title: Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression.
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 germline loss-of-function VHL(R200W) mutation is common in Chuvashia, Russia, and also occurs elsewhere. VHL(R200W) homozygotes have elevated hypoxia-inducible factor 1α (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 was 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 < .001). In contrast, a significant independent relationship of serum erythropoietin, hemoglobin, or RBC count with hepcidin was not observed. In conclusion, up-regulation of the hypoxic response leads to decreased expression of hepcidin that may be independent of increased erythropoietin levels and increased RBC counts.
authors.affiliation: Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC 20060, USA. vgordeuk@howard.edu
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Galina Y
authors.initials: GY
authors.lastname: Miasnikova
authors.forename: Adelina I
authors.initials: AI
authors.lastname: Sergueeva
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Niu
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Okhotin
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Polyakova
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ammosova
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000235:genetics*; D016022:Case-Control Studies; D015536:Down-Regulation; D004921:Erythropoietin / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D018095:Germ-Line Mutation; D064451:Hepcidins; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011086:Polycythemia / Q000097:blood* / Q000235:genetics*; D012426:Russia; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D023181:Antimicrobial Cationic Peptides; C554270:EPO protein, human; C578702:HAMP protein, human; D064451:Hepcidins; D004921:Erythropoietin; D005293:Ferritins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human