Mediating factors between autoimmune thyroiditis and breast cancer: a bidirectional Mendelian randomization study

The association between autoimmune thyroiditis (AIT) and breast cancer was still confused and the mediators was not cleared. In this study, we designed to search a probably causality and mediators between AIT and breast cancer.

We adopted a bidirectional Mendelian Randomization (MR) analysis to explore the causal association and the potential mediating effects. We used Genome-Wide Association Studies (GWAS) data to construct instrumental variables. We extracted single nucleotide polymorphisms (SNPs) which were significantly associated with exposure factors and the significance threshold was set at p < 1.0 × 10 ^-5. Inverse variance weighted (IVW) is adopted as the main method.

When AIT was exposed, all the methods indicated that AIT increased the risk of breast cancer (OR values were all > 1 and P < 0.05). When breast cancer was exposed, no significant result was found. Single-factor MR analysis was used for 1400 metabolites and 211 gut microbiome, and showed AIT has a significant causal relationship with 7-methylxanthine IVW: (95% CI 0.001-0.059; p = 0.039). In reverse, there was no causality. 7-Methylxanthine has a causal relationship with breast cancer (95% CI 1.032-1.203; p = 0.006). Multi-factor MR analysis was adopted by adding of 7-methylxanthine to AIT on Breast cancer, the result was still significant, the AIT IVW (95% CI 0.007-0.055; p = 0.011), 7-methylxanthine IVW (95% CI 0.031-0.200; P = 0.007).

AIT can increase the risk of breast cancer, there is no causal link in the reverse direction. Among the 1400 metabolites, 7-methylxanthine is a mediator of AIT to breast cancer. There were no mediators from AIT to breast cancer in the 211 gut microbiome taxa.