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HFE Gene (hfe + gene)
Selected AbstractsH63D homozygotes with hyperferritinaemia: is this genotype, the primary cause of iron overload?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Carles De Diego Abstract Objectives:,Hereditary haemochromatosis is a disease that affects iron metabolism and leads to iron overload. Homozygosity for the H63D mutation is associated with increased transferrin saturation (TS) and ferritin levels. Our objective was to find out if the homozygosity of H63D mutation was the primary cause of iron overload. Patients and methods:,We studied 45 H63D homozygotes (31 males and 14 females) with biochemical iron overload and/or clinical features of haemochromatosis. The simultaneous detection of 18 known HFE, TFR2 and FPN1 mutations and sequencing of the HAMP gene were performed to rule out the possible existence of genetic modifier factors related with iron overload. Results:,Values of biochemical iron overload, measured as percentage TS and serum ferritin concentration (SF), in our H63D homozygotes were significantly higher in patients than in controls: TS 55 ± 15% vs. 35 ± 15% and SF 764 (645,883) ,g/L vs. 115 (108,123) ,g/L for patients and controls, respectively. These H63D homozygotes presented extreme hyperferritinaemia and no additional mutations in HFE, TFR2, FPN1 and HAMP genes were detected. Conclusions:,The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes. [source] Further characterization of MHC haplotypes demonstrates conservation telomeric of HLA-A: update of the 4AOH and 10IHW cell panelsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5-6 2000S. K. Cattley Cell panels have been used extensively in studies of polymorphism and disease associations within the major histocompatibility complex (MHC), but the results from these panels require continuous updates with the increasing availability of novel data. We present here an updated table of the typings of the 10IHW and 4AOH panels. Local data included are HFE, HERV-K(C4) and six microsatellites telomeric of HLA-A. Typings for class I, MICA (PERB11.1), MICB (PERB11.2), XA, XB, LMP2 and 10 microsatellites reported by others have also been consolidated in this table. The tabulation shows that the length of conservation in the human MHC is even more extensive than previously thought. Human MHC ancestral haplotypes are inherited as a conserved region of genomic sequence spanning some 6,8 megabases from the HLA class II region and beyond the HLA class I region up to and including the HFE gene. Numerous examples of historical recombinations were also observed. [source] Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2006Colin A Sherrington Abstract Background and Aim:, Mutations in the hemochromatosis (HFE) gene are carried by one in three individuals of British Isles descent and may result in increased iron stores. These increased iron stores could potentially induce or exacerbate diseases, such as arthritis, in which iron has a role in pathogenesis. Although arthritis is a well-known association of clinically overt hereditary hemochromatosis, controversy surrounds the role of mutations in the HFE gene as risk factors for arthritis. The aim of the present study was to determine whether mutations in the HFE gene are associated with an increased prevalence of arthritis. Methods:, A population-based study was conducted in Busselton, Western Australia, of the prevalence of arthritis in 1372 individuals of British Isles descent. Participants completed a questionnaire and general physical examination. Analysis for C282Y and H63D HFE mutations was undertaken. Unadjusted and adjusted odds ratios (OR) were calculated for the relationship between HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis. Results:, There was no association between the presence of HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis (C282Y/wild type (WT) adjusted OR = 1.041 (95% confidence interval (CI) 0.68,1.61), H63D/WT OR = 0.76 (95% CI 0.53,1.08), C282Y/C282Y OR = 0.39 (95% CI 0.04,3.63), C282Y/H 63D OR = 0.808 (95% CI 0.27,2.42), H63D/H63D OR = 0.419 (95% CI 0.13,1.36)). Overall adjusted OR for arthritis in participants with one or more HFE mutations was 0.81 (95% CI 0.61,1.09). Conclusions:, Mutations of the HFE gene are not risk factors for arthritis in populations of British Isles descent. [source] Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis MutationsALCOHOLISM, Issue 1 2007Jonathan M. Flanagan Background: Alcoholic liver disease is associated with increased hepatic iron accumulation. The liver-derived peptide hepcidin is the central regulator of iron homeostasis and recent animal studies have demonstrated that exposure to alcohol reduces hepcidin expression. This down-regulation of hepcidin in vivo implies that disturbed iron sensing may contribute to the hepatosiderosis seen in alcoholic liver disease. Alcohol intake is also a major factor in expression of the hemochromatosis phenotype in patients homozygous for the C282Y mutation of the HFE gene. Methods: To assess the effect of alcohol in mice with iron overload, alcohol was administered to mice with disrupted Hfe and IL-6 genes and Tfr2 mutant mice and their respective 129x1/SvJ, C57BL/6J, and AKR/J wild-type congenic strains. Iron absorption, serum iron levels, and hepcidin expression levels were then measured in these mice compared with water-treated control mice. Results: Alcohol was shown to have a strain-specific effect in 129x1/SvJ mice, with treated 129x1/SvJ mice showing a significant increase in iron absorption, serum iron levels, and a corresponding decrease in hepcidin expression. C57BL/6J and AKR/J strain mice showed no effect from alcohol treatment. 129x1/SvJ mice heterozygous or homozygous for the Hfe knockout had a diminished response to alcohol. All 3 strains were shown to have high blood alcohol levels. Conclusions: The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption. [source] Lack of association of iron metabolism and Dupuytren's diseaseJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 4 2008J Hnanicek Abstract Background,Iron accumulation as seen in genetic haemochromatosis is a major cause of hepatic fibrogenesis. A link between chronic liver disease and Dupuytren's disease (DD) is well established, especially in alcoholics. Aim The aim of the present study was to test the hypothesis that iron accumulation might cause fibrosis of the palmar aponeurosis leading to DD. Patients and methods We examined iron metabolism, mutations of the HFE gene, serum cholesterol, alcohol consumption, presence of chronic liver disease, diabetes and history of severe manual work in a group of 90 patients who had undergone surgery for a severe form of DD. The tissue removed during surgery was histologically examined to confirm the diagnosis of DD. For a control group, we used 33 healthy subjects with similar profiles. Results The DD group consisted of 82 men and 8 women. Chronic liver disease was found in 27% of DD patients, compared with 6.1% of control subjects (P = 0.013). A history of hand traumatization was present in 33% of DD patients vs. 15% of control subjects (P = 0.048). Excessive alcohol consumption was present in 35.5% of DD patients compared with 15.1% of controls (P = 0.029). None of the other tested parameters, including the prevalence of HFE gene mutations, showed a significant difference between the two groups. Conclusions Iron accumulation does not play a major role in the pathogenesis of DD. However, sex, age, manual labour and alcohol consumption are risk factors for progression of DD. We observed a high incidence of chronic liver disease in patients with DD. [source] The increasing hospital disease burden of haemochromatosis in EnglandALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2010M. L. COWAN Summary Background, Hereditary haemochromatosis is a preventable cause of liver disease with an increasing disease burden. Aims, To investigate time trends for hospital admission ascribed to haemochromatosis in England during the period from 1989/1990 to 2002/2003 and mortality from 1979 to 2005. Methods, Hospital admission data, relating to both in-patients and day-cases, were obtained from the Hospital Episodes Statistics service. Mortality rates for England and Wales were provided by the Office for National Statistics. Results, Haemochromatosis is an uncommon cause for hospital admission. Age-standardized in-patient admission rates increased over the study period by 269% in men and by 290% in women: (from 0.64 to 2.36 and from 0.21 to 0.81 per year per 100 000). The increase in age-standardized day-case admission rates was even higher (men: from 2.78 to 34.9 per year per 100 000, 1155%; women: from 0.58 to 11.67 per year per 100 000, 1924%). Haemochromatosis was recorded as an uncommon cause of death. Conclusions, Hospital in-patient and day case admissions for haemochromatosis increased markedly over the study period while mortality remained low. Both admission rates and mortality were higher in men than in women. The increase in admission rate may reflect improved recognition and diagnosis of iron overload disorders following identification of the HFE gene. Aliment Pharmacol Ther,31, 247,252 [source] Review article: the modern diagnosis and management of haemochromatosisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2006P. C. ADAMS Summary Haemochromatosis is the most common genetic disease in populations of European ancestry. Despite estimates based on genetic testing in Caucasian populations of 1 in 227, many physicians consider haemochromatosis to be a rare disease. The diagnosis can be elusive because of the non-specific nature of the symptoms. Of all the symptoms, liver disease has the most consistent relationship to haemochromatosis and the prognosis of haemochromatosis is most closely linked to the degree of iron overload. With the discovery of the HFE gene in 1996, comes new insights into the pathogenesis of the disease and new diagnostic strategies. However, a growing number of new iron-related genes have been discovered and linked to other iron overload syndromes. [source] Liver pathology in compound heterozygous patients for hemochromatosis mutationsLIVER INTERNATIONAL, Issue 4 2002Maximilian Schöniger-Hekele Abstract: Background: While hepatic pathology of homozygous carriers of the C282Y mutation of the HFE haemochromatosis gene is well defined, the impact of the C282Y/H63D compound heterozygous carrier state is unknown. Aims: To evaluate the range of hepatic pathology in C282Y/H63D compound heterozygous patients. Patients: 25 C282Y/H63D compound heterozygous patients with and without known underlying liver disease underwent liver biopsies for evaluation or abnormal liver tests. Eleven cadaveric liver donors with HFE wild type served as controls. Methods: Mutations in the HFE gene were detected by polyacrylamide gel electrophoresis (PAGE) separation of digested polymerase chain reaction (PCR)-amplificates. The extent of light microscopic changes of liver architecture were studied on haematoxylin, eosin (H. E.) stains. In addition, the extent and the distribution of iron deposition was graded on Prussian blue-stained sections and hepatic iron was quantified by atom absorption spectroscopy. Serum ferritin concentration and the transferrin saturation index were measured using routine laboratory methods. Results: Patients without underlying liver disease (n = 15): Hepatic inflammation was seen in only 8% but fibrosis was found in 36% of compound heterozygous patients. Eighty six percent of those patients had stainable iron predominantly found in Rappaport's zone 1 and 2, but all had a liver iron-index < 1.9. Transferrin saturation was found elevated in 36% of compound heterozygous patients. Patients with liver fibrosis showed significantly higher ferritin levels than patients without liver fibrosis (1110 ng/mL versus 307 ng/mL, p < 0.05). Patients with underlying disease (n = 10): In compound heterozygous patients, 77% had hepatic inflammation and 88% fibrosis. Stainable iron (44%) was less frequently found than in patients without underlying liver disease. Hepatic iron-index in patients with underlying liver disease was always below 1.17; transferrin saturation was elevated in only 22% of the compound heterozygous patients. Histologic hepatic iron-index was significantly lower in patients with underlying disease (median 0.047) as compared to patients without underlying liver disease (median 0.274, P < 0.05). Conclusions: The underlying liver disease determines the extent of hepatic pathology seen in livers of compound heterozygous patients. However, considerable histologic fibrosis can also be found in compound heterozygous patients without underlying liver disease. [source] Analysis of haemochromatosis gene mutations in a population from the Mediterranean BasinLIVER INTERNATIONAL, Issue 4 2001Salvatore Campo Abstract:Background/Aims: The C282Y mutation in the haemochromatosis gene (HFE) located on chromosome 6 has been identified as the main genetic basis of hereditary haemochromatosis (HH). Two more mutations of that gene, H63D and S65C, appear to be associated with milder forms of HH. A high allele frequency for C282Y and H63D mutations was reported in populations from North Europe, while incomplete information is available for individuals from the Mediterranean Basin where C282Y homozygotes comprise a smaller percentage of HH cases. In this study we investigated the allele frequency of HFE mutations and the association between HFE mutations and cases of HH in a population from the South of Italy (Sicily and Calabria). In addition, we evaluated a possible association between HFE mutations and either chronic liver disease or type II diabetes. Patients and Methods: Three hundred and twenty-seven individuals (654 chromosomes) were tested for C282Y, H63D and S65C mutations of the HFE gene by restriction fragment length polymorphism. Four had HH, 23 had hepatocellular carcinoma, 100 had chronic liver disease, 100 had type II diabetes, and 100 were healthy controls. Results: Both C282Y and S65C mutations were each detected in one of the 654 chromosomes analysed (allele frequency=0.15%), while H63D change was found in 122 chromosomes (allele frequency=18.6%) and was equally distributed in all the categories examined. One healthy individual had compound heterozygosity for C282Y and H63D mutations. The frequency of C282Y in this Southern Italian sample was the lowest yet reported for a population of European origin. None of the four HH patients was either homozygous or heterozygous for C282Y. Conclusions: In Mediterranean populations from Southern Italy the C282Y mutation occurs sporadically and HFE polymorphisms seem to have little diagnostic relevance. [source] Hereditary iron overload: Update on pathophysiology, diagnosis, and treatmentAMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2006Massimo Franchini Abstract Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated timely. The elucidation of the molecular pathways of iron transport through cells and its control has led to the understanding of various genetic iron-loading conditions. Four types of inherited iron overload have been recognized: type 1, the most common form with an autosomal recessive inheritance, is associated with mutations in the HFE gene on chromosome 6; type 2 (juvenile hemochromatosis) is an autosomal recessive disorder with causative mutations identified in the HJV gene (subtype A) on chromosome 1 and the HAMP gene (subtype B) on chromosome 19; type 3 has also an autosomal recessive inheritance with mutations in the TfR2 gene on chromosome 3; type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene on chromosome 2. In this review, the genetics, pathophysiology, diagnosis, clinical features, and management of these different types of hereditary hemochromatosis are briefly discussed. Am. J. Hematol. 81:202,209, 2006. © 2006 Wiley-Liss, Inc. [source] Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis MutationsALCOHOLISM, Issue 1 2007Jonathan M. Flanagan Background: Alcoholic liver disease is associated with increased hepatic iron accumulation. The liver-derived peptide hepcidin is the central regulator of iron homeostasis and recent animal studies have demonstrated that exposure to alcohol reduces hepcidin expression. This down-regulation of hepcidin in vivo implies that disturbed iron sensing may contribute to the hepatosiderosis seen in alcoholic liver disease. Alcohol intake is also a major factor in expression of the hemochromatosis phenotype in patients homozygous for the C282Y mutation of the HFE gene. Methods: To assess the effect of alcohol in mice with iron overload, alcohol was administered to mice with disrupted Hfe and IL-6 genes and Tfr2 mutant mice and their respective 129x1/SvJ, C57BL/6J, and AKR/J wild-type congenic strains. Iron absorption, serum iron levels, and hepcidin expression levels were then measured in these mice compared with water-treated control mice. Results: Alcohol was shown to have a strain-specific effect in 129x1/SvJ mice, with treated 129x1/SvJ mice showing a significant increase in iron absorption, serum iron levels, and a corresponding decrease in hepcidin expression. C57BL/6J and AKR/J strain mice showed no effect from alcohol treatment. 129x1/SvJ mice heterozygous or homozygous for the Hfe knockout had a diminished response to alcohol. All 3 strains were shown to have high blood alcohol levels. Conclusions: The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption. [source] | ||||||||||||||||||||||