Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis.

Simon, M; Bourel, M; Fauchet, R.; Genetet, B

doi:10.1136/gut.17.5.332

Cited by 383 publications

(127 citation statements)

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“…The discovery that the disorder was HLA-linked [20,21], and the fact that serum iron determinations and methods for measuring serum ferritin were becoming commonplace changed the landscape. Quickly, and, in retrospect, uncritically, hemochromatosis was considered to be the most common genetic disease of Europeans.…”

Section: The History 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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Section: The History Of Hereditary Hemochromatosismentioning

confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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“…HH has been known for more than 20 years to be associated with the HLA-A3 allele and with the HLA-A3-B7 or HLA-A3-B14 haplotypes in particular (Simon et al 1976). The strong linkage disequilibrium between the C282Y mutation and the extended haplotype containing the HLA-A3 allele was a posteriori confirmed by others (Ajioka et al 1997; reviewed in Jaswinska 2000; Thomas et al 1998).…”

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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“…The genetic basis of hemochromatosis (HH) has been known for more than 20 years, following the demonstration of the association between the major histocompatibility complex (MHC) class I antigen HLA-A3 and the disease (Edwards et al 1977;Simon et al 1976). These and subsequent studies of the strong linkage disequilibrium between HH and various markers in the MHC region all led to the expectation that a putative HH gene would lie within approximately 1 cM of the HLA-A locus (Gasparini et al 1993;Jazwinska et al 1993;Raha-Chowdhury et al 1995;Yaouanq et al 1994).…”

Section: Introductionmentioning

confidence: 99%