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Chuvash polycythemia VHLR200W mutation is associated with downregulation of hepcidin expression. Blood. 2011 Aug 29; Authors: Gordeuk VR, Miasnikova GY, Sergueeva AI, Niu X, Nouraie M, Okhotin DJ, Polyakova LA, Ammosova T, Nekhai S, Ganz T, Prchal JT Abstract
Hypoxia is known to reduce the expression of hepcidin, the master regulator of iron metabolism. However, it is not clear whether this response is primarily related to increased erythropoiesis driven by hypoxically stimulated erythropoietin or to a more direct effect of hypoxia on hepcidin expression. The germ-line loss-of-function VHL(R200W) mutation is common in Chuvashia, Russia and also occurs elsewhere. VHL(R200W) homozygotes have elevated hypoxia inducible factor (HIF)-1α and HIF-2α levels, increased red cell mass, propensity to thrombosis and early mortality. Ninety VHL(R200W) homozygotes and 52 controls with normal VHL alleles from Chuvashia, Russia were studied under basal circumstances. In univariate analyses, serum hepcidin concentration correlated positively with serum ferritin concentration and negatively with homozygosity for VHL(R200W). After adjustment for serum erythropoietin and ferritin concentrations by multiple linear regression, the geometric mean (95% confidence interval of mean) hepcidin concentration was 8.1 (6.3-10.5) ng/ml in VHL(R200W) homozygotes versus 26.9 (18.6-38.0) ng/ml in controls (P <0.001). In contrast, a significant independent relationship of serum erythropoietin, hemoglobin or red blood cell count with hepcidin was not observed. In conclusion, upregulation of the hypoxic response leads to decreased expression of hepcidin that may be independent of increased erythropoietin levels and increased red blood cell counts.
PMID: 21876117 [PubMed - as supplied by publisher] Read more |
