randomization study

Abstract

Abstract Background Several experimental studies already proved that the increase of total testosterone could lead to the development of gynecological disease. Animal experiments have shown that testosterone may be associated with the progression of cervical cancer (CC). And the metabolism of cholesterol which serves as the initial raw material for testosterone synthesis is crucial for the occurrence of CC. However, the causal relationship between CC and Total testosterone still remained unknown. Methods We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies (GWAS) of Total testosterone and CC. Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) from GWAS in this study. The random-effects inverse-variance weighted (IVW) estimation method was applied as the primary method with several other estimators as complementary methods. Total testosterone was seen as exposure in forward MR analysis and CC was utilized as exposure in reverse MR analysis, and their SNPs were read and screened by "TwoSampleMR" R package. The bidirectional MR results were verified by a series of sensitive analyses. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of genes regulated by instrumental variable SNPs were conducted using “cluster Profiler”. Results In our study, the inverse-variance weighted (IVW) analysis in forward MR analysis (OR:1.0016, 95% confidence interval [CI]: 1.0005–1.0027; p < 0.05) clarified that these SNPs could effectively predict that total testosterone could lead to increases the risk of CC, indicating a direct effect of total testosterone on CC. The IVW analysis in reverse MR analysis did not find a significant effect of CC on Total testosterone (p = 0.557). Moreover, in forward MR, most genes regulated by instrumental variable SNPs are mainly involved in C21-steroid hormone metabolic process, MHC protein complex and progesterone metabolic process, and the signal pathways are mainly involved in Th1 and Th2 cell differentiation, Hematopoietic cell lineage, Th17 cell differentiation. Conclusion The present study strengthened the evidence that Total testosterone is a potential risk factor for CC. Whether CC affects Total testosterone needs further research.