Tumor Necrosis Factor-α −308G&amp;gt;A Allelic Variant Modulates Iron Accumulation in Patients with Hereditary Hemochromatosis

Krayenbuehl, Pierre-Alexandre; Maly, Friedrich E.; Hersberger, Martin; Wiesli, Peter; Himmelmann, Andreas; Eid, Karim; Greminger, P; Vetter, W; Schulthess, G

doi:10.1373/clinchem.2005.065417

Cited by 19 publications

(22 citation statements)

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“…5,6 Association studies between genetic markers and disease phenotype have given conflicting results. [7][8][9][10][11][12][13][14] More recently, candidate gene studies revealed significant associations between single nucleotide polymorphisms (SNPs) in genes involved in iron metabolism and indices of iron overload in p.C282Y homozygotes. Milet et al focused on two biologically relevant gene categories: genes involved in non-HFE-hereditary hemochromatosis (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression (BMP2, BMP4, HJV, SMAD1, 4 and 5, and IL6).…”

Section: Hfe-hereditarymentioning

confidence: 99%

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundMost patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and MethodsIn the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. ResultsWe found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. ConclusionsWhile our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.Key words: hemochromatosis, SNP, iron, gene, ferritin, transferrin saturation.Citation: Pelucchi S, Mariani R, Calza S, Fracanzani AL, Modignani GL, Bertola F, Busti F, Trombini P, Fraquelli M, Forni GL, Girelli D, Fargion S, Specchia C, and Piperno A. CYBRD1 as a modifier gene that modulates iron phenotype in HFE p. C282Y homozygous patients. Haematologica 2012;97(12):1818-1825. doi:10.3324/haematol.2012 ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Section: Hfe-hereditarymentioning

confidence: 99%

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

et al. 2012

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“…Considerable effort has been expended, particularly by our laboratory [52][53][54][55][56][57][58] but also by others [59][60][61][62][63][64][65][66][67] to find mutations that interact with HFE mutations to increase or decrease the penetrance. These efforts have been virtually entirely fruitless.…”

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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“…Studies in patients with hereditary hemochromatosis have found differing results with the TNF Ϫ308 A allele. One study found a trend toward lower ferritin levels and protection from liver damage, 24 another increased iron loading 25 and 2 studies found no effect. 42,43 These studies were in iron-overloaded adults rather than in children at risk of iron deficiency and the numbers of TNF Ϫ308 AA homozygotes were few (n ϭ 0-2).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the TNF Ϫ308 and the TNF Ϫ238 promoter polymorphisms were found to alter the phenotypic expression of hereditary hemochromatosis. 24,25 The TNF Ϫ308 polymorphism was associated with an increased risk of severe anemia in low-birth-weight children in Kenya, 26 although not severe malaria anemia. 26,27 The TNF Ϫ238 polymorphism was associated with an increased risk of severe malarial anemia in Gambian children.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children

Atkinson

Rockett

Morgan

et al. 2008

Blood

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Tumor Necrosis Factor-α −308G>A Allelic Variant Modulates Iron Accumulation in Patients with Hereditary Hemochromatosis

Cited by 19 publications

References 51 publications

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

Iron storage disease: Facts, fiction and progress

Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children

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