The aging male : the official journal of the International Society for the Study of the Aging Male · 2025
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.
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Zhang Jinyu, Zhu Weijie, Li Jiongzheng, Li Jiaxuan, Yan Quanshun, Zhang Yubo, Li Jing
Аннотация
BACKGROUND: 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.
METHODS: 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 γ-H2AX, cell-cycle distribution, and EMT markers. Mechanistic follow-up used SMR with HEIDI, enrichment, and colocalization analyses.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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 γ-H2AX, cell-cycle distribution, and EMT markers. Mechanistic follow-up used SMR with HEIDI, enrichment, and colocalization analyses.
RESULTS: 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.
CONCLUSION: 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.