A large-sample analysis of vitamin B12 deficiency anemia, the red cell distribution width, and prostate cancer: identification of their causal relationships, shared gene signatures, and key biological mechanisms

The causal relationship and mechanisms connecting Vitamin B12 (VB12) deficiency anemia, red cell distribution width (RDW), and prostate cancer (PCa) remain unclear due to small, methodologically limited studies. We performed bidirectional two-sample Mendelian randomization (2SMR) using GWAS to test the causal effects of VB12 deficiency anemia and RDW on PCa. VB12-deprivation cell assays assessed <i>γ</i>-H2AX, cell-cycle distribution, and EMT markers. Mechanistic follow-up used SMR with HEIDI, enrichment, and colocalization analyses. Both VB12 deficiency anemia (OR_IVW = 1.054, 95% CI: 1.018–1.090) and higher RDW (OR_IVW = 1.095, 95% CI: 1.040–1.153) showed modest positive associations with PCa risk by 2SMR. Multiple sensitivity analyses supported robustness, bidirectional tests found no evidence of reverse causation, and VB12-deprivation cell assays further corroborated the MR signals. In multivariable MR, the positive RDW-PCa association persisted after conditioning on CRP and ferritin. SMR identified 68 genes shared between VB12 deficiency anemia and PCa. Colocalization highlighted two priority loci: B3GAT1 (PP4 = 0.94) and SIK2 (PP4 = 0.78), suggesting that expression changes at these genes may mediate prostate cancer susceptibility. Genetic liability to VB12 deficiency anemia and higher RDW showed modest, directionally consistent associations with increased PCa risk. This risk may be mediated through B3GAT1 and SIK2.