Assessing the causal relationship between P2RY12 and breast cancer: a Mendelian Randomization study

Background Breast cancer (BC) is one of the most common malignant tumors in women, and its incidence ranks among the highest among female malignancies. Studies have shown that the P2RY12 gene can be a potential target for BC chemotherapy drugs, but the causal relationship between them remains unclear. Methods This study obtained the P2RY12 dataset (ENSG00000169313) and BC dataset (ukb-b-13584) from the IEU OpenGWAS database for two-way Mendelian Randomization (MR) analysis. Univariate analysis was performed using five methods: Mr Egger, weighted median, inverse variance weighting (IVW), simple mode and weighted mode. To evaluate the reliability of MR results, a heterogeneity test, a horizontal pleiotropic test, and a leave-one-out (LOO) method were performed. Gene Ontology (GO) was used to perform enrichment analysis of genes corresponding to instrumental variables (IVs). We explored the potential interactions of P2RY12 by constructing a protein-protein interaction (PPI) network. Results After screening IVs, 10 and 13 single-nucleotide polymorphisms (SNPs) were used for forward and reverse MR analyses, respectively. The results of forward analysis showed that P2RY12 increased the risk of BC, P = 0.0306, odds ratio (OR) = 1.004, 95% CI: 1-1.008, In contrast, in reverse MR analysis, the incidence of BC was not a direct factor leading to changes in P2RY12 (P = 0.262, OR = 0.361, 95% CI: 0.061–2.143). The reliability of the forward MR analysis results was demonstrated through a sensitivity analysis. Through GO enrichment analysis, genes related to SNPs are mainly enriched in muscle cell growth and expansion, G protein-coupled receptors, etc. Based on the PPI network, the biological processes primarily involved in P2RY12 include purine nucleotide receptor activity, G protein-coupled receptor activation, etc. Conclusion There is a causal relationship between P2RY12 and BC, and P2RY12 is a risk factor for BC. In contrast, there is no direct causal relationship between BC and P2RY12. This study provides a theoretical basis for finding therapeutic targets for BC through P2RY12.