Defective release of Hepcidin not defective synthesis is the primary pathogenic mechanism in HFE-Haemochromatosis

Arnold, Jayantha; Sangwaiya, Arvind; Bhatkal, Bharati; Arnold, Ahran

doi:10.1016/j.mehy.2007.10.007

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…The HFE protein is thought to regulate the interaction of other key molecules involved in iron uptake and circulation [ 25 ], including transferrin, a plasma protein that binds absorbed iron for circulation; the transferrin receptor (TfR, encoded by TFRC and TRF2 genes), a transmembrane glycoprotein facilitating intake of transferrin-bound iron into cells; ferroportin ( FPN1 or SLC40A1 ), a transmembrane protein located on the basolateral surface of gut cells macrophages, which allows transport of absorbed iron out of cells into circulation; and hepcidin ( HAMP ), a negative regulator of iron transport that competitively binds ferroportin, preventing release of iron from cells. HFE primarily interacts with TfR by decreasing the affinity of transferrin for the TfR, thus reducing the uptake of transferring-bound iron [ 26 , 27 ] as well as possibly influencing regulation of hepcidin levels, with decreases in hepcidin levels reducing the negative inhibition of ferroportin and thus increasing export for iron from gut cells into circulation and tissues [ 25 , 28 ]. The H63D polymorphism has been shown to reduce the ability of the HFE protein to bind to its ligand, thereby preventing the inhibition of transferrin-TfR binding and resulting in increased transport of iron into circulation and cells [ 26 , 27 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes

et al. 2015

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Polygenic profiling has been proposed for elite endurance performance, using an additive model determining the proportion of optimal alleles in endurance athletes. To investigate this model’s utility for elite triathletes, we genotyped seven polymorphisms previously associated with an endurance polygenic profile (ACE Ins/Del, ACTN3 Arg577Ter, AMPD1 Gln12Ter, CKMM 1170bp/985+185bp, HFE His63Asp, GDF8 Lys153Arg and PPARGC1A Gly482Ser) in a cohort of 196 elite athletes who participated in the 2008 Kona Ironman championship triathlon. Mean performance time (PT) was not significantly different in individual marker analysis. Age, sex, and continent of origin had a significant influence on PT and were adjusted for. Only the AMPD1 endurance-optimal Gln allele was found to be significantly associated with an improvement in PT (model p = 5.79 x 10−17, AMPD1 genotype p = 0.01). Individual genotypes were combined into a total genotype score (TGS); TGS distribution ranged from 28.6 to 92.9, concordant with prior studies in endurance athletes (mean±SD: 60.75±12.95). TGS distribution was shifted toward higher TGS in the top 10% of athletes, though the mean TGS was not significantly different (p = 0.164) and not significantly associated with PT even when adjusted for age, sex, and origin. Receiver operating characteristic curve analysis determined that TGS alone could not significantly predict athlete finishing time with discriminating sensitivity and specificity for three outcomes (less than median PT, less than mean PT, or in the top 10%), though models with the age, sex, continent of origin, and either TGS or AMPD1 genotype could. These results suggest three things: that more sophisticated genetic models may be necessary to accurately predict athlete finishing time in endurance events; that non-genetic factors such as training are hugely influential and should be included in genetic analyses to prevent confounding; and that large collaborations may be necessary to obtain sufficient sample sizes for powerful and complex analyses of endurance performance.

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Section: Introductionmentioning

confidence: 99%

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes

et al. 2015

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“…Hereditary hemochromatosis is an autosomal recessive disease that is characterized by progressive iron overload due to increased iron absorption and is responsible for damage to the liver, heart, joints, pancreas, and endocrine glands. Mutations in the HFE gene are detected in the large majority of patients of northern European descent and cause reduced release of hepcidin, the hepatic hormone that inhibits iron absorption by interacting with ferroportin‐1, which is responsible for iron export from the basal membrane of duodenocytes and from macrophages 1, 2…”

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confidence: 99%

Hemochromatosis in Italy in the Last 30 Years: Role of Genetic and Acquired Factors

et al. 2010

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The clinical presentation of hereditary hemochromatosis has changed markedly in recent years. The aim of this study was to analyze a large series of consecutive Italian patients with hemochromatosis diagnosed between 1976 and 2007 to determine whether the genetic background and the presence of acquired risk factors influenced the severity of iron overload and the natural history of the disease. A cohort of 452 Italian patients with iron overload-338 HFE-related (C282Y homozygotes or compound C82Y/H63D heterozygotes) and 114 non-HFE-related-were followed prospectively for a median of 112 months. Alcohol intake, smoking habits, and iron removed to depletion were similar in patients with and without HFE-related iron overload. Hepatitis B virus (4% and 9%; P ‫؍‬ 0.04) and hepatitis C virus (6% and 19%; P ‫؍‬ 0.002) infections were more frequent in patients with non-HFErelated iron overload. Seventy-three percent of patients with HFE and 61% of patients with non-HFE-related disease had no acquired risk factor. Cirrhosis was significantly more frequent in non-HFE patients independent of the presence of acquired risk factors (P ‫؍‬ 0.02). Sex, alcohol intake, prevalence of smoking, hepatitis C virus infection, glucose, lipids, iron-related parameters, and prevalence of C282Y/H63D differed significantly over the years. At enrollment, cirrhosis was present in 145 cases and was significantly more frequent in the first decade (80%, 47%, and 13%; P ‫؍‬ 0.001). Survival did not differ across the decades in cirrhotic patients; hepatocellular carcinoma occurred similarly in HFE and non-HFE patients.

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“…Similarly, serum levels increase with iron loading, suggesting it is a compensatory response to limit iron absorption from the intestine. Current theory implicates defective hepcidin synthesis in the pathophysiology of hemochromatosis whereby individuals with HFE gene mutations do not produce the normal surge in hepcidin secretion in response to gut absorption of iron 21,22 . With inappropriately low hepcidin secretion there would be unopposed iron absorption, even when iron replete.…”

Section: Discussionmentioning

confidence: 99%

“…Current theory implicates defective hepcidin synthesis in the pathophysiology of hemochromatosis whereby individuals with HFE gene mutations do not produce the normal surge in hepcidin secretion in response to gut absorption of iron. 21,22 With inappropriately low hepcidin secretion there would be unopposed iron absorption, even when iron replete. Hepcidin is cleared by the kidney and serum hepcidin levels are higher in HD patients, kidney transplant patients, and patients with chronic renal failure compared with controls.…”

Section: Hemodialysis Patients With Hfe Mutationsmentioning

confidence: 99%

Hemochromatosis gene mutations and treatment of anemia in patients on hemodialysis

Brown

Gaffney

Gemmell

et al. 2009

Hemodialysis International

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Hemochromatosis causes iron overload by enhanced intestinal absorption. This study examined erythropoietin and intravenous (i.v.) iron requirements in hemodialysis (HD) patients with HFE mutations. Patients on HD for > 90 days with no cause of anemia except chronic kidney disease were tested for HFE mutations (H63D and C282Y). Intravenous iron and erythropoietin doses were adjusted to achieve recommended targets. Monthly hemoglobin (Hb), ferritin, mean corpuscular volume, mean cell hemoglobin, erythropoietin, and i.v. iron doses for 3 consecutive months were averaged. Of 172 patients, 71 (41.3%) had > or = 1 HFE mutation: 24 (14%) C282Y heterozygotes, 40 (23.3%) H63D heterozygotes, 5 compound heterozygotes, and 2 homozygotes. Comparing patients with > or = 1 HFE mutation to those without mutations showed no significant difference in Hb or serum ferritin. There was a trend toward lower median weekly erythropoietin dose in patients with > or = 1 HFE mutation (94.0 vs. 135.4 U/kg body weight; P=0.13). There was no difference in median weekly i.v. iron dose (1.0 vs. 0.9 mg/kg body weight; P=0.56). Comparing the 30 patients with a C282Y mutation to patients without HFE mutations produced similar results. Comparing the 47 patients with an H63D mutation, with those without HFE mutations, no discernable trend was observed. In this study, patients with HFE gene mutations on HD for established renal failure do not require less iron supplementation to achieve recommended Hb targets. We observed a trend toward lower erythropoietin requirement in patients possessing C282Y mutations. Larger studies may clarify the role of HFE mutations, regulators of iron metabolism and erythropoiesis in chronic kidney disease.

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Defective release of Hepcidin not defective synthesis is the primary pathogenic mechanism in HFE-Haemochromatosis

Cited by 4 publications

References 23 publications

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes

Hemochromatosis in Italy in the Last 30 Years: Role of Genetic and Acquired Factors

Hemochromatosis gene mutations and treatment of anemia in patients on hemodialysis

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