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Relationship between gene expression of duodenal iron transporters and iron stores in hemochromatosis subjects.

ABSTRACT: To test the hypothesis that differences in duodenal iron absorption may explain the variable phenotypic expression among HFE C282Y homozygotes, we have compared relative gene expression of duodenal iron transporters among C282Y homozygotes [hereditary hemochromatosis (HH)] with and without iron overload. Duodenal biopsy samples were analyzed using real-time PCR for expression of DMT1, FPN1, DCYTB, and HEPH relative to GAPDH from 23 C282Y homozygotes, including 5 "nonexpressors" (serum ferritin < upper limit of normal and absence of phenotypic features of hemochromatosis) and 18 "expressors." Four subjects of wild type for HFE mutations without iron overload or liver disease served as controls. There was a significant difference in expression of DMT1 (P = 0.03) and DMT1(IRE) (P = 0.0013) but not FPN1, DCYTB, or HEPH between groups. Expression of DMT1(IRE) was increased among HH subjects after phlebotomy compared with untreated (P = 0.006) and nonexpressor groups (P = 0.026). A positive relationship was observed among all HH subjects regardless of phenotype or treatment status between relative expression of FPN1 and DMT1 (r = 0.5854, P = 0.0021), FPN1, and DCYTB (r = 0.5554, P = 0.0040), FPN1 and HEPH (r = 0.5100, P = 0.0092), and DCYTB and HEPH (r = 0.5400, P = 0.0053). In summary, phlebotomy is associated with upregulation of DMT1(IRE) expression in HH subjects. HFE C282Y homozygotes without phenotypic expression do not have significantly decreased duodenal gene expression of iron transport genes compared with HH subjects with iron overload. There is coordinated regulation between duodenal expression of FPN1 and DMT1, FPN1 and DCYTB, and FPN1 and HEPH and also DCYTB and HEPH in HH subjects regardless of phenotype.

SUBMITTER: Nelson JE

PROVIDER: S-EPMC2806103 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Relationship between gene expression of duodenal iron transporters and iron stores in hemochromatosis subjects.

Nelson James E JE Mugford Virginia R VR Kilcourse Ellen E Wang Richard S RS Kowdley Kris V KV

American journal of physiology. Gastrointestinal and liver physiology 20091105 1

To test the hypothesis that differences in duodenal iron absorption may explain the variable phenotypic expression among HFE C282Y homozygotes, we have compared relative gene expression of duodenal iron transporters among C282Y homozygotes [hereditary hemochromatosis (HH)] with and without iron overload. Duodenal biopsy samples were analyzed using real-time PCR for expression of DMT1, FPN1, DCYTB, and HEPH relative to GAPDH from 23 C282Y homozygotes, including 5 "nonexpressors" (serum ferritin < ...[more]

PMID: 19892936

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Project description:BackgroundIron deficiency (ID) has been associated with adverse pregnancy outcomes, maternal anaemia, and altered susceptibility to infection. In Papua New Guinea (PNG), monthly treatment with sulphadoxine-pyrimethamine plus azithromycin (SPAZ) prevented low birthweight (LBW; <2500 g) through a combination of anti-malarial and non-malarial effects when compared to a single treatment with SP plus chloroquine (SPCQ) at first antenatal visit. We assessed the relationship between ID and adverse birth outcomes in women receiving SPAZ or SPCQ, and the mediating effects of malaria infection and haemoglobin levels during pregnancy.MethodsPlasma ferritin levels measured at antenatal enrolment in a cohort of 1892 women were adjusted for concomitant inflammation using C-reactive protein and α-1-acid glycoprotein. Associations of ID (defined as ferritin <15 μg/L) or ferritin levels with birth outcomes (birthweight, LBW, preterm birth, small-for-gestational-age birthweight [SGA]) were determined using linear or logistic regression analysis, as appropriate. Mediation analysis assessed the degree of mediation of ID-birth outcome relationships by malaria infection or haemoglobin levels.ResultsAt first antenatal visit (median gestational age, 22 weeks), 1256 women (66.4%) had ID. Overall, ID or ferritin levels at first antenatal visit were not associated with birth outcomes. There was effect modification by treatment arm. Amongst SPCQ recipients, ID was associated with a 81-g higher mean birthweight (95% confidence interval [CI] 10, 152; P = 0.025), and a twofold increase in ferritin levels was associated with increased odds of SGA (adjusted odds ratio [aOR] 1.25; 95% CI 1.06, 1.46; P = 0.007). By contrast, amongst SPAZ recipients, a twofold increase in ferritin was associated with reduced odds of LBW (aOR 0.80; 95% CI 0.67, 0.94; P = 0.009). Mediation analyses suggested that malaria infection or haemoglobin levels during pregnancy do not substantially mediate the association of ID with birth outcomes amongst SPCQ recipients.ConclusionsImproved antenatal iron stores do not confer a benefit for the prevention of adverse birth outcomes in the context of malaria chemoprevention strategies that lack the non-malarial properties of monthly SPAZ. Research to determine the mechanisms by which ID protects from suboptimal foetal growth is needed to guide the design of new malaria prevention strategies and to inform iron supplementation policy in malaria-endemic settings.Trial registrationClinicalTrials.gov NCT01136850 .

Project description:It has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described.The study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region.Eighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 +/- 0.14 x 106/ml), in comparison with subjects carrying only one copy of those alleles (0.46 +/- 0.19 x 106/ml) and subjects without any copy of those alleles (0.79 +/- 0.15 x 106/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 +/- 0.14; 0.45 +/- 0.21 and 0.41 +/- 0.17 x 106/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009).The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed.

Dataset Information

Relationship between gene expression of duodenal iron transporters and iron stores in hemochromatosis subjects.

Publications

Relationship between gene expression of duodenal iron transporters and iron stores in hemochromatosis subjects.

Similar Datasets

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