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Статті в журналах з теми "Haemochromatosis, iron, genetics"
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Cox, Timothy. "Haemochromatosis: Strike while the iron is hot." Nature Genetics 13, no. 4 (August 1996): 386–88. http://dx.doi.org/10.1038/ng0896-386.
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Demetz, Egon, Piotr Tymoszuk, Richard Hilbe, Chiara Volani, David Haschka, Christiane Heim, Kristina Auer, et al. "The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development." European Heart Journal 41, no. 40 (March 30, 2020): 3949–59. http://dx.doi.org/10.1093/eurheartj/ehaa140.
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Abstract Aims Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. Methods and results Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE−/− mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. Conclusion Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.
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Lv, Tingxia, Wei Zhang, Anjian Xu, Yanmeng Li, Donghu Zhou, Bei Zhang, Xiaojin Li, et al. "Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants." Journal of Medical Genetics 55, no. 10 (August 30, 2018): 650–60. http://dx.doi.org/10.1136/jmedgenet-2018-105348.
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IntroductionHereditary haemochromatosis (HH) caused by a homozygous p.C282Y mutation in haemochromatosis (HFE) gene has been well documented. However, less is known about the causative non-HFE mutation. We aimed to assess mutation patterns of haemochromatosis-related genes in Chinese patients with primary iron overload.MethodsPatients were preanalysed for mutations in the classic HH-related genes: HFE, HJV, HAMP, TFR2 and SLC40A1. Whole exome sequencing was conducted for cases with variants in HJV signal peptide region. Representative variants were analysed for biological function.ResultsNone of the cases analysed harboured the HFE p.C282Y; however, 21 of 22 primary iron-overload cases harboured at least one non-synonymous variant in the non-HFE genes. Specifically, p.E3D or p.Q6H variants in the HJV signal peptide region were identified in nine cases (40.9%). In two of three probands with the HJV p.E3D, exome sequencing identified accompanying variants in BMP/SMAD pathway genes, including TMPRSS6 p.T331M and BMP4 p.R269Q, and interestingly, SUGP2 p.R639Q was identified in all the three cases. Pedigree analysis showed a similar pattern of combination of heterozygous mutations in cases with HJV p.E3D or p.Q6H, with SUGP2 p.R639Q or HJV p.C321X being common mutation. In vitro siRNA interference of SUGP2 showed a novel role of downregulating the BMP/SMAD pathway. Site-directed mutagenesis of HJV p.Q6H/p.C321X in cell lines resulted in loss of membrane localisation of mutant HJV, and downregulation of p-SMAD1/5 and HAMP.ConclusionCompound heterozygous mutations of HJV or combined heterozygous mutations of BMP/SMAD pathway genes, marked by HJV variants in the signal peptide region, may represent a novel aetiological factor for HH.
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Dallos, Tomáš, Enijad Sahinbegovic, Elmar Aigner, Roland Axmann, Maximilian Schöniger-Hekele, Thomas Karonitsch, Tanja Stamm, et al. "Validation of a radiographic scoring system for haemochromatosis arthropathy." Annals of the Rheumatic Diseases 69, no. 12 (August 2, 2010): 2145–51. http://dx.doi.org/10.1136/ard.2009.122119.
Повний текст джерелаАнотація:
BackgroundArthropathy is one of the earliest and most common manifestations of hereditary haemochromatosis with a significant impact on quality of life. Although its radiographic features are well known, there is no assessment tool for their evaluation.ObjectiveTo develop and validate a novel scoring system for the evaluation of radiographic features of haemochromatosis arthropathy.MethodsA dichotomous scoring system assessing four radiographic features of haemochromatosis arthropathy and a 4-grade scale reflecting severity of radiographic change have been developed. Standard radiographs (hand, wrist, knee and ankle) of 170 subjects (116 male, 54 female) with genetically confirmed haemochromatosis and laboratory signs of iron overload were assessed by three readers and construct validity, feasibility and cross-sectional reliability (intrareader and inter-reader) were assessed.ResultsIntrareader and inter-reader reliability as assessed by percentage pairwise agreement and Cohen's weighed κ were good to excellent for most features and locations evaluated. Radiographic scores correlated well with clinical parameters (bony swollen joint count, hand function and physician's global health assessment; Pearson's correlation, r2=0.18–0.62, p<0.0001). A complete set of radiographs took 3.4±1.2 (mean±SD) min to be assessed. An atlas of characteristic radiographic features was compiled.ConclusionA feasible and reliable radiological assessment tool for the evaluation of haemochromatosis arthropathy has been validated and an atlas of characteristic radiographic features provided.
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Pinson, S., J. Yaouanq, A. M. Jouanolle, B. Turlin, and H. Plauchu. "Non-C282Y familial iron overload: evidence for locus heterogeneity in haemochromatosis." Journal of Medical Genetics 35, no. 11 (November 1, 1998): 954–56. http://dx.doi.org/10.1136/jmg.35.11.954.
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Mura, C. "Variation of iron loading expression in C282Y homozygous haemochromatosis probands and sib pairs." Journal of Medical Genetics 38, no. 9 (September 1, 2001): 632–36. http://dx.doi.org/10.1136/jmg.38.9.632.
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Heiland, Gisela Ruiz, Elmar Aigner, Tomáš Dallos, Enijad Sahinbegovic, Veit Krenn, Christoph Thaler, Günter Weiss, et al. "Synovial immunopathology in haemochromatosis arthropathy." Annals of the Rheumatic Diseases 69, no. 6 (November 23, 2009): 1214–19. http://dx.doi.org/10.1136/ard.2009.120204.
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BackgroundHereditary haemochromatosis (HH) is a common autosomal recessive inherited disorder that frequently causes arthritis. The pathophysiology of musculoskeletal involvement is, however, unclear.ObjectiveTo analyse synovial tissue obtained at surgery from patients with HH arthropathy and compare it qualitatively and quantitatively with specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).MethodsSynovial tissue from 15 patients with HH, 20 with RA and 39 with OA was obtained during surgery. A synovitis grading system was used to determine the severity of synovial inflammation. Using immunohistochemistry, synovial neovascularisation and infiltration of macrophages, neutrophils and lymphocytes were quantitatively assessed.ResultsSynovitis in HH arthropathy largely resembles OA with mild infiltration of mononuclear cells and lymphocytes, formation of synovial microvessels and a low degree of synovial hyperplasia. While many features of HH arthropathy are reminiscent of OA, macrophage and especially neutrophil invasion is clearly more prominent in HH arthropathy than in primary OA and mimics features of RA. This finding was observed particularly in synovial tissue of HH samples with marked haemosiderin deposition.DiscussionThe histological picture of the synovium in HH arthropathy largely resembles a process reminiscent of OA. Neutrophil invasion is, however, markedly increased in HH arthropathy, especially in joints with iron deposition. Accumulation of neutrophils may be crucial for the production of matrix enzymes, which enables cartilage degradation and more rapidly progressive articular damage.
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Chart, Henrik, and Elwyn Griffiths. "The availability of iron and the growth ofVibrio vulnificusin sera from patients with haemochromatosis." FEMS Microbiology Letters 26, no. 2 (February 1985): 227–31. http://dx.doi.org/10.1111/j.1574-6968.1985.tb01596.x.
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Beiranvand, Elham, Saeid Abediankenari, Mosayeb Rostamian, Behnoush Beiranvand, and Saeed Naazeri. "The Study of HFE Genotypes and Its Expression Effect on Iron Status of Iranian Haemochromatosis, Iron Deficiency Anemia Patients, Iron-Taker and Non Iron-Taker Controls." Recent Advances in DNA & Gene Sequences (Formerly Recent Patents on DNA & Gene Sequences) 9, no. 1 (January 26, 2016): 58–64. http://dx.doi.org/10.2174/2352092209666150211233434.
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McNamee, Antony P., Surendran Sabapathy, Indu Singh, Jarod Horobin, Janelle Guerrero, and Michael J. Simmonds. "Acute Free-Iron Exposure Does Not Explain the Impaired Haemorheology Associated with Haemochromatosis." PLOS ONE 11, no. 1 (January 7, 2016): e0146448. http://dx.doi.org/10.1371/journal.pone.0146448.
Повний текст джерелаДисертації з теми "Haemochromatosis, iron, genetics"
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Pointon, Jennifer Jane. "The genetics of haemochromatosis." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249468.
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Hallendorff, Michelle-Angelique. "Ironing out haemochromatosis : a study of an Indian family." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21458.
Повний текст джерелаАнотація:
Thesis (MSc)--University of Stellenbosch, 2008.ENGLISH ABSTRACT: Iron metabolism disorders comprise the most common disorders in humans. Hereditary haemochromatosis (HH) is a common condition resulting from inappropriate iron absorption. The most common form of the disease (Type 1) is associated with mutations in the HFE gene. The C282Y homozygous genotype accounts for approximately 80% of all reported cases of HH within the Caucasian population. A second HFE mutation, H63D, is associated with less severe disease expression. The C282Y mutation is extremely rare in Asian and African populations. The H63D mutation is more prevalent and has been observed in almost all populations. Iron overload resulting from haemochromatosis is predicted to be rare in Asian Indian populations and is not associated with common HFE mutations that are responsible for HH in the Caucasian population. The aberrant genes associated with HH in India have not yet been identified. The present study attempted to identify variants in six iron regulatory genes that were resulting in the Type 1 HH phenotype observed in two Asian Indian probands from a highly consanguineous family. The promoter and coding regions of the HMOX1, HFE, HAMP, SLC40A1, CYBRD1 and HJV genes were subjected to mutation analysis. Gene fragments were amplified employing the polymerase chain reaction (PCR) and subsequently subjected to heteroduplex single-strand conformational polymorphism (HEX-SSCP) analysis. Samples displaying aberrations were then analysed using bi-directional semi-automated DNA sequencing analysis to identify any known or novel variants within the six genes. Variants disrupting restriction enzyme recognition sites were genotyped employing restriction fragment length polymorphism (RFLP) analysis. Mutation analysis of the six genes revealed 24 previously identified variants, five novel variants (HFE: 5’UTR-840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR- 1272T→C; HJV: 5’UTR-534G→T, 5’UTR-530G→T), one previously described microsatellite and two novel repeats. Variants identified within the SLC40A1, CYBRD1 and HJV genes do not seem to be associated with the iron overload phenotype. A previously described HAMP variant (5’UTR-335G→T) was observed in the homozygous state in both probands. This variant seems to be the genetic aberration responsible for iron overload in this Indian family. The severe juvenile haemochromatosis phenotype usually associated with HAMP mutations, was not exhibited by the two Indian probands. Their symptoms resembled those observed in classic Type 1 HH. It is suggested that variants identified in the HMOX1 and HFE genes are modifying the effect of the HAMP variant and resulting in the less severe disease phenotype. Although this variant has only been identified in one Indian family, it could shed some light in the hunt for the iron-loading gene in India.
AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is ‘n algemene siektetoestand wat ontstaan as gevolg van oneffektiewe opname van yster in die liggaam. Die mees algemene vorm van die siekte (Tipe 1) word geassosieer met mutasies in die HFE-geen. Die C282Y homosigotiese genotipe is verantwoordelik vir ongeveer 80% van alle gerapporteerde gevalle van OH binne die Kaukasiese bevolking. ‘n Tweede HFE mutasie, H63D, word geassosieer met minder ernstige siekte simptome. Die C282Y mutasie is besonder skaars in Asiese en Afrika bevolkings. Daar word bespiegel dat oorerflike ysteroorlading as gevolg van hemochromatose skaars is in Asiese Indiër bevolkings en word nie geassosieer met algemene HFE mutasies wat verantwoordelik is vir OH in Kaukasiese bevolkings nie. Die abnormale gene wat wél geassosieer word met OH in Indië is tot dusver nog nie identifiseer nie. Die doel van hierdie studie was om die variante in ses yster-regulerende gene te identifiseer wat die Tipe 1 OH fenotipe in hierdie familie veroorsaak. Hierdie fenotipe is waargeneem in twee Asies Indiese familielede afkomstig van ‘n bloedverwante familie. Die promotor en koderingsareas van die HMOX1, HFE, HAMP, SLC40A1, CYBRD1 en HJV gene is gesif vir mutasies. Geen fragmente is geamplifiseer met behulp van die polimerase kettingsreaksie (PKR) en daarna aan heterodupleks enkelstring konformasie polimorfisme (HEX-SSCP) analise blootgestel. PKR produkte wat variasies getoon het, is daarna geanaliseer deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise om enige bekende of nuwe variante binne die ses gene te identifiseer. Variante waar restriksie ensiem herkenningsetels teenwoordig is, is verder analiseer met behulp van die restriksie fragment lengte polimorfisme (RFLP) analise sisteem. Mutasie analise van die ses gene het 24 bekende variante, vyf nuwe variante (HFE: 5’UTR- 840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR-1272T→C, HJV: 5’UTR-534G→T, 5’UTR-530G→T), een bekende herhaling en twee nuwe herhalings gewys. Variante wat binne die SLC4041, CYBRD1 en HJV gene geïdentifiseer is, blyk nie om by te dra tot die ysteroorladings-fenotipe nie. Die bekende HAMP variant (5’UTR-335G→T) is waargeneem in die homosigotiese toestand in beide van die aangetaste individue. Hierdie variant blyk om die genetiese fout te wees wat verantwoordelik is vir die ysteroorlading in die betrokke Indiese familie. Die erge juvenielehemochromatose fenotipe wat meestal geassosieer word met HAMP-mutasies, is nie waargeneem in hierdie familie nie. Hul simptome kom ooreen met die simptome van die klassieke Tipe 1 OH. Dit blyk moontlik te wees dat die variante identifiseer in die HMOX1 en HFE gene die impak van die HAMP variant modifiseer en die matiger siekte-fenotipe tot gevolg het. Alhoewel hierdie variant slegs in een Indiese familie geïdentifiseer is, kan dit lig werp op die soektog na die veroorsakende ysterladingsgeen in Indië.
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Lord, Deirdre Karen. "The molecular genetics of hereditary haemochromatosis and characterization of the iron-binding purple phosphatase of the human macrophage." Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/46417.
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Cullen, Lara Michelle. "Molecular analysis of hereditary haemochromatosis." Thesis, Queensland University of Technology, 1999.
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Hawula, Zachary John. "Identification and analysis of genetic and chemical modulators of iron metabolism." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/225904/1/Zachary_Hawula_Thesis.pdf.
Повний текст джерелаАнотація:
This dissertation focused on identifying novel chemical and genetic modulators of iron homeostasis. Iron is an essential element for human health. Disorders such as anaemia and haemochromatosis can develop when iron levels are not maintained within a normal physiological range. The findings of this program included the identification of a new iron chelating compound, demonstration of iron chelation in a haemochromatosis mouse model by a flavonol, identification of iron metabolism-related genes and variants which may assist in distinguishing suitable blood donors, and the identification of novel genes which may contribute to modulating iron homeostasis by regulating the iron exporter ferroportin.
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Pratiwi, Rarastoeti. "Genetic analysis of haemochromatosis and characterisation of the role of HFE in iron metabolism /." [St. Lucia, Qld.], 2000. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16204.pdf.
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George, David Keith. "The role of liver matrix degradation in the development of hepatic fibrosis in genetic haemochromatosis." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299332.
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Kuek, Conchita Maria. "Hereditary haemochromatosis and the C282Y genotype : implications in diagnosis and disease." University of Western Australia. School of Surgery and Pathology, 2003. http://theses.library.uwa.edu.au/adt-WU2004.0024.
Повний текст джерелаАнотація:
[Truncated abstract. Please see the pdf format for the complete text.] The discovery of the C282Y mutation and its role in the development of hereditary haemochromatosis has allowed a greater understanding into the effects of iron overload and its involvement in other conditions such as diabetes and heart disease. It has also allowed the better classification of heterozygotes, who were previously only diagnosed through the use of family studies. There are however, areas of conflict between phenotyping and genotyping methods. My research involved examining the relationship between Haemochromatosis and certain diseases such as diabetes and heart disease; genotyping versus phenotyping discrepancies and the possible interaction of secondary mutations. In Chapter 3 a population study was undertaken with the aim of comparing genotyping versus phenotyping methods as well as increasing general practitioner awareness regarding hereditary haemochromatosis and its diagnosis. It was determined that a minimum of 5000 subjects would be required to give the study sufficient power. Individuals were to be between the ages of 20—40 years, and thus presumably presymptomatic. Participation was entirely voluntary and a consent form was to be signed. Recruitment of subjects proved to be difficult and there was a selective bias towards individuals already displaying symptoms of haemochromatosis. In total less than a 100 subjects were recruited for the study. There were several issues encountered in the implementation of this study. Firstly the number of GPs participating was probably insufficient to recruit the subjects required. A more extensive campaign was probably required to enroll more GPs. Secondly it is very difficult for a busy GP to find the time necessary to explain the study to each of his patients and to get them to sign the consent form. Finally a bias developed in some of the requests. The subjects participating in this study were supposed to be random but in many cases the GPs had enrolled them in the study because they had symptoms of iron overload. In effect the biggest obstacle this study faced was the recruitment of subjects. Due to the small number of subjects little statistical data could be obtained from this study. It was noted, however, that genotyping methods detected two individuals who were homozygous for the C282Y mutation. Both also had increased transferrin saturation levels. Phenotyping detected 5 individuals with increased transferrin saturation. The three others detected via phenotyping were C282Y heterozygotes. Haemochromatosis has long been though to be related to the development of diabetes due to the effect of iron overload on the pancreas. If this is so it would be logical to assume that the prevalence of haemochromatosis would be higher in a diabetic population. Chapter 4 examined the possibility that diabetics have a higher frequency of the C282Y mutation. A population group consisting of 1355 diabetics was genotyped for the C282Y mutation and iron studies were performed on all heterozygotes and C282Y homozygotes. Initial findings indicated that there was a significant difference between the diabetic and control population. However, this finding was the opposite of what was expected, there seemed to be a decreased frequency of the Y allele in the diabetic population rather than an increased one. The control and diabetic populations were not matched in terms of ethnicity. The removal of the ethnic bias in the diabetic population altered the statistics so there was no longer a significant difference between the two groups. This study highlighted the importance of using appropriate control populations as comparison groups. The final results of the study indicated that there was no significant difference between the diabetic population and the control population. This would seem to indicate that there is not an increased occurrence of the C282Y mutation in the diabetic population when compared to the control group. Chapter 5 considered the possible association between C282Y heterozygosity and cardiovascular disease as well as the potential for early mortality. Several recent studies have indicated that C282Y heterozygosity may be a risk factor for the development of atherosclerosis, possibly on the basis of increased iron loading. Using a control population and a population of individuals with known coronary events the incidence of the C282Y mutation was compared against other risk factors. C282Y heterozygosity did not appear to be a risk factor for atherosclerosis. There was however, a statistically significant link between increased ferritin in women and carotid plaques. A population of elderly women was genotyped in order to examine the effects of C282Y heterozygosity on longevity. The first hypothesis addressed in chapter 5 was that C282Y heterozygosity was a risk factor for the development of coronary heart disease.
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Sydes, Elizabeth R. "Genetic variation of the HFE gene and associated proteomes in chronic venous leg ulceration." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/127835/1/Elizabeth_Sydes_Thesis.pdf.
Повний текст джерелаАнотація:
This project was conducted to determine whether the genetic variance of an iron regulatory gene was associated with the development or severity of chronic venous leg ulceration. In addition, the study examined the association of wound exudate protein composition with both the genetic variance of the target gene and wound healing outcomes. The evidence collected supported the hypothesis that wound healing may be affected by dysregulation of iron. By virtue of the discovery phase protein profiling methods used, a wound fluid protein reference library was created, against which future studies may be searched to identify potential therapeutic targets.
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Brew, Jennifer Mary. "Investigations of Potential Modifier Genes in Hereditary Haemochromatosis." Phd thesis, 2010. http://hdl.handle.net/1885/8701.
Повний текст джерелаАнотація:
Hereditary haemochromatosis (OMIM #235200) is a late onset disorder resulting from excess iron absorption. It causes symptoms such as bronze pigmentation of the skin, joint pain, abdominal pain, weight loss, impotence, cardiomyopathy, diabetes and may lead to cirrhosis of the liver. The most common cause of this disease in Caucasians is homozygosity for the C282Y mutation in the HFE gene on chromosome 6p21.3. The penetrance of the C282Y mutation is not complete with many environmental and genetic factors influencing the phenotypic expression of the disease.
A number of SNPs in genes in the iron metabolic pathway previously associated with altered serum iron indices were tested in the current study. The results suggested that two of the SNPs, namely rs1799852 in Transferrin and rs884409 in CYBRD1 may contribute to altered SF levels in HFE-associated haemochromatosis.
The first major finding of this study was a significantly higher serum ferritin (SF) level observed in iron-loaded male C282Y homozygotes who were symptomatic compared to those that were asymptomatic. This was not associated with age and suggests there is a threshold level of SF above which symptoms occur. This discordance between the symptomatic and asymptomatic C282Y homozygotes formed the basis of subsequent analyses.
A second major finding was the association of the TNFalpha 21112 promoter haplotype with increased SF levels in symptomatic male C282Y homozygotes. To explore the mechanism underlying this association, luciferase assays were performed in the presence and absence of extracellular iron. The results revealed there was no definitive change in TNFalpha expression associated with the 21112 haplotype compared to the other haplotypes.
The expression levels of a number of genes in the iron pathway (HFE, HAMP, TFRC, TFR2 and TNFalpha) were measured in lymphoblastoid cell lines derived from males of different TNFalpha haplotypes and HFE genotypes. The C282Y homozygotes analysed in this study included both symptomatic and asymptomatic samples. The major finding of the expression studies was that the TNFalpha 21112 haplotype was associated with altered TFRC expression levels specifically in the symptomatic C282Y homozygotes. This provides an explanation of the increased SF levels seen in these patients. While a mechanism for the modulation of TFRC expression by the TNFalpha haplotype remains unclear, this study has confirmed TNFalpha as a significant modifier gene in HFE-associated haemochromatosis.
The discovery of modifier genes in both conventional and unconventional pathways of iron metabolism may allow for the development of novel preventative and treatment strategies in a new era for hereditary haemochromatosis.
Книги з теми "Haemochromatosis, iron, genetics"
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Keshav, Satish, and Palak Trivedi. Genetic liver disease. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0214.
Повний текст джерелаАнотація:
This chapter discusses three of the major inherited forms of liver disease (all autosomal recessive): hereditary haemochromatosis, Wilson’s disease, and alpha-1-antitrypsin deficiency. Hereditary haemochromatosis is characterized by excessive absorption of dietary iron, with a pathological increase in total body iron that accumulates in tissues and organs, disrupting their function. Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive genetic disorder in which copper accumulates in tissues. Alpha-1-antitrypsin deficiency is characterized by reduced circulating levels of alpha-1-antitrypsin, a liver-derived protease inhibitor, and accumulation within the hepatocytes of the abnormal, poorly degraded protein; the consequent excessive activity of proteases such as elastase in pulmonary alveoli, unopposed by protease inhibitors, leads to emphysema, and the accumulation of alpha-1-antitrypsin in hepatocytes causes liver dysfunction.
Частини книг з теми "Haemochromatosis, iron, genetics"
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Griffiths, William J. H., and T. M. Cox. "Hereditary haemochromatosis." In Oxford Textbook of Medicine, 1673–88. Oxford University Press, 2010. http://dx.doi.org/10.1093/med/9780199204854.003.120701_update_003.
Повний текст джерелаАнотація:
Haemochromatosis is a hereditary disorder generally caused by inappropriate absorption of iron by the small intestine which leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult haemochromatosis, but juvenile and neonatal forms are recognized, and several other genetic syndromes associated with iron storage have been identified; these may rarely involve specific tissues selectively, such as the lens of the eye or basal ganglia of the brain, or a characteristic range of tissues including the liver, heart, and endocrine system. Early-onset (juvenile) haemochromatosis has a predilection for the heart, pituitary gonadotrophs and the pancreatic islet—thus myocardial disease (which may be fatal if untreated), hypogonadism and diabetes mellitus are prominent features. Prompt diagnosis and depletion of tissue iron by chelating agents—and venesection where possible—may be life-saving. Unravelling the molecular genetics of haemochromatosis is underpinning promising new therapies for disorders of iron homeostasis....
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Griffiths, William J. H., and Timothy M. Cox. "Hereditary haemochromatosis." In Oxford Textbook of Medicine, edited by Timothy M. Cox, 2098–114. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0233.
Повний текст джерелаАнотація:
Hereditary haemochromatosis syndromes are inherited disorders whereby inappropriate absorption of iron by the small intestine leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult (HFE-related) haemochromatosis, but other forms are recognized. Extended genetic platforms are increasingly used for specific diagnosis and noninvasive methods are increasingly used to evaluate hepatic damage. The mainstay of treatment is venesection although iron chelation therapy is an emerging oral alternative. Unravelling the molecular genetics of haemochromatosis is underpinning promising new therapies for disorders of iron homeostasis. Classical adult (HFE-related) haemochromatosis: aetiology and pathogenesis—inherited as a recessive trait and due to mutations in the major histocompatibility complex class I-related HFE gene that appear to reduce liver production of hepcidin. The principal mutant allele of HFE, designated C282Y, is carried by approximately 1 in 10 individuals of European ancestry, hence around 1 in 200 are homozygotes, usually with biochemical abnormalities of iron storage that may lead to full-blown clinical haemochromatosis. Clinical features—expression of disease may range from slight abnormalities of blood parameters that reflect iron metabolism to the established clinical syndrome of cutaneous pigmentation, cardiomyopathy, endocrine failure (especially diabetes mellitus and hypogonadism), arthritis, and pigment cirrhosis. Diagnosis—usually established by demonstrating abnormalities of iron metabolism. Molecular analysis of the HFE gene, in particular for homozygosity for the C282Y allele, is confirmatory. Management and prognosis—this is directed to the removal of iron by phlebotomy until the serum ferritin concentration is reduced to within the low normal range, after which the frequency of phlebotomy is reduced. Family members—first-degree relatives should be offered screening.
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Elliott, Perry, Pier D. Lambiase, and Dhavendra Kumar. "The heart and inherited haematological disorders." In Inherited Cardiac Disease, 367–82. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198829126.003.0016.
Повний текст джерелаАнотація:
This chapter covers inherited haematological disorders. It explains the pathophysiology, genetics, and iron overload of thalassaemia; cardiac disease in both β and αthalassaemia; the pathophysiology, genetics, and iron overload in haemochromatosis; the evaluation of patients; and finally the management of patients at risk of cardiac iron overload.
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Deugnier, Yves, and Edouard Bardou-Jacquet. "Haemochromatosis and Other Inherited Diseases of Iron Metabolism." In Oxford Textbook of Endocrinology and Diabetes 3e, edited by John A. H. Wass, Wiebke Arlt, and Robert K. Semple, 1901–9. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198870197.003.0235.
Повний текст джерелаАнотація:
Haemochromatosis was described centuries ago, yet the biological mechanisms involved were delineated only recently. Mutation in genes involved in iron metabolism (HFE in the most frequent form) leads to systemic iron overload which particularly affect the liver, pancreas, heart, joints, and pituitary. This can lead to cirrhosis, hepatocellular carcinoma, diabetes, heart failure, hypogonadism, and arthropathy. The diagnosis now relies on definite genetic testing, allowing earlier diagnosis and family screening. This chapter looks at how this lifelong treatment is based on bloodletting to normalize body iron stores and, provided it is initiated before the onset of massive iron overload, allows a normal life expectancy.
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Cox, Timothy M., and John B. Porter. "Iron metabolism and its disorders." In Oxford Textbook of Medicine, edited by Chris Hatton and Deborah Hay, 5371–402. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0534.
Повний текст джерелаАнотація:
Iron deficiency and iron storage disease—the latter principally due to inherited and acquired anaemias such as thalassemia—are disorders of massive clinical significance across the globe. Iron deficiency is the commonest cause of anaemia, affecting about 1 billion people, and about 0.75 million people have thalassaemia. Largely neglected by health services in rich and resource-poor countries alike, disorders of iron metabolism, whether inherited, nutritional, or otherwise, represent a long-standing public health challenge. Improved screening methods for detection, diagnosis, and appropriate supplementation—as well as genetic counselling—can offer a great deal to relieve the burden in stricken communities. Advances in chelation therapy have improved the survival of patients with iron-loading anaemias and transfusion-related haemochromatosis, and better understanding of the molecular pathophysiology of iron homeostasis now offers the prospect of definitive therapies to control pathological erythropoiesis and the inappropriate drive to acquire lethal quantities of toxic iron.
Тези доповідей конференцій з теми "Haemochromatosis, iron, genetics"
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Atkins, Janice L., Luke C. Pilling, and David Melzer. "OP56 Hereditary haemochromatosis: genetic iron overload – a missed opportunity for diagnosis and treatment." In Society for Social Medicine Annual Scientific Meeting Abstracts. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jech-2022-ssmabstracts.55.
Повний текст джерела