Concordance of iron indices in homozygote and heterozygote sibling pairs in hemochromatosis families: implications for family screening

Whiting, P.; Fletcher, Linda M.; Dixon, Jeanette K; Gochee, Peter A.; Powell, Lawrie W.; Crawford, Darrell H. G.

doi:10.1016/s0168-8278(02)00216-7

Cited by 20 publications

(14 citation statements)

References 19 publications

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“…Their study demonstrated that iron storage in hemochromatosis is predominantly under genetic control. In a similar study, Whiting et al [18] reported a concordance of iron indices in C282Y homozygote(s) and heterozygote(s) sibling pairs. There is only one twin study known on the heritability of iron parameters.…”

Section: Heritability Of Serum Iron Ferritin and Transferrin Saturatmentioning

confidence: 74%

Heritability of Serum Iron, Ferritin and Transferrin Saturation in a Genetically Isolated Population, the Erasmus Rucphen Family (ERF) Study

Njajou¹,

Alizadeh²,

Aulchenko³

et al. 2006

Hum Hered

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Background: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. Methods: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. Results: The heritability (h² ± SE) estimates were 0.23 ± 0.07 (p < 0.0001) for iron, 0.29 ± 0.09 (p < 0.0001) for ferritin and 0.28 ± 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age² and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. Conclusion: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network.

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Section: Heritability Of Serum Iron Ferritin and Transferrin Saturatmentioning

confidence: 74%

Heritability of Serum Iron, Ferritin and Transferrin Saturation in a Genetically Isolated Population, the Erasmus Rucphen Family (ERF) Study

Njajou¹,

Alizadeh²,

Aulchenko³

et al. 2006

Hum Hered

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“…Perhaps we should not be too surprised that no genetic modifiers have emerged. The evidence that the expression of hemochromatosis is genetically determined is very modest [69]. Because of the fact that there was a modest sibto-sib correlation in serum ferritin levels in fraternal and identical twins homozygous for the C282Y HFE mutation, it was concluded that genetic factors were operative.…”

Section: Genetic Modifiers Of Hereditary Hemochromatosismentioning

confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves.Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it became to be considered the most common disease of Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and it is only the genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype.Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias.While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.It is a great honor for me to present this lecture in memory of my good friend Bracha Ramot. It is because this lecture is in honor of Bracha that I do not feel the least bit uncomfortable speaking about iron storage diseases in a symposium entitled "Genomics and Molecular Biology of Hematopoietic Malignancies". I know that had it been possible to ask her whether this might be appropriate Bracha would have said: "Of course, Ernie. Talk about whatever you want to". That was her way. And, of course, Bracha was no stranger to iron metabolism. She was scientifically broad, a Renaissance hematologist. A MEDLINE search reveals 261 publications by Bracha and eight of those deal with iron --iron in thalassemia, iron in sideroblastic anemia, and iron in iron deficiency anemia.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable...

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“…13 We now think that this approach is likely to be unproductive also because studies of dizygotic twins and siblings indicate that the heritability of the phenotype is actually relatively low. 14 But there is an indicator that robustly predicts the risk of cirrhosis, the main clinical manifestation of hereditary hemochromatosis, and that measurement is the serum ferritin level. Three studies from different parts of the world agree that cirrhosis of the liver occurs only extremely rarely in hemochromatosis patients with serum ferritin levels of less than 1000 g/L.…”

Section: Introductionmentioning

confidence: 99%

Screening for hemochromatosis by measuring ferritin levels: a more effective approach

Waalen

Felitti

Gelbart

et al. 2008

Blood

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Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 g/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 g/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who IntroductionAt one time, hereditary hemochromatosis was regarded as the "poster child" for genetic screening for a common, treatable disease. However, enthusiasm for screening for hemochromatosis waned after several large controlled studies showed that the penetrance of the homozygous state for the HFE C282Y mutation is much lower than had previously been thought. These studies showed that the nonspecific symptoms attributed to iron overload in C282Y homozygotes were equally prevalent in controls, leading to a more specific definition of penetrance based on the presence of liver disease. Although there may be disagreement of whether the penetrance in males is of the order of 2% as shown by our studies 1 and those of others, 2,3 or whether it approaches 5% as suggested by the prevalence of cirrhosis found by others, 4,5 it is clear that earlier penetrance estimates of 95% 6 or 43% 7 on which calculation of the cost-effectiveness of screening strategies were based are no longer tenable.Because such cost estimates are based on the number of patients who may be helped by therapy, the low penetrance of hemochromatosis makes screening much more expensive than had originally been estimated. Accordingly, strategies aimed at lowering the expense of screening, such as performing less costly unsaturated iron binding capacity measurements rather than transferrin saturation determinations, 8 or focusing on "at-risk" groups 9-12 have been proposed to bring population screening closer to cost-effectiveness. Although such approaches may decrease somewhat the cost per case found, the majority of detected subjects will not have a clinical phenotype, nor will they be fated to develop one in the future. As a result, many essentially normal patients will be subjected to further extensive and often expensive examinations from which they will not benefit.What is needed is a means of limiting screening to subjects who are not only at high risk of being homozygous for the C282Y mutation (which occurs almost exclusively in persons of European ancestry) but who also are at increased ris...

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Concordance of iron indices in homozygote and heterozygote sibling pairs in hemochromatosis families: implications for family screening

Cited by 20 publications

References 19 publications

Heritability of Serum Iron, Ferritin and Transferrin Saturation in a Genetically Isolated Population, the Erasmus Rucphen Family (ERF) Study

Heritability of Serum Iron, Ferritin and Transferrin Saturation in a Genetically Isolated Population, the Erasmus Rucphen Family (ERF) Study

Iron storage disease: Facts, fiction and progress

Screening for hemochromatosis by measuring ferritin levels: a more effective approach

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