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Clancy J, Ritari J, Vaittinen E, Arvas M, Tammi S, Koskela S, Partanen J. Blood donor biobank as a resource in personalised biomedical genetic research. Eur J Hum Genet 2024:10.1038/s41431-023-01528-0. [PMID: 38212662 DOI: 10.1038/s41431-023-01528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/14/2023] [Accepted: 12/19/2023] [Indexed: 01/13/2024] Open
Abstract
Health questionnaires and donation criteria result in accumulation of highly selected individuals in a blood donor population. To understand better the usefulness of a blood donor-based biobank in personalised disease-associated genetic studies, and for possible personalised blood donation policies, we evaluated the occurrence and distributions of common and rare disease-associated genetic variants in Finnish Blood Service Biobank. We analysed among 31,880 blood donors the occurrence and geographical distribution of (i) 53 rare Finnish-enriched disease-associated variants, (ii) mutations assumed to influence blood donation: four Bernard-Soulier syndrome and two hemochromatosis mutations, (iii) type I diabetes risk genotype HLA-DQ2/DQ8. In addition, we analysed the level of consanguinity in Blood Service Biobank. 80.3% of blood donors carried at least one (range 0-9 per donor) of the rare variants, many in homozygous form, as well. Donors carrying multiple rare variants were enriched in Eastern Finland. Haemochromatosis mutation HFE C282Y homozygosity was 43.8% higher than expected, whereas mutations leading to Bernard-Soulier thrombocytopenia were rare. The frequency of HLA-DQ2/DQ8 genotype was slightly lower than expected. First-degree consanguinity was higher in Blood Service Biobank than in the general population. We demonstrate that despite donor selection, the Blood Service Biobank is a valuable resource for personalised medical research and for genotype-selected samples from unaffected individuals. The geographical genetic substructure of Finland enables efficient recruitment of donors carrying rare variants. Furthermore, we show that blood donor biobank material can be utilised for personalised blood donation policies.
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Affiliation(s)
- Jonna Clancy
- Blood Service Biobank, Finnish Red Cross Blood Service, Vantaa, Finland.
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland.
| | - Jarmo Ritari
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | | | - Mikko Arvas
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Silja Tammi
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Satu Koskela
- Blood Service Biobank, Finnish Red Cross Blood Service, Vantaa, Finland
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Jukka Partanen
- Blood Service Biobank, Finnish Red Cross Blood Service, Vantaa, Finland
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
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Olynyk JK, Grainger R, Currie H, Ramm LE, Ramm GA. The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis. Sci Rep 2023; 13:7775. [PMID: 37179448 PMCID: PMC10183001 DOI: 10.1038/s41598-023-35028-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/11/2023] [Indexed: 05/15/2023] Open
Abstract
Advanced hepatic fibrosis occurs in up to 25% of individuals with C282Y homozygous hemochromatosis. Our aim was to determine whether human leukocyte antigen (HLA)-A3 and B7 alleles act as genetic modifiers of the likelihood of advanced hepatic fibrosis. Between 1972 and 2013, 133 HFE C282Y homozygous individuals underwent clinical and biochemical evaluation, HLA typing, liver biopsy for fibrosis staging and phlebotomy treatment. Hepatic fibrosis was graded according to Scheuer as F0-2 (low grade hepatic fibrosis), F3-4 (advanced hepatic fibrosis), and F4 cirrhosis. We analysed associations between the severity of fibrosis and HLA-A3 homozygosity, heterozygosity or absence, with or without the presence of HLA-B7 using categorical analysis. The mean age of HLA-A3 homozygotes (n = 24), heterozygotes (n = 65) and HLA-A3 null individuals (n = 44) was 40 years. There were no significant differences between the groups for mean(± SEM) serum ferritin levels (1320 ± 296, 1217 ± 124, 1348 ± 188 [Formula: see text]g/L), hepatic iron concentration (178 ± 26, 213 ± 22, 199 ± 29 [Formula: see text]mol/g), mobilizable iron stores (9.9 ± 1.5, 9.5 ± 1.5, 11.5 ± 1.7 g iron removed via phlebotomy), frequency of advanced hepatic fibrosis (5/24[12%], 13/63[19%], 10/42[19%]) or cirrhosis (3/24[21%], 12/63[21%], 4/42[24%]), respectively. The presence or absence of HLA-B7 did not influence the outcome. Thus, HLA-A3 and HLA-B7 alleles are not associated with the risk of advanced hepatic fibrosis or cirrhosis in C282Y hemochromatosis.
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Affiliation(s)
- John K Olynyk
- Medical School, Curtin University, Bentley, WA, Australia.
- Department of Gastroenterology, Fiona Stanley Fremantle Hospital Group, Murdoch, WA, Australia.
| | - Richard Grainger
- Department of Gastroenterology, Fiona Stanley Fremantle Hospital Group, Murdoch, WA, Australia
| | - Helen Currie
- Department of Gastroenterology, Fiona Stanley Fremantle Hospital Group, Murdoch, WA, Australia
| | - Louise E Ramm
- QIMR-Berghofer Medical Research Institute, Herston, QLD, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
| | - Grant A Ramm
- QIMR-Berghofer Medical Research Institute, Herston, QLD, Australia
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Anderson GJ, Bardou-Jacquet E. Revisiting hemochromatosis: genetic vs. phenotypic manifestations. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:731. [PMID: 33987429 PMCID: PMC8106074 DOI: 10.21037/atm-20-5512] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100–200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels per se, but determine the propensity for tissue pathology.
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Affiliation(s)
- Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute and School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
| | - Edouard Bardou-Jacquet
- Liver Disease Department, University of Rennes and French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
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Adams PC. Hemochromatosis: Ancient to the Future. Clin Liver Dis (Hoboken) 2020; 16:83-90. [PMID: 33042529 PMCID: PMC7539181 DOI: 10.1002/cld.940] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/01/2019] [Indexed: 02/04/2023] Open
Abstract
Watch an interview with the author.
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Affiliation(s)
- Paul C. Adams
- Department of MedicineUniversity HospitalLondonOntarioCanada
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Kim Y, Stahl MC, Huang X, Connor JR. H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity. J Neurochem 2020; 155:177-190. [PMID: 32574378 DOI: 10.1111/jnc.15107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022]
Abstract
Pathological features of Parkinson's disease include the formation of Lewy bodies containing α-synuclein and the accumulation of iron in the substantia nigra. Previous studies have suggested that iron accumulation contributes to the Parkinson's disease pathology through reactive oxygen species production and accelerated α-synuclein aggregation. This study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on α-synuclein pathology in cell culture and animal models. H63D HFE expression in SH-SY5Y cells lowered endogenous α-synuclein levels and significantly decreased pre-formed fibril-induced α-synuclein aggregation. H63D HFE cells were also protected from pre-formed fibril-induced apoptosis. Autophagic flux, a major pathway for α-synuclein clearance, was increased in H63D HFE cells. Expression of REDD1 was elevated and rapamycin treatment was unable to further induce autophagy, indicating mTORC1 inhibition as the main mechanism of autophagy induction. Moreover, siRNA knockdown of REDD1 in H63D HFE cells decreased autophagic flux and increased the sensitivity to PFF-mediated toxicity. While iron chelator (deferiprone) treatment rescued WT HFE cells from pre-formed fibril toxicity, it exacerbated or was unable to rescue H63D HFE cells. In the in vivo pre-formed fibril intracranial injection model, H67D Hfe (mouse homolog of the human H63D HFE variant) C57BL/6J × 129 mice showed less α-synuclein aggregation and less decline in motor function compared to WT Hfe. Collectively, this study suggests that H63D HFE variant modifies α-synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease.
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Affiliation(s)
- Yunsung Kim
- Department of Neurology, Penn State College of Medicine, Hershey, PA, USA
| | - Mark C Stahl
- Department of Neurology, Penn State College of Medicine, Hershey, PA, USA
- Neurocrine Biosciences, San Diego, CA, USA
| | - Xuemei Huang
- Department of Neurology, Penn State College of Medicine, Hershey, PA, USA
- Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA
- Translational Brain Research Center, Penn State College of Medicine, Hershey, PA, USA
| | - James R Connor
- Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA
- Translational Brain Research Center, Penn State College of Medicine, Hershey, PA, USA
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Kim Y, Connor JR. The roles of iron and HFE genotype in neurological diseases. Mol Aspects Med 2020; 75:100867. [PMID: 32654761 DOI: 10.1016/j.mam.2020.100867] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/21/2020] [Accepted: 05/24/2020] [Indexed: 12/13/2022]
Abstract
Iron accumulation is a recurring pathological phenomenon in many neurological diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and others. Iron is essential for normal development and functions of the brain; however, excess redox-active iron can also lead to oxidative damage and cell death. Especially for terminally differentiated cells like neurons, regulation of reactive oxygen species is critical for cell viability. As a result, cellular iron level is tightly regulated. Although iron accumulation related to neurological diseases has been well documented, the pathoetiological contributions of the homeostatic iron regulator (HFE), which controls cellular iron uptake, is less understood. Furthermore, a common HFE variant, H63D HFE, has been identified as a modifier of multiple neurological diseases. This review will discuss the roles of iron and HFE in the brain as well as their impact on various disease processes.
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Affiliation(s)
- Yunsung Kim
- Penn State College of Medicine, Department of Neurosurgery, Hershey, PA, USA
| | - James R Connor
- Penn State College of Medicine, Department of Neurosurgery, Hershey, PA, USA.
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de Campos WN, Massaro JD, Cançado ELR, Wiezel CEV, Simões AL, Teixeira AC, Souza FFD, Mendes-Junior CT, Martinelli ADLC, Donadi EA. Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload. World J Hepatol 2019; 11:186-198. [PMID: 30820268 PMCID: PMC6393716 DOI: 10.4254/wjh.v11.i2.186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/17/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may or not develop iron overload (IO), which is associated with worst prognosis, because can cause serious damage to organs. HFE gene controls the iron uptake from gut, particularly in patients with hereditary hemochromatosis (HH).
AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.
METHODS We sequenced exons 2 to 5 and boundary introns of HFE gene, evaluating all polymorphic sites in patients presenting hereditary (hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls, using Sanger sequencing. We also determined the ensemble of extended haplotype in healthy control individuals, including several major histocompatibility complex loci, using sequence specific probes. Haplotype reconstruction was performed using the Arlequin and Phase softwares, and linkage disequilibrium (LD) between histocompatibility loci and HFE gene was performed using the Haploview software.
RESULTS The HFE*003 allele was overrepresented (f = 71%) and HFE*001 allele was underrepresented (f = 14%) in HH patients compared to all groups. A strong linkage disequilibrium was observed among the H63D-G, IVS2(+4)-C and C282Y-G gene variants, particularly in HH; however, the mutation IVS2(+4)T>C was not directly associated with HH susceptibility. The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO (P = 0.02, OR = 14.14). Although HFE is telomeric to other histocompatibility genes, the H63D-G/IVS2(+4)-C (P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls. No LD was observed between HFE alleles and other major histocompatibility loci.
CONCLUSION A differential HFE association was observed for HH and for diseases associated with acquired IO (HCV, HCC). Since HFE is very distant from other histocompatibility loci, only weak associations were observed with these alleles.
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Affiliation(s)
- Wagner Narciso de Campos
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Juliana Doblas Massaro
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Eduardo Luiz Rachid Cançado
- Department of Gastroenterology, Clinical Gastroenterology and Clinical Hepatology of Clinical Hospital, University of São Paulo School of Medicine, São Paulo 01329-000, Brazil
| | - Cláudia Emília Vieira Wiezel
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Aguinaldo Luiz Simões
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Andreza Correa Teixeira
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Fernanda Fernandes de Souza
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Celso Teixeira Mendes-Junior
- Departamento de Química, Laboratório de Pesquisas Forenses e Genômicas, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-901, Brazil
| | - Ana de Lourdes Candolo Martinelli
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
| | - Eduardo Antônio Donadi
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
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Apostolakis S, Kypraiou AM. Iron in neurodegenerative disorders: being in the wrong place at the wrong time? Rev Neurosci 2018; 28:893-911. [PMID: 28792913 DOI: 10.1515/revneuro-2017-0020] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/02/2017] [Indexed: 12/22/2022]
Abstract
Brain iron deposits have been reported consistently in imaging and histologic examinations of patients with neurodegenerative disorders. While the origins of this finding have not been clarified yet, it is speculated that impaired iron homeostasis or deficient transport mechanisms result in the accumulation of this highly toxic metal ultimately leading to formation of reactive oxygen species and cell death. On the other hand, there are also those who support that iron is just an incidental finding, a by product of neuronal loss. A literature review has been performed in order to present the key findings in support of the iron hypothesis of neurodegeneration, as well as to identify conditions causing or resulting from iron overload and compare and contrast their features with the most prominent neurodegenerative disorders. There is an abundance of experimental and observational findings in support of the hypothesis in question; however, as neurodegeneration is a rare incident of commonly encountered iron-associated disorders of the nervous system, and this metal is found in non-neurodegenerative disorders as well, it is possible that iron is the result or even an incidental finding in neurodegeneration. Understanding the underlying processes of iron metabolism in the brain and particularly its release during cell damage is expected to provide a deeper understanding of the origins of neurodegeneration in the years to come.
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Barton JC, Barton JC, Acton RT. White blood cells and subtypes in HFE p.C282Y and wild-type homozygotes in the Hemochromatosis and Iron Overload Screening Study. Blood Cells Mol Dis 2017; 63:9-14. [DOI: 10.1016/j.bcmd.2016.11.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 11/10/2016] [Accepted: 11/11/2016] [Indexed: 12/24/2022]
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Abstract
A haplotype is a string of nucleotides or alleles at nearby loci on one chromosome, usually inherited as a unit. Within the major histocompatibility complex (MHC) region on human chromosome 6p, independent population studies of multiple families have identified conserved extended haplotypes (CEHs) that segregate as long stretches (≥1 megabase) of essentially identical DNA sequence at relatively high (≥0.5 %) population frequency ("genetic fixity"). CEHs were first identified through segregation analysis in the early 1980s. In European Caucasian populations, the most frequent 30 CEHs account for at least one-third of all MHC haplotypes. These CEHs provide all of the known individual MHC susceptibility and protective genetic markers within those populations for several complex genetic diseases. Haplotypes are rigorously determined directly by sequencing single chromosomes or by Mendelian segregation analysis using families with informative genotypes. Four parental haplotypes are assigned unambiguously using genotypes from the two parents and from two of their haploidentical (to each other) children. However, the most common current technique to phase haplotypes is probabilistic statistical imputation, using unrelated subjects. Such probabilistic techniques have failed to detect CEHs and are thus of questionable value in identifying long-range haplotype structure and, consequently, genetic structure-function relationships. Finally, with haplotypes rigorously defined, association studies can determine frequencies of alleles among unrelated patient haplotypes vs. those among only unaffected family members (i.e., control alleles/haplotypes). Such studies reduce, as much as possible, the confounding effects of population stratification common to all genetic studies.
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Affiliation(s)
- Chester A Alper
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, CLS_03, 3 Blackfan Circle, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
| | - Charles E Larsen
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, CLS_03, 3 Blackfan Circle, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA
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Wang ZX, Wan Y, Tan L, Liu J, Wang HF, Sun FR, Tan MS, Tan CC, Jiang T, Tan L, Yu JT. Genetic Association of HLA Gene Variants with MRI Brain Structure in Alzheimer’s Disease. Mol Neurobiol 2016; 54:3195-3204. [DOI: 10.1007/s12035-016-9889-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 03/28/2016] [Indexed: 12/20/2022]
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Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 2015; 574:179-92. [PMID: 26456104 PMCID: PMC6660136 DOI: 10.1016/j.gene.2015.10.009] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/04/2015] [Accepted: 10/06/2015] [Indexed: 01/05/2023]
Abstract
The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Corwin Q Edwards
- Department of Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA.
| | - Ronald T Acton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives. J Immunol Res 2015; 2015:453046. [PMID: 26504855 PMCID: PMC4609477 DOI: 10.1155/2015/453046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/02/2015] [Indexed: 12/17/2022] Open
Abstract
We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
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Abstract
The review deals with genetic, regulatory and clinical aspects of iron homeostasis and hereditary haemochromatosis. Haemochromatosis was first described in the second half of the 19th century as a clinical entity characterized by excessive iron overload in the liver. Later, increased absorption of iron from the diet was identified as the pathophysiological hallmark. In the 1970s genetic evidence emerged supporting the apparent inheritable feature of the disease. And finally in 1996 a new "haemochromatosis gene" called HFE was described which was mutated in about 85% of the patients. From the year 2000 onward remarkable progress was made in revealing the complex molecular regulation of iron trafficking in the human body and its disturbance in haemochromatosis. The discovery of hepcidin and ferroportin and their interaction in regulating the release of iron from enterocytes and macrophages to plasma were important milestones. The discovery of new, rare variants of non-HFE-haemochromatosis was explained by mutations in the multicomponent signal transduction pathway controlling hepcidin transcription. Inhibited transcription induced by the altered function of mutated gene products, results in low plasma levels of hepcidin which facilitate entry of iron from enterocytes into plasma. In time this leads to progressive accumulation of iron and subsequently development of disease in the liver and other parenchymatous organs. Being the major site of excess iron storage and hepcidin synthesis the liver is a cornerstone in maintaining normal systemic iron homeostasis. Its central pathophysiological role in HFE-haemochromatosis with downgraded hepcidin synthesis, was recently shown by the finding that liver transplantation normalized the hepcidin levels in plasma and there was no sign of iron accumulation in the new liver.
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Affiliation(s)
- Rune J Ulvik
- Department of Clinical Science, University of Bergen and Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen N-5021, Norway.
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15
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Powell LW. A career forged in iron. Hepatology 2015; 61:4-14. [PMID: 25043645 DOI: 10.1002/hep.27293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 06/27/2014] [Indexed: 12/07/2022]
Affiliation(s)
- Lawrie W Powell
- The Center for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital, and The University of Queensland Center for Clinical Research, Brisbane, Queensland, Australia
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16
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Massarotti EM. Hemochromatosis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00196-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Ogilvie C, Gaffney D, Murray H, Kerry A, Haig C, Spooner R, Fitzsimons EJ. Improved detection of hereditary haemochromatosis. J Clin Pathol 2014; 68:218-21. [PMID: 25540266 DOI: 10.1136/jclinpath-2014-202720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS There is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin (SF) estimation but appear uncertain as how to investigate patients with raised SF values. Our aim was to develop a laboratory algorithm with high predictive value for the diagnosis of HH in patients from primary care with raised SF values. METHODS Transferrin saturation (Tsat) was measured on SF samples sent from primary care; 1657 male and 2077 female patients age ≥ 30 years with SF ≥ 200 μg/L. HFE genotyping was performed on all 878 male and 867 female patients with Tsat >30%. RESULTS This study identified 402 (206 men; 196 women) C282Y carriers and 132 (58 men; 74 women) C282Y homozygotes. Optimal limits for combined SF and Tsat values for HH recognition were established. The detection rate for homozygous C282Y HH for male patients with both SF ≥ 300 μg/L and Tsat >50% was 18.8% (52/272) and 16.3% (68/415) for female patients with both SF ≥ 200 μg/L and Tsat >40%. CONCLUSIONS The large number of SF requests received from primary care should be used as a resource to improve the diagnosis of HH in areas of high prevalence.
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Affiliation(s)
- Catherine Ogilvie
- Department of Haematology, West Glasgow Hospitals University NHS Trust, Glasgow, UK
| | - Dairena Gaffney
- Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK
| | - Heather Murray
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Andrew Kerry
- Department of Clinical Biochemistry, Royal Alexandra Hospital, Paisley, UK
| | - Caroline Haig
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Richard Spooner
- Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK
| | - Edward J Fitzsimons
- Department of Haematology, West Glasgow Hospitals University NHS Trust, Glasgow, UK
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Ali-Rahmani F, Schengrund CL, Connor JR. HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease. Front Pharmacol 2014; 5:165. [PMID: 25071582 PMCID: PMC4086322 DOI: 10.3389/fphar.2014.00165] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/24/2014] [Indexed: 12/14/2022] Open
Abstract
Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer's disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.
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Affiliation(s)
- Fatima Ali-Rahmani
- Departments of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, Center for Aging and Neurodegenerative Diseases, Penn State Hershey Medical CenterHershey, PA, USA
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of MedicineHershey, PA, USA
| | - Cara-Lynne Schengrund
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of MedicineHershey, PA, USA
| | - James R. Connor
- Departments of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, Center for Aging and Neurodegenerative Diseases, Penn State Hershey Medical CenterHershey, PA, USA
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Pretorius E, Bester J, Vermeulen N, Lipinski B, Gericke GS, Kell DB. Profound morphological changes in the erythrocytes and fibrin networks of patients with hemochromatosis or with hyperferritinemia, and their normalization by iron chelators and other agents. PLoS One 2014; 9:e85271. [PMID: 24416376 PMCID: PMC3887013 DOI: 10.1371/journal.pone.0085271] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 11/25/2013] [Indexed: 12/22/2022] Open
Abstract
It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise.
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Affiliation(s)
- Etheresia Pretorius
- Department of Physiology, University of Pretoria, Arcadia, South Africa
- * E-mail:
| | - Janette Bester
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Natasha Vermeulen
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Boguslaw Lipinski
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | | | - Douglas B. Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, Lancs, United Kingdom
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Abstract
Iron is a redox active metal which is abundant in the Earth's crust. It has played a key role in the evolution of living systems and as such is an essential element in a wide range of biological phenomena, being critical for the function of an enormous array of enzymes, energy transduction mechanisms, and oxygen carriers. The redox nature of iron renders the metal toxic in excess and consequently all biological organisms carefully control iron levels. In this overview the mechanisms adopted by man to control body iron levels are described.Low body iron levels are related to anemia which can be treated by various forms of iron fortification and supplementation. Elevated iron levels can occur systemically or locally, each giving rise to specific symptoms. Systemic iron overload results from either the hyperabsorption of iron or regular blood transfusion and can be treated by the use of a selection of iron chelating molecules. The symptoms of many forms of neurodegeneration are associated with elevated levels of iron in certain regions of the brain and iron chelation therapy is beginning to find an application in the treatment of such diseases. Iron chelators have also been widely investigated for the treatment of cancer, tuberculosis, and malaria. In these latter studies, selective removal of iron from key enzymes or iron binding proteins is sought. Sufficient selectivity between the invading organism and the host has yet to be established for such chelators to find application in the clinic.Iron chelation for systemic iron overload and iron supplementation therapy for the treatment of various forms of anemia are now established procedures in clinical medicine. Chelation therapy may find an important role in the treatment of various neurodegenerative diseases in the near future.
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Affiliation(s)
- John N Feder
- Disease Sciences and Biologics, Bristol-Myers Squibb, Princeton, NJ, USA.
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22
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An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population. Asian J Androl 2012; 14:599-603. [PMID: 22504868 DOI: 10.1038/aja.2012.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe, and excess iron is associated with the impairment of spermatogenesis. The aim of this study is to investigate the association between three mutations (C282Y, H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population. Two groups of Chinese men were recruited: 444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility. The HFE gene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The experimental results demonstrated that no C282Y or S65C mutations were detected. Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801, 95% confidence interval=0.452-1.421, χ(2)=0.577, P=0.448). The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896, P=0.404 and P=0.05, respectively). Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction.
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Bacon BR. Hemochromatosis: discovery of the HFE gene. MISSOURI MEDICINE 2012; 109:133-136. [PMID: 22675794 PMCID: PMC6181731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about 1 in 250 individuals. HH results in an increased absorption of iron at the baso-lateral surface of the enterocyte with aberrant regulation of ferroportin-mediated transfer of iron in turn brought on by a decrease in circulating hepcidin. The medical literature describes a colorful history of HH with important contributions from faculty at Saint Louis University.
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Affiliation(s)
- Bruce R Bacon
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, USA.
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24
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Abstract
Liver biopsy with histological examination of liver tissue was for many years the cornerstone of the diagnosis of haemochromatosis, allowing assessment of the degree of iron overload and examination of liver histology for the acute and chronic effects of iron overload. In the past two decades the role of liver biopsy in haemochromatosis has changed dramatically. Liver biopsy is rarely requested for two main reasons: (1) genetic testing for human haemochromatosis (HFE) mutations has proved to be very reliable in the diagnosis of haemochromatosis in Caucasian populations, and (2) the majority of patients with haemochromatosis are now diagnosed at an early stage well before permanent tissue damage occurs, so the need to assess tissue and organ damage has diminished. Liver biopsy continues to have a very important role in a small number of haemochromatosis patients for whom it has both diagnostic and prognostic implications. Liver biopsy is essential for the accurate assessment of patients with non-HFE haemochromatosis and in patients who have dual pathology. It is also useful where there appears to be a discrepancy between HFE genotypes and iron studies, particularly in HFE heterozygotes. Finally, liver biopsy is currently the 'gold standard' for the diagnosis of fibrosis and cirrhosis, although this is changing as non-invasive methods for assessing fibrosis become more reliable and available. Therefore, it is important that pathologists maintain their knowledge and skills in the use of liver biopsy in haemochromatosis and other iron storage disorders.
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Abstract
Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.
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Affiliation(s)
- Wint Nandar
- Department of Neurosurgery, Pennsylvania State University, M. S. Hershey Medical Center, Hershey, PA 17033, USA
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Chitturi S, Farrell GC. Identifying who is at risk of drug-induced liver injury: is human leukocyte antigen specificity the key? Hepatology 2011; 53:358-62. [PMID: 21254184 DOI: 10.1002/hep.24094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Shivakumar Chitturi
- Gastroenterology and Hepatology Unit, The Canberra Hospital and Australian National University Medical School Canberra, ACT, Australia
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27
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Deugnier Y, Lainé F, Le Lan C, Bardou-Jacquet E, Jouanolle AM, Brissot P. Hémochromatoses et autres surcharges hépatiques en fer. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/s1155-1976(11)40364-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Sebastiani G, Pantopoulos K. Disorders associated with systemic or local iron overload: from pathophysiology to clinical practice. Metallomics 2011; 3:971-86. [DOI: 10.1039/c1mt00082a] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Massarotti EM. Hemochromatosis. Rheumatology (Oxford) 2011. [DOI: 10.1016/b978-0-323-06551-1.00192-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Olsson KS, Konar J, Dufva IH, Ricksten A, Raha-Chowdhury R. Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? HLA haplotype observations of hemochromatosis from the west coast of Sweden. Eur J Haematol 2010; 86:75-82. [PMID: 20946107 DOI: 10.1111/j.1600-0609.2010.01536.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses. METHODS HFE mutations in controls, bone marrow donors with HLA-A3/A3 and patients with hemochromatosis. HLA haplotypes, extended haplotype analysis and pedigree studies. RESULTS The allelic C282Y frequency 0.04, (CI 0.01-0.07) was lower (P < 0.001) in Sweden than in Ireland 0.10 (CI 0.08-0.11), and Swedish bone marrow donors with HLA-A3/A3 (n = 77) had a low risk of hemochromatosis. HLA haplotypes available from 239/262 (91.5%) proband patients homozygous for C282Y showed a dominance of A3-B7 and A3-B14 both in linkage disequilibrium with controls (P < 0.001). Pedigree studies extended into the 17th century supported a local founder effect of A3-B14 in the county of Bohuslän. The A3-B14 haplotype may well be the original and A3-B7 the result of centromeric recombinations. The haplotype diversity and recombination events were not different from a Celtic series. These findings do not support the hypothesis of the C282Y mutation being of an Irish Celtic origin. CONCLUSIONS The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.
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Affiliation(s)
- Karl Sigvard Olsson
- Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
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31
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Spínola C, Brehm A, Spínola H. Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal). Ann Hematol 2010; 90:29-32. [PMID: 20714725 DOI: 10.1007/s00277-010-1034-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Accepted: 07/25/2010] [Indexed: 11/30/2022]
Abstract
Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results from mutations in the HFE gene. Almost all patients with hereditary hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to hereditary hemochromatosis. One hundred and fifty-four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y, and S65C, by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33%, and 1% for H63D, C282Y, and S65C, respectively. Accordingly to our estimates, both genotypes associated to hereditary hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population.
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Affiliation(s)
- Carla Spínola
- Human Genetics Laboratory, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal
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Olsson KS, Ritter B, Raha-Chowdhury R. HLA-A3-B14 and the origin of the haemochromatosis C282Y mutation: founder effects and recombination events during 12 generations in a Scandinavian family with major iron overload. Eur J Haematol 2010; 84:145-53. [DOI: 10.1111/j.1600-0609.2009.01376.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Brissot P. Les hémochromatoses. Nouvelle compréhension, nouveaux traitements. ACTA ACUST UNITED AC 2009; 33:859-67. [DOI: 10.1016/j.gcb.2009.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Harper STP. Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda - suggestions for a handling programme. Scandinavian Journal of Clinical and Laboratory Investigation 2009. [DOI: 10.1080/003655100448338] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Distante S. Genetic predisposition to iron overload: Prevalence and phenotypic expression of hemochromatosis‐associated HFE‐C282Y gene mutation. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 66:83-100. [PMID: 16537242 DOI: 10.1080/00365510500495616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- S Distante
- Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.
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Olsson KS, Eriksson K, Ritter B, Heedman PA. Screening for iron overload using transferrin saturation. ACTA MEDICA SCANDINAVICA 2009; 215:105-12. [PMID: 6702489 DOI: 10.1111/j.0954-6820.1984.tb04979.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
People with parenchymal iron overload exhibit an elevated serum iron concentration and a raised transferrin (TIBC) saturation early in the course of the disease. They can therefore be detected by simple laboratory tests before organ damage has occurred. In this study running for 2 months, 10512 samples from approximately 8750 patients and blood donors were examined in a county hospital in Central Sweden. Abnormal TIBC saturation (greater than 70%) was found in 1.7% of the samples. This abnormality was caused by physiological fluctuations in serum iron in 44%, liver disease in 22%, blood disorder in 10%, iron therapy in 10.5% and parenchymal iron overload in 11.5%. The diagnosis of iron overload was confirmed by measuring the serum ferritin concentration and by performing the desferrioxamine test, liver biopsy, quantitative phlebotomy and family studies including HLA typing. We found a prevalence of iron overload of 0.24%. This figure is almost certainly too low because some affected patients were probably lost because of TIBC desaturation induced by inflammatory conditions.
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Eade OE, Grice D, Krawitt EL, Trowell J, Albertini R, Festenstein H, Wright R. HLA A and B locus antigens in patients with unexplained hepatitis following halothane anaesthesia. TISSUE ANTIGENS 2008; 17:428-32. [PMID: 7330846 DOI: 10.1111/j.1399-0039.1981.tb00724.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
HLA A and B locus antigens were determined in 17 patients who had recovered from unexplained hepatitis following halothane anaesthesia. The greatest deviations from expected frequencies were observed with A1, A11 and BW22, but these differences were not statistically significant when the P values were corrected for the number of antigens tested. Although a larger series might show such deviations to be significantly different, HLA typing is of no predictive value in determining those at risk to hepatitis following repeated halothane exposure.
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Abstract
C282Y homozygosity is the only common HFE genotype able to produce a complete hemochromatosis phenotype. However, its biochemical penetrance is incomplete (75% in men and 50% in women) and its clinical penetrance is low, especially in women (1 vs 25% in men). Environmental (e.g., diet, alcohol, drugs and metabolic syndrome) and genetic (digenism, common polymorphisms in the bone morphogenetic protein pathway involved in the regulation of hepcidin synthesis) explain a part of the variability of the C282Y homozygous phenotype. All other common HFE genotypes--including C282Y-H63D compound heterozygosity--are not associated with significant biochemical and clinical expression in the absence of comorbid factors (e.g., alcohol, diabetes or steatohepatitis). Better identification of acquired and genetic modifiers of iron burden and iron-related organ damage is needed to improve the preventive, diagnostic and therapeutic management of HFE hemochromatosis.
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Affiliation(s)
- Yves Deugnier
- Service des maladies du Foie, INSERM CIC 0203, Université de Rennes 1 and IFR 140, CHU Pontchaillou, 35033 Rennes, France.
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Hyperferritinemia in the Chinese and Asian community: a retrospective review of the University of British Columbia experience. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:37-40. [PMID: 18209779 DOI: 10.1155/2008/245096] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND METHODS Elevated serum ferritin is a common clinical finding. The etiology of hyperferritinemia in the Asia-Pacific population is less clear due to a low prevalence of known HFE mutations such as C282Y and H63D, as well as an increased prevalence of viral hepatitis and hereditary anemia. A retrospective case review of 80 patients of Asian ethnicity referred to three subspecialists in tertiary care teaching hospitals between January 1997 and March 2005 for assessment of hyperferritinemia was performed. RESULTS Only four patients (5%) had iron overload on liver biopsy or quantitative phlebotomy. Forty-nine patients (61%) had secondary causes for their hyperferritinemia, of which 26 had liver disease; 16 of those patients also had viral hepatitis. Thirteen patients fulfilled criteria for the insulin resistance syndrome. Other causes included hematological disorders (n=10), malignancy (n=2) and inflammatory arthritis (n=2). Twenty-seven cases (34%) of unexplained hyperferritinemia were found. Of a total of 22 patients who underwent liver biopsy, significant iron deposition was found in one patient. Fifteen patients underwent C282Y and H63D genotyping, with two cases of H63D heterozygosity. Fourteen patients had first-degree relatives with hyperferritinemia. Three families were identified with more than two members affected, which is suggestive of a possible hereditary hyperferritinemia syndrome. CONCLUSION Secondary causes of elevated ferritin in the Asian population, particularly liver disease, are common, but primary iron overload syndromes appear to be rare. In a significant proportion of patients, the etiology remains unexplained. The genetic basis for hyperferritinemia in Asians is poorly defined and requires further study.
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Aguilar-Martinez P. Surcharges en fer héréditaires non liées au gène HFE. Presse Med 2007; 36:1279-91. [PMID: 17540536 DOI: 10.1016/j.lpm.2007.01.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Revised: 01/22/2007] [Accepted: 01/24/2007] [Indexed: 10/22/2022] Open
Abstract
Hereditary iron overload is mainly due to mutations of the HFE gene, implicated in most cases of hereditary hemochromatosis. Non-HFE-related hereditary iron overload is rare. It includes hereditary hemochromatosis related to mutations of other genes, ferroportin disease (also known as hemochromatosis type 4), and entities associated with specific clinical manifestations. Four genes have been implicated in hereditary hemochromatosis: HFE and TFR2 (which codes for the second transferrin receptor), both involved in adult forms of hereditary hemochromatosis, and HAMP and HJV, which code for hepcidin and hemojuvelin, respectively, and are responsible for juvenile hemochromatosis. All types of hereditary hemochromatosis share common clinical and biological characteristics, including an autosomal recessive inheritance pattern, elevation of transferrin saturation as the initial manifestation, hepatic parenchymal iron overload, and sensitivity to therapeutic phlebotomy. They are due to hyperabsorption of dietary iron and are linked to a deficit of hepcidin, the principal iron regulator in the body. Ferroportin disease is a special dominantly inherited clinical form of iron overload due to mutations of the SLC40A1 gene. Its expression differs significantly from that of hereditary hemochromatosis, and its mechanism is related to impairment of iron release from reticuloendothelial cells. Other causes of non-HFE-related hereditary iron overload are usually associated with recognizable clinical manifestations, such as anemia or neurological disorders.
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Holoshitz J, Ling S. Nitric Oxide Signaling Triggered by the Rheumatoid Arthritis Shared Epitope: A New Paradigm for MHC Disease Association? Ann N Y Acad Sci 2007; 1110:73-83. [PMID: 17911422 DOI: 10.1196/annals.1423.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Many immune-mediated diseases are associated with particular MHC class I or class II alleles. In rheumatoid arthritis (RA-shared), the vast majority of patients possess HLA-DRB1 alleles encoding a shared epitope, which is a five-amino acid sequence motif in positions 70-74 of the HLA-DRbeta chain. The mechanistic basis for this association is unknown. Here we discuss recent evidence suggesting that the shared epitope may act as an allele-specific ligand that triggers increased nitric oxide (NO) production in opposite cells with resultant immune dysregulation. We propose that by doing that, the RA-shared shared epitope may form an unintended bridge between the innate and adaptive immune systems, thereby allowing aberrant signaling events that could trigger disease.
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Affiliation(s)
- Joseph Holoshitz
- Department of Internal Medicine, University of Michigan Medical Center, 5520 MSRB I, Ann Arbor, Michigan 48109-0680, USA.
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Beutler E. Iron storage disease: facts, fiction and progress. Blood Cells Mol Dis 2007; 39:140-7. [PMID: 17540589 PMCID: PMC2030637 DOI: 10.1016/j.bcmd.2007.03.009] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2007] [Accepted: 03/19/2007] [Indexed: 02/09/2023]
Abstract
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 up-regulated 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 was considered the most common disease among Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and only its 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.
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Affiliation(s)
- Ernest Beutler
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Loréal O, Ropert M, Mosser A, Déhais V, Deugnier Y, David V, Brissot P, Jouanolle AM. Physiopathologie et génétique de l'hémochromatose HFE de type 1. Presse Med 2007; 36:1271-7. [PMID: 17521857 DOI: 10.1016/j.lpm.2007.03.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Accepted: 03/22/2007] [Indexed: 01/19/2023] Open
Abstract
Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene (C282Y mutation). The p.Cys282Tyr mutation of the HFE gene leads to an abnormal reduction in hepatic expression of hepcidin, a protein that appears to control the release of iron from enterocytes and macrophages towards plasma. Abnormally low hepcidin levels promote an increase in the bioavailability of plasma iron, characterized by elevated transferrin saturation and the appearance of non transferrin bound iron. This nontransferrin-bound iron is avidly taken up by the liver, heart, and pancreas, the principal target organs for systemic iron overload. The variable penetrance of this disease is related to environmental and genetic factors. Among the genetic factors, mutations of some newly identified genes may aggravate the phenotype of iron overload associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene; these new genes include those of hemojuvelin (HJV), transferrin receptor 2 (TfR2), and hepcidin (HAMP).
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Cukjati M, Koren S, Curin Serbec V, Vidan-Jeras B, Rupreht R. A novel homozygous frameshift deletion c.471del of HFE associated with hemochromatosis. Clin Genet 2007; 71:350-3. [PMID: 17470136 DOI: 10.1111/j.1399-0004.2007.00777.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A 47-year-old white male patient who manifested biochemical evidence of iron overload was found not to be a carrier of the three most common mutations, C282Y, H63D and S65C, of the HFE gene. Sequencing of the patient's entire HFE-coding region revealed a presence of a previously undescribed frameshift deletion c.471del in exon 3 resulting in a premature termination of a nonsense HFE protein. Interestingly, the patient was a homozygous carrier of this novel mutation and his hemochromatosis phenotype can be explained by the fact that he has no intact HFE protein. To the best of our knowledge, this is the first description of a complete loss of function of the HFE gene because of a homozygous mutation. The patient's son was found to be a heterozygous carrier of the mutation and has so far exhibited no indications of iron overload. Similarly, A*02-B*40/A*02-B*40 homozygous human leukocyte antigen (HLA) genotype was determined in the patient and heterozygous A*02-B*40/A*03-B*35 HLA genotype in his son. Thus, the novel HFE frameshift deletion c.471del was linked to the HLA-A*02-B*40 haplotype.
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Affiliation(s)
- M Cukjati
- Blood Transfusion Centre of Slovenia, Slajmerjeva 6, SI-1000 Ljubljana, Slovenia
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Abstract
Hereditary hemochromatosis is a condition affecting many organs, as reflected by the fact that it is managed variably by hematologists, gastroenterologists, rheumatologists and endocrinologists, depending on local preferences. A potential pitfall of this approach is that certain aspects of diagnosis and management may be overlooked, particularly if they fall beyond the normal scope of practice of the specialist physician concerned. The purpose of this article is to review the nature of the endocrine complications of hereditary hemochromatosis, which have changed dramatically since the condition was first described over 100 years ago.
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Affiliation(s)
- Eoin P O'Sullivan
- a South Infirmary Victoria University Hospital, Specialist Registrar in Diabetes and Endocrinology, Department of Endocrinology, Old Blackrock Road, Cork, Ireland.
| | - C Howel Walsh
- b South Infirmary Victoria University Hospital, Consultant Endocrinologist, Department of Endocrinology, Old Blackrock Road, Cork, Ireland.
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Abstract
A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
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Affiliation(s)
- Ernest Beutler
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
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Abstract
The molecular basis of haemochromatosis has proved more complex than expected. After the 1996 identification of the main causative gene HFE and confirmation that most patients were homozygous for the founder C282Y mutation, it became clear that some families were linked to rarer conditions, first named 'non-HFE haemochromatosis'. The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes. Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. In turn, recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body's iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations.
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Abstract
Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.
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Affiliation(s)
- Robert E Fleming
- Department of Pediatrics, Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
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Abstract
The polygenic HLA system is a well known region of the human genome. Its main function is to present antigenic peptides to the immune system and thereby regulate induction of immune responses. Extensive genetic polymorphisms characterize some HLA genes. Initially, genetic variations were analyzed by a serological typing technique (microlymphocytotoxicity). The introduction of polymerase chain reaction (PCR) in the mid-1980s led the development of a variety of methods that use molecular biology. An international nomenclature, regularly updated, governs the names of HLA antigens defined by serology as well as of HLA alleles. Knowledge of the specific polymorphisms of individuals is essential in organ and stem cell transplantation and highly useful in disease association studies.
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Affiliation(s)
- V Moalic
- Laboratoire de génétique moléculaire et d'histocompatibilité, CHU Augustin Morvan, Brest (29).
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