Causal relationship and pathogenic mechanism analysis of breast cancer and coronary heart disease based on mendelian...

Breast cancer (BC) is closely linked to coronary heart disease (CHD), yet the genetic causal relationship and common driving mechanism between the two have not been fully elucidated. The purpose of this study is to infer the causal relationship between BC and CHD at the genetic level and identify the cross-omic molecular characteristics of them through the integrated analysis of multiple genomics. Firstly, large-scale Genome Wide Association Study (GWAS) data were used for bidirectional Mendelian randomization (MR) analysis. Secondly, multi-center transcriptome data were integrated and combined with differential expression analysis (DEGs) and weighted gene co-expression network analysis (WGCNA) to screen for key comorbidity genes. Univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses were used to construct a prognostic model. The Benjamin Hochberg method was used for False Discovery Rate (FDR) correction. Finally, molecular pathways were explored through Gene Set Enrichment Analysis (GSEA), and key genes were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in independent clinical samples. MR analysis revealed a significant positive correlation between BC and CHD in Asian populations (OR = 1.095, 95% CI: 1.005-1.192, P = 0.037). However, no significant association was observed in European populations. Transcriptome analysis identified a prognostic risk score composed of 5 CHD-related genes (HES1, MLPH, TRIB3, HSPBP1, and STARD3), which can independently predict the prognosis of BC patients. GSEA analysis indicated that the comorbidity mechanism involved dysregulation of cell cycle, immune inflammation, and metabolism-related pathways. qRT-PCR verification confirmed that compared with patients with BC, the expression levels of HES1, TRIB3, HSPBP1, and STARD3 in the peripheral blood of BC combined with CHD patients were significantly upregulated (P < 0.05). This study established for the first time the genetic causal relationship between BC and CHD in Asian populations, and revealed the inflammation-immune-metabolism molecular axis mediating comorbidities. The identified key genes not only serve as biomarkers for BC prognosis, but also provide a new perspective for understanding the pathological mechanisms and precise diagnosis and treatment of tumor cardiovascular comorbidities.