The role of preeclampsia in breast cancer risk: insights from Mendelian randomization study

Background The relationship between preeclampsia and breast cancer risk is still debated, with observational studies yielding inconsistent results. This research aims to clarify the causal link between preeclampsia and breast cancer using Mendelian randomization (MR) methods. Methods We utilized genome-wide association study (GWAS) data to identify single nucleotide polymorphisms (SNPs) that are significantly associated with preeclampsia, which served as genetic instruments. A two-sample Mendelian randomization (TSMR) approach was applied, primarily using inverse variance weighting (IVW) to assess the causal impact of preeclampsia on breast cancer risk. To strengthen our findings, a meta-analysis of IVW estimates from both discovery and validation cohorts was performed, complemented by sensitivity analyses to investigate heterogeneity and potential horizontal pleiotropy. Results In the discovery cohort, IVW analysis revealed a potential inverse relationship between preeclampsia and breast cancer risk (OR, 0.971; 95% CI, 0.947-0.996; P = 0.022). However, the validation cohort did not demonstrate a significant causal association (OR, 0.992; 95% CI, 0.975-1.008; P = 0.327). The combined meta-analysis indicated that preeclampsia might be linked to a lower risk of breast cancer (OR, 0.986; 95% CI, 0.972-0.999; P = 0.041). In subgroup analysis, preeclampsia was found to have a potential association only with estrogen receptor (ER)-negative breast cancer (OR, 0.956; 95% CI, 0.916-0.999; P = 0.043), while no significant link was observed with estrogen receptor (ER)-positive breast cancer (OR, 0.972; 95% CI, 0.945-1.000; P = 0.051). Sensitivity analyses indicated no significant heterogeneity or evidence of horizontal pleiotropy (P > 0.05). Conclusion This MR study, supported by a robust meta-analysis, suggests that preeclampsia may have a protective effect against breast cancer, especially ER-negative breast cancer. However, to firmly establish this relationship, additional prospective studies with larger populations are warranted. Moreover, further exploration of the biological mechanisms underlying this potential association is needed through both in vitro and in vivo research.