Clinical and genetic heterogeneity in hereditary haemochromatosis: association between lymphocyte counts and expression of iron overload

Porto, Graça; Cardoso, Carla; Cruz, Eugénia; Fraga, José Carlos Soares de; Areias, Jorge; Oliveira, José Carlos; Bravo, Fernanda; Gangaidzo, Innocent T.; Macphail, A. P.; Gomo, Zvenyika A. R.; Moyo, Victor; Melo, Graça; Silva, Cidália Maria Ferreira; Justiça, Benvindo; Sousa, Maria de

doi:10.1034/j.1600-0609.2001.t01-1-00481.x

Cited by 25 publications

(27 citation statements)

References 48 publications

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“…Also, there is strong linkage disequilibrium in the HLA region where the HFE gene is located and other closely linked genes may modify the phenotype. 15 Our findings in the general elderly population suggest that the value for screening for high iron based on HFE genotypes is limited in that only a small percentage of subjects with elevated levels of iron will be detected. However, the aim of a population-based screening is to identify at an early stage individuals at risk of developing serious iron overload, to prevent organ damage.…”

Section: Discussionmentioning

confidence: 98%

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

et al. 2003

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The C282Y and H63D mutations in the HFE gene are important causes of hemochromatosis. In the elderly, these mutations might be associated with increased morbidity because of the lifelong accumulation of iron. In a population-based sample of the elderly, we determined the value of genotyping for HFE mutations to screen for subclinical hemochromatosis. HFE genotype frequencies were determined in a random group of 2095 subjects (55 years and over). In this random group, we selected within the six genotype groups a total of 342 individuals and measured their serum transferrin saturation, iron and ferritin levels. We also estimated the heritability and parameters needed to evaluate screening, including the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of HFE genotypes. Iron parameters were significantly increased in subjects homozygous, heterozygous or compound heterozygous. The effect of the mutations was more pronounced in men than in women. For the H63D mutation, an allele dose effect was observed. The HFE gene explained about 5% of the variability in serum iron indices. The PPV for hemochromatosis for the C282Y homozygous was 100% in men and 67% in women. The NPV of the wild-type allele was 97% for both men and women. The sensitivity of both mutations was 70% for men and 52% for women and the specificity was 62% for men and 64% for women. Our study shows that the HFE C282Y and H63D are determinants of iron parameters in the elderly and will be effective in detecting individuals at high risk of hemochromatosis. However, when screening based on these two mutations, some individuals with subclinical hemochromatosis will be missed.

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Section: Discussionmentioning

confidence: 98%

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

et al. 2003

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“…Several reports show that serum CP [47,48] and its ferroxidase activity [49] are decreased in HH patients. Moreover, defective numbers of huPBL were associated with a greater degree of Fe loading in HH [50] while Fe deposition and damage in liver from HH patients were shown to be associated with low numbers of CD8+ cells in the lobuli [51]. Interestingly, in healthy individuals liverassociated lymphocytes are characterized by a three-fold increase in the percentage of CD56+ cells (NK cells) and also an increase in the percentage of CD8+ cells compared to PBL [52].…”

Section: Discussionmentioning

confidence: 99%

Ceruloplasmin expression by human peripheral blood lymphocytes: A new link between immunity and iron metabolism

Banha

Marques

Palmeira‐de‐Oliveira

et al. 2008

Free Radical Biology and Medicine

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Ceruloplasmin (CP) is a multicopper oxidase involved in the acute phase reaction to stress. Although the physiological role of CP is uncertain, its role in iron (Fe) homeostasis and protection against free radical-initiated cell injury has been widely documented. Previous studies showed the existence of two molecular isoforms of CP: secreted CP (sCP) and a membrane glycosylphosphatidylinositol (GPI)-anchored form of CP (GPI-CP). sCP is produced mainly by the liver and is abundant in human serum whereas GPI-CP is expressed in mammalian astrocytes, rat leptomeningeal cells, and Sertolli cells. Herein, we show using RT-PCR that human peripheral blood lymphocytes (huPBL) constitutively express the transcripts for both CP molecular isoforms previously reported. Also, expression of CP in huPBL is demonstrated by immunofluorescence with confocal microscopy and flow cytometry analysis using cells isolated from healthy blood donors with normal Fe status. Importantly, the results obtained show that natural killer cells have a significantly higher CP expression compared to all other major lymphocyte subsets. In this context, the involvement of lymphocyte-derived CP on host defense processes via its anti/prooxidant properties is proposed, giving further support for a close functional interaction between the immune system and the Fe metabolism.

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“…Strong linkage disequilibrium between H63D and the HLA-A29 allele itself was confirmed. To address the question of the biological significance with regard to both our earlier work demonstrating a significant association between lymphocyte numbers and the phenotypic expression of iron overload in humans (reviewed in De Sousa et al 2000;Porto et al 1998Porto et al , 2001, and in experimental models of iron overload (De Sousa et al 1994;Levy et al 2000;Fleming et al 2001;Santos et al 2000;Sproule et al 2001;Ten-Elshof et al 1999), we examined lymphocyte subpopulations in normal subjects based on the presence or absence of the H63D mutation and the HLA-A29 allele. Significantly higher CD8 + T lymphocyte counts were observed in subjects simultaneously carrying the H63D and the HLA-A29 alleles.…”

Section: Introductionmentioning

confidence: 99%

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Cardoso¹,

Alves

Mascarenhas³

et al. 2002

Immunogenetics

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The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8 + T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

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Clinical and genetic heterogeneity in hereditary haemochromatosis: association between lymphocyte counts and expression of iron overload

Cited by 25 publications

References 48 publications

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

Ceruloplasmin expression by human peripheral blood lymphocytes: A new link between immunity and iron metabolism

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

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