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RED CELLS, IRON, AND ERYTHROPOIESIS
Chuvash polycythemia VHLR200W mutation is associated with down-regulation of
hepcidin expression
Victor R. Gordeuk,1 Galina Y. Miasnikova,2 Adelina I. Sergueeva,3 Xiaomei Niu,1 Mehdi Nouraie,1 Daniel J. Okhotin,4
Lydia A. Polyakova,2 Tatiana Ammosova,1 Sergei Nekhai,1 Tomas Ganz,5 and Josef T. Prchal6
1Center for Sickle Cell Disease and Department of Medicine, Howard University, Washington, DC; 2Chuvash Republic Clinical Hospital No. 1, Cheboksary,
Russia; 3Cheboksary Children’s Hospital, Cheboksary, Russia; 4Russian Research Services, Camas, WA; 5Department of Medicine, David Geffen School of
Medicine, University of California-Los Angeles, Los Angeles, CA; and 6Division of Hematology, University of Utah and Veterans Administration Hospital, Salt
Lake City, UT
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 VHLR200W
mutation is common in Chuvashia, Russia,
and also occurs elsewhere. VHLR200W homozygotes have elevated hypoxia-inducible
factor 1␣ (HIF-1␣) and HIF-2␣ levels, in-
creased red cell mass, propensity to thrombosis, and early mortality. Ninety VHLR200W
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 VHLR200W. 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 VHLR200W 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, upregulation of the hypoxic response leads to
decreased expression of hepcidin that may
be independent of increased erythropoietin
levels and increased RBC counts. (Blood.
2011;118(19):5278-5282)
Introduction
Oxygen sensing is a fundamental physiologic function, and hypoxiainducible factors (HIFs) are the principal transcriptional regulators
of the response to hypoxia in mammalian cells.1 HIF is a
heterodimer composed of an HIF-␤ subunit that is constitutively
expressed and one of several HIF-␣ subunits that are regulated
posttranslationally, principally by the oxygen tension. The von
Hippel Lindau (VHL) protein and prolyl hydroxylase domain
proteins (PHDs) are critical to the oxygen-related regulation of
cellular HIF-␣ levels, which then determine the levels of HIF
dimers. The VHL protein is the recognition component of an
E3 ubiquitin-protein ligase complex that mediates proteasomal
degradation of HIF-1␣ and HIF-2␣ under normoxic conditions.2
PHDs are enzymes that require oxygen as a substrate and that serve
to hydroxylate HIF-1␣ and HIF-2␣ on specific proline residues;
this proline hydroxylation is required for the interaction of HIF-1␣
and HIF-2␣ with VHL.1,3 Therefore, HIF-1 and HIF-2 levels
increase in response to hypoxia, and this leads to increased
expression of erythropoietin4 and either increased or decreased
expression of other hypoxia-responsive genes.1,5-7
The R200W mutation of the VHL gene is present on the same
haplotype in almost all persons of heterogeneous racial and ethnic
background, indicating that the mutation may have originated in a
founder before the divergence of the human races.8 Only one
individual with this mutation present on a different haplotype has
been reported.9 Homozygosity for VHLR200W is responsible for Chuvash polycythemia, the first recognized congenital disorder of aug-
mented hypoxia sensing.10,11 Chuvash polycythemia is common in the
Chuvash Republic of the Russian Federation,12 where approximately
200 cases are recognized among a population of approximately 1.5 million people, with an estimated heterozygosity frequency of 1.7%
(V.G., unpublished observations, 2011) and in the Italian island of
Ischia13; the condition also occurs sporadically in other parts of the
world.9,14,15 Homozygosity for VHLR200W leads to up-regulation of
HIF-1 and HIF-2 under normoxic conditions.11,16 Several of the target
genes of HIF are up-regulated in Chuvash polycythemia, including
those for endothelin-1, glucose transporter 1, plasminogen activator
inhibitor-1, transferrin, the transferrin receptor, and VEGF.11,17,18 Matched
cohort, case-control, and other analyses have shown that homozygosity
is associated with lower systemic blood pressure, higher pulmonary
artery pressure, and other changes in pulmonary vascular physiology. It
is also associated with varicose veins, vertebral and hepatic hemangiomas, lower white blood cell and platelet counts, increased serum
concentrations of inflammatory cytokines, changes in plasma thiol
concentrations, arterial and venous thrombosis, major bleeding episodes, cerebral vascular events, and premature mortality. Malignant
tumors typical of classic VHL tumor predisposition syndrome have not
been found, and no increased risk of cancer has been demonstrated.17-22
Hepcidin is the master regulator of systemic iron metabolism,
leading to decreased iron absorption and increased iron storage in
macrophages through its interaction with ferroportin.23,24 Expression of hepcidin in the liver is up-regulated by a bone morphogenetic protein receptor complex in response to intracellular iron
Submitted March 30, 2011; accepted August 10, 2011. Prepublished online as Blood
First Edition paper, August 29, 2011; DOI 10.1182/blood-2011-03-345512.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2011 by The American Society of Hematology
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BLOOD, 10 NOVEMBER 2011 䡠 VOLUME 118, NUMBER 19
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BLOOD, 10 NOVEMBER 2011 䡠 VOLUME 118, NUMBER 19
stores25,26 and is also stimulated by elevated circulating levels of
transferrin bound to iron.25-28 Expression in the liver is also
up-regulated by IL-6 in response to inflammation.29 In contrast,
hepcidin responds to hypoxia with decreased expression,30,31 but it
is not clear whether this is a direct response to up-regulation of
HIFs31 or to an indirect response related to erythropoietin signaling32 or to increased erythropoiesis itself.33 The present study was
conducted to determine whether the VHLR200W genotype leads
directly to decreased serum levels of hepcidin or whether such an
effect is mediated by an increase in erythropoietin expression and
increased erythropoiesis.
VHLR200W MUTATION AND DOWN-REGULATION OF HEPCIDIN
5279
Table 1. Clinical characteristics of study participants according to
VHLR200W status
Controls
(n ⴝ 52)
Age, y
49 (14)
Female sex, no (%)
VHLR200W
homozygotes
(n ⴝ 90)
P
43 (13)
.008
34 (65%)
52 (58%)
.4
History of smoking, no (%)
6 (12%)
25 (28%)
.024
History of alcohol consumption,
9 (17%)
16 (18%)
.9
3 (6%)
8 (9%)
.5
no (%)
History of bleeding in the past
year (principally menorrhagia
or gastrointestinal), no (%)
Methods
Research protocol
The Howard University institutional review board approved the research
and all participants provided written informed consent in accordance with
the Declaration of Helsinki. The study was carried out in the Chuvash
Autonomous Republic of the Russian Federation, which is located approximately 650 kilometers southeast of Moscow along the Volga River. Patients
with the diagnosis of Chuvash polycythemia, relatives of patients, and
community controls were studied. Participants were ⬎ 20 years of age,
were recruited from the community, and were in their usual state of health.
The study participants were characterized by medical history, physical
examination including blood pressure and body weight, and laboratory tests
of the peripheral blood. Serum samples were collected from 2004-2008 and
stored at ⫺70°C. Collection and storage of samples from Chuvash
polycythemia patients and controls was identical. Samples were transported
in dry shippers with liquid nitrogen or on dry ice. They were analyzed for
hepcidin in 2010, and had undergone 2 or fewer freeze-thaw cycles.
Approximately 1/2 of the patients with Chuvash polycythemia had been
treated with phlebotomy within the year before the date of the study. The
other half had either never undergone phlebotomy or had received
phlebotomy ⬎ 1 year before the date of the study.
History of thrombosis, no (%)
5 (10%)
Phlebotomy in past year, no (%)
0
3 (3%)
.12
46 (51%)
⬍ .001*
Body mass index, kg/m2
25.5 (5.2)
23.1 (3.4)
.004*
Systolic blood pressure, mmHg
132 (23)
122 (19)
.010
Diastolic blood pressure, mmHg
84 (11)
81 (10)
.14
100 (14)
95 (12)
.031
Mean blood pressure, mmHg
Results are means (SD) unless otherwise indicated.
*Significant after the Bonferroni correction for multiple comparisons.
Results
Clinical characteristics according to VHL genotype
The clinical characteristics of the study participants are summarized in Table 1. Mean ages were 43 years in 90 VHLR200W
homozygotes compared with 49 years in 52 controls (P ⫽ .008).
Females made up slightly more than half of both cohorts. Histories
of alcohol consumption, substantial bleeding in the past year,
thrombosis, and systemic hypertension were not different in
VHLR200W homozygotes compared with controls. Body mass index
was lower in VHLR200W homozygotes than controls (P ⫽ .004), and
history of smoking was higher (P ⫽ .024).
Complete blood count, iron measures, erythropoietin, and
hepcidin concentrations according to VHL genotype
Laboratory procedures
The complete blood count was performed by an automated analyzer
(Sysmex XT 2000i; Sysmex Corporation). Serum ferritin concentration was
determined by enzyme immunoassay (Ramco Laboratories). Serum concentration of erythropoietin was determined by ELISA (R&D Systems). Serum
hepcidin was measured by competitive ELISA, as described previously.34
Serum albumin, total protein, and iron concentrations and total iron binding
capacity were determined by Quest Diagnostics using spectrophotometric
methodology. The globulin fraction, the albumin/globulin ratio, and the
transferrin saturation were calculated.
Statistics
The primary study comparison was between VHLR200W homozygotes and
genotypically normal subjects with regard to serum hepcidin concentration
using multiple linear regression. For hepcidin concentrations below the
detection limit, we assigned a value of 2.6 ng/mL, which is halfway
between the limit of detection of 5.2 ng/mL and 0. Skewed continuous
variables were log-transformed to approximate a normal distribution.
Generalized linear models were also applied to validate the linear regression. The clinical characteristics of the VHLR200W homozygotes and controls
were assessed with the Student t test or Pearson ␹2 test. Bivariate
relationships of various measurements with hepcidin were performed with
Spearman correlation. Analyses were performed with Stata 10.0 software
(StataCorp).
After adjustment for sex by multiple linear regression, the geometric mean (95% confidence interval of the mean [95% CI])
hemoglobin concentration was 17.3 (16.8-17.8) g/L in the VHLR200W
homozygotes and 12.8 (12.3-13.3) g/L in controls without mutated
VHL alleles (P ⬍ .001). The mean value for mean corpuscular
volume was lower among the VHLR200W homozygotes than controls
(P ⬍ .001), which is consistent with their frequent history of
phlebotomy. The white blood cell and platelet counts were lower in
the VHLR200W homozygotes (P ⱕ .002). The serum ferritin concentration, serum iron concentration, and transferrin saturation were
lower in VHLR200W homozygotes compared with controls, and the
total iron binding capacity was significantly higher (P ⬍ .001). The
serum ferritin concentration was ⱕ 25 ␮g/L in 60 of 90 VHLR200W
homozygotes (67%) compared with 12 of 52 controls (23%), also
consistent with the frequent history of phlebotomy in the VHLR200W
homozygotes. Serum concentrations of erythropoietin were higher
and of hepcidin were lower in the VHLR200W homozygotes (P ⬍ .001;
Table 2).
Univariate correlates of hepcidin by VHL genotype
Table 3 and Figure 1 show that serum hepcidin concentration
was correlated strongly with the serum ferritin concentration in
both VHLR200W homozygotes and controls. The correlations of
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BLOOD, 10 NOVEMBER 2011 䡠 VOLUME 118, NUMBER 19
GORDEUK et al
Table 2. Laboratory tests according to VHLR200W status
N
Controls
N
VHLR200W homozygotes
P
Hemoglobin, g/dL*
52
12.8 (12.3-13.3)
90
17.3 (16.8-17.8)
⬍ .001†
RBCs, ⫻106/␮L
52
4.3 (4.2-4.5)
90
6.5 (6.3-6.7)
⬍ .001†
Mean corpuscular volume, fL
52
89 (87-91)
79
80 (78-82)
⬍ .001†
Mean corpuscular hemoglobin concentration, g/dL
52
32.9 (32.3-33.5)
80
32.9 (32.4-33.5)
WBCs, ⫻1000/␮L
52
6.5 (6.2-6.9)
90
5.6 (5.3-6.0)
Platelets, ⫻1000/␮L
52
248 (232-265)
90
208 (193-224)
Ferritin, ␮g/L*
50
53 (39-73)
77
11 (9-15)
⬍ .001†
Iron, ␮g/dL
52
68 (60-78)
88
36 (29-45)
⬍ .001†
Iron-binding capacity, ␮g/dL
52
354 (339-370)
77
483 (465-503)
⬍ .001†
Transferrin saturation, %
52
19 (17-22)
77
10 (8-12)
Protein, g/dL
52
7.2 (7.0-7.4)
88
7.4 (7.3-7.5)
Albumin, g/dL
52
4.4 (4.3-4.5)
88
4.4 (4.3-4.5)
0.6
Globulin, g/dL
52
2.8 (2.7-2.9)
88
3.0 (2.9-3.0)
0.008
Albumin/globulin ratio
52
1.6 (1.5-1.7)
88
1.5 (1.4-1.5)
0.006
Erythropoietin, IU/L
50
9.7 (8.6-11.1)
77
51.5 (42.3-62.8)
⬍ .001†
Hepcidin, ng/mL
52
40.8 (29.6-56.3)
90
6.0 (5.0-7.6)
⬍ .001†
.8
.002†
⬍ .001†
⬍ .001†
0.10
Results are geometric means (95% CI).
*Adjusted for sex.
†Significant after the Bonferroni correction for multiple comparisons.
serum hepcidin with serum ferritin were stronger than the
correlations of hepcidin with serum iron, total iron-binding
capacity, and transferrin saturation. Figure 1 also demonstrates
that hepcidin concentrations were lower in VHLR200W homozygotes compared with controls with similar ferritin concentrations. The slope of the regression line for hepcidin as a function
of ferritin was significantly lower in VHLR200W homozygotes
compared with controls (P ⫽ .002).
Table 3. Spearman correlation of serum hepcidin concentration
with clinical and laboratory variables
Controls
VHLR200W
homozygotes
N
Rho (P)
N
Age
52
0.26 (.06)
90
Rho (P)
0.12 (.3)
Female sex
52
⫺0.19 (.19)
90
⫺0.02 (.8)
⫺0.05 (.7)
History of smoking
52
0.10 (.5)
90
History of alcohol consumption
52
0.01 (.9)
90
0.16 (.12)
History of bleeding in the past year
52
⫺0.21 (.14)
90
⫺0.14 (.19)
History of thrombosis
52
⫺0.08 (.6)
90
0.14 (.18)
Body mass index
52
0.18 (.2)
90
0.11 (.3)
Systolic blood pressure
52
0.21 (.14)
90
⫺0.05 (.7)
Diastolic blood pressure
52
0.05 (.7)
90
⫺0.07 (.5)
Hemoglobin
52
0.29 (.038)
90
0.08 (.5)
RBCs, ⫻106
52
0.20 (.16)
90
⫺0.03 (.8)
Mean corpuscular volume
52
⫺0.04 (.8)
79
0.08 (.5)
Mean corpuscular hemoglobin
52
0.18 (.2)
80
⫺0.07 (.5)
⫺0.03 (.8)
Independent relationships of hepcidin to VHLR200W
homozygosity, erythropoietin, and ferritin
By multiple linear regression, serum hepcidin concentration was
significantly lower in VHLR200W homozygotes than controls
without mutated VHL alleles after adjustment for serum ferritin
and serum erythropoietin (Table 4). In ANOVA and after
adjustment for ferritin and erythropoietin, the geometric mean
(95% CI) hepcidin concentration was 8.1 (6.3-10.5) ng/mL in
VHLR200W homozygotes versus 26.9 (18.6-30.0) ng/mL in controls (P ⬍ .0001). The independent inverse relationship of
hepcidin with VHLR200W homozygosity persisted in subgroup
analyses of subjects with low iron stores on the basis of serum
ferritin concentration ⱕ 25 ␮g/L or sufficient iron stores based
on serum ferritin concentration ⬎ 25 ␮g/L. In contrast, none of
these analyses showed a significant, independent relationship of
erythropoietin with hepcidin. Although not shown in Table 4,
concentration
WBCs
52
0.30 (.031)
90
Platelets
52
0.12 (.4)
90
0.07 (.5)
Ferritin
50
77
0.36 (.001)*
0.68 (⬍ .0001)*
Iron
52
0.14 (.3)
88
0.07 (.5)
Iron-binding capacity
52
⫺0.33 (.019)
77
⫺0.09 (.4)
Iron saturation
52
0.23 (.11)
77
0.12 (.3)
Protein
52
0.32 (.021)
88
⫺0.05 (.7)
Albumin
52
0.42 (.002)*
88
⫺0.14 (.19)
Globulin
52
0.03 (.8)
88
0.07 (.5)
Albumin/globulin ratio
52
0.13 (.3)
88
⫺0.17 (.10)
Erythropoietin
50
⫺0.33 (.021)
77
⫺0.06 (.6)
*Significant after the Bonferroni correction for multiple comparisons.
Figure 1. The relationship of serum hepcidin concentration and serum ferritin
concentration in VHLR200W homozygotes and controls. The Spearman correlation
between hepcidin and ferritin was 0.68 (P ⬍ .0001) in controls and 0.36 (P ⫽ .001) in
VHLR200W homozygotes. Forty-four of 90 VHLR200W homozygotes versus 1 of
50 controls with overlapping serum ferritin concentrations had hepcidin levels that
were below the limit of detection, which is consistent with a relationship between
VHLR200W homozygosity and a reduction in hepcidin expression.
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BLOOD, 10 NOVEMBER 2011 䡠 VOLUME 118, NUMBER 19
VHLR200W MUTATION AND DOWN-REGULATION OF HEPCIDIN
Table 4. Variables having an independent association with log
hepcidin concentration by multiple linear regression
Beta (95% CI)
P
⫺0.52 (⫺0.74 to ⫺0.30)
⬍ .0001
All subjects (nⴝ126)*
VHLR200W homozygosity
Serum ferritin (log)
Serum erythropoietin (log)
0.43 (0.27-0.58)
⬍ .0001
⫺0.06 (⫺0.30-0.18)
.6
⫺0.42 (⫺0.72 to ⫺0.13)
.006
Subjects with ferritin < 25 ␮g/L
(n ⴝ 71)†
VHLR200W homozygosity
Serum ferritin (log)
Serum erythropoietin (log)
0.05 (⫺0.22-0.33)
.7
⫺0.05 (⫺0.33-0.24)
.7
Subjects with ferritin > 25 ␮g/L
(n ⴝ 55)‡
VHLR200W homozygosity
Serum ferritin (log)
Serum erythropoietin (log)
⫺0.38 (⫺0.72 to ⫺0.05)
.026
0.78 (0.41-1.16)
.006
⫺0.31 (⫺0.70-0.09)
.13
*One observation was removed because of outlier (R2 ⫽ 0.58).
†One observation was removed because of outlier (R2 ⫽ 0.19).
‡R2 ⫽ 0.53.
hemoglobin concentration did not have a significant independent correlation with hepcidin concentration if it was substituted
for erythropoietin in these models or if it was included along
with erythropoietin.
The serum hepcidin concentration decreases rapidly after
phlebotomy (within 1-2 days), but the serum ferritin concentration
takes longer to respond. Therefore, we repeated the multiple linear
regression analysis with 44 controls with normal VHL alleles and
44 VHLR200W homozygotes whose last phlebotomy was more than
1 year before the time of the study or who had never had a
phlebotomy. The VHLR200W homozygous state had an independent
negative relationship with serum hepcidin concentration
(␤ ⫽ ⫺0.37, 95% CI ⫺0.66 to ⫺0.04, P ⫽ .014) and serum ferritin
concentration had a significant positive relationship (␤ ⫽ 0.59,
95% CI 0.40-0.79, P ⬍ .0001), but erythropoietin did not have a
significant independent relationship with hepcidin (P ⫽ .5). Hemoglobin concentration also did not have a significant relationship
with hepcidin (data not shown).
Discussion
Hepcidin expression is reduced by both hypoxia and anemia,30
but the mechanisms for this effect are still under discussion.
Under normoxic and iron-sufficient conditions, HIF-1␣ and
HIF-2␣ undergo proteasomal degradation in a process that is
mediated by the VHL protein, the recognition component of an
E3 ubiquitin-protein ligase complex.2 HIF-1␣ and HIF-2␣ are
subject to hydroxylation on specific proline residues by prolyl
hydroxylase domain protein 2 (PHD2), an iron-dependent
enzyme that requires oxygen as a substrate, and proline
hydroxylation is required for the interaction of HIF-1␣ and
HIF-2␣ with VHL.1,35 Therefore, HIF-1␣ and HIF-2␣ levels
increase in response to hypoxia or iron deficiency, and this leads
to increased expression of erythropoietin.4
Several lines of evidence indicate that the reduction in hepcidin
expression associated with hypoxia and anemia might be mediated
by erythropoietin or by the increased erythropoiesis associated with
increased erythropoietin. Erythropoietin injection leads to decreased circulating hepcidin levels in humans36 and to reduced
murine hepatic hepcidin gene expression in vivo.30,37,38 Stimulation
of a hepatoma cell line with erythropoietin led to decreased
5281
hepcidin mRNA and protein,39 and studies in hepatocytes cultured
in vitro suggested that erythropoietin may directly down-regulate
hepcidin through erythropoietin receptor signaling and regulation
of C/EBP␣.32 However, in vivo, the effect of erythropoietin on
reducing hepcidin expression depends on intact erythropoiesis,33,40
suggesting an indirect effect of erythropoietin on reducing hepcidin
expression. Such an effect might be mediated by soluble factors
derived from erythroblasts41,42 or by the effects of heightened
erythropoiesis on iron levels.40
Evidence is also available for a more direct effect of HIFs on
hepcidin expression. It has been reported that the promoter
region of the murine hepcidin gene contains candidate HIF
recognition elements, and that HIF-1 binds to and negatively
transactivates the hepcidin promotor.31 Inactivation of hepatic
HIF-1␣ leads to a reduced ability to down-regulate hepcidin in
the setting of iron deficiency.31 Stabilization of HIF-1␣ and
HIF-2␣ in the liver contributes to the induction of matriptase-243
and stabilization of HIF-1␣ to the induction of furin.44
Maptriptase-2 and furin cleave HJV to sHJV, which leads to a
decrease in BMP-6 activation via interaction with HJV and to a
reduction in hepcidin expression.44,45
In the present study, circulating hepcidin concentrations
were significantly decreased among individuals with congenital
up-regulation of HIF-1␣ and HIF-2␣ due to homozygosity for
VHLR200W compared with the levels in control individuals with
wild-type VHL. The significant association of lower serum
hepcidin concentration with homozygosity for VHLR200W persisted after adjustment by multiple linear regression for serum
ferritin concentration and for serum erythropoietin concentration or RBC count, which were also significantly altered in the
VHLR200W homozygotes. Therefore, our findings are consistent
with results showing that HIFs are engaged in coordinate
regulation of iron metabolism and erythropoiesis through upregulation of erythropoietin and down-regulation of hepcidin.31
In contrast, the present study did not observe independent
relationships between erythropoietin, hemoglobin concentration, or RBC count and hepcidin. Therefore, our results are
consistent with the idea that hypoxia signaling may suppress
hepcidin in vivo, independently of the effects of erythropoietin,
hemoglobin concentration, or RBC counts.
A limitation to this study is that we did not study hepcidin
expression at the cellular level. The multiple linear regression
model of serum hepcidin concentration in this study does not
exclude the possibility that erythropoietin down-regulates hepcidin
expression. Another limitation is that inflammatory cytokines tend
to be elevated in Chuvash polycythemia,19 and cytokine levels were
not measured in this study. However, increased inflammatory
cytokines tend to increase hepcidin expression rather than lead to
the decreased levels observed in this paper. Therefore, failure to
account for cytokine levels would tend to bias the analysis against
our finding of reduced hepcidin levels associated with VHLR200W
homozygosity rather than in favor of this finding.
Acknowledgments
This work was supported in part by grant no. UH1-HL03679-05
from the National Heart, Lung, and Blood Institute (to V.R.G.) and
the Office of Research on Minority Health; by Howard University
General Clinical Research Center grant MO1-RR10284; and by
National Institutes of Health grants R01HL079912-01 (to V.R.G.),
and R01HL50077-14 (to J.T.P.).
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Authorship
Contribution: V.R.G. and J.T.P. designed and conducted the
study, interpreted the data, and wrote the manuscript; G.Y.M.,
A.I.S., D.J.O., and L.A.P. designed and conducted the study;
X.N., T.A., and S.N. conducted the study and wrote the
manuscript; M.N. analyzed the data and wrote the manuscript;
and T.G. conducted the study, interpreted the data, and wrote the
manuscript.
Conflict-of-interest disclosure: J.T.P. has received research
funding and served as a consultant for Amgen. V.R.G. has
received research funding from Amgen and Merck and served as
a consultant for Amgen, Merck, and Fibrogen. D.J.O. has
received research funding from Amgen. The remaining authors
declare no competing financial interests.
Correspondence: Victor R. Gordeuk, MD, Center for Sickle
Cell Disease, Howard University, 2041 Georgia Ave NW, Washington, DC 20060; e-mail: [email protected].
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2011 118: 5278-5282
doi:10.1182/blood-2011-03-345512 originally published
online August 29, 2011
Chuvash polycythemia VHLR200W mutation is associated with
down-regulation of hepcidin expression
Victor R. Gordeuk, Galina Y. Miasnikova, Adelina I. Sergueeva, Xiaomei Niu, Mehdi Nouraie, Daniel
J. Okhotin, Lydia A. Polyakova, Tatiana Ammosova, Sergei Nekhai, Tomas Ganz and Josef T. Prchal
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