Polycythemia Vera (PV)是一种骨髓增生性肿瘤，由JAK2激活突变驱动，导致不受控制的红细胞生成，增加患者的血液比容和血红蛋白浓度，使其面临生命威胁的血栓事件。我们利用英国生物库数据对440个PV病例和403,351个对照进行GWAS，发现HFE上的SNP被广泛认为是导致血色病的HFE基因高度与PV诊断相关，将铁调节与PV联系起来。芬兰基因组学数据集的分析独立证实了PV患者中同型HFE变体的过度表达。HFE影响hepcidin的表达，这是系统性铁稳态的主要调节器。通过对PV小鼠模型进行基因解剖，我们表明PV红细胞表型直接与hepcidin表达相关：内源性hepcidin上调缓解红细胞性疾病，而hepcidin消融则加剧它。此外，我们证明在PV中，hepcidin并非被扩展红细胞生成调节，而是可能受炎症细胞因子信号通过GP130偶联受体调节。这些发现对于理解PV的病理生理学具有重要意义，并提供了治疗该疾病的新策略。版权所有 ©2023美国血液学会。

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.Copyright © 2023 American Society of Hematology.