A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

Njajou, Omer T.; Houwing-Duistermaat, Jeanine J.; Osborne, Richard H.; Vaessen, Norbert; Vergeer, Jeanette; Heeringa, Jan; Pols, Huibert A. P.; Hofman, Albert; Duijn, Cornelia M. van

doi:10.1038/sj.ejhg.5200955

Cited by 49 publications

(51 citation statements)

References 28 publications

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“…Reduced left ventricular ejection fraction was established only by the presence of CAD or MI and not by the heterozygosity of the C282Y mutation. These data do not support increased myocardial damage owing to iron overload in heterozygotes, in contrast to the development of cardiomyopathy in several homozygotes suffering from hereditary haemochromatosis [21]. Our findings in a large cohort of patients do not invalidate epidemiological studies inquiring the association between heterozygosity and cardiovascular mortality.…”

Section: Discussioncontrasting

confidence: 85%

Evaluation of HFE Gene (C282Y) Mutation and Its Association Relation with Coronary Artery Diseases in Indian Population

Shah¹,

Ahmed²,

Mushatq³

et al. 2017

Mol Biol

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Background: The gene associated with the CAD disease was found out to be the HFE (High Iron Fe) gene and the disease is described with the two, missense mutations of the gene-C282Y and H63D. The focus of this study was to assess the C282Y mutation in CAD patients that results from transition of guanine to adenine (G-A) at the nucleotide position 845, which in turn changes cysteine to tyrosine at the 282 nd position.

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Section: Discussioncontrasting

confidence: 85%

Evaluation of HFE Gene (C282Y) Mutation and Its Association Relation with Coronary Artery Diseases in Indian Population

Shah¹,

Ahmed²,

Mushatq³

et al. 2017

Mol Biol

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“…In contrast, Beutler argued that the H63D is a disease-related mutation having very low clinical penetrance (28). Subsequent population studies have supported the argument that H63D has a mild effect on parameters of iron homeostasis (16)(17)(18). Scarce data are available on the effect of the H63D mutation on hepatic iron concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, normal iron parameters are observed in approximately half of individuals compound heterozygous for H63D and C282Y (15). Homozygosity for the H63D mutation is associated with increased serum transferrin saturations and ferritin levels in some populations (16)(17)(18). However, the majority of individuals homozygous for H63D have normal iron parameters.…”

Section: H Ereditary Hemochromatosis (Hh) Is An Autosomal Recessivementioning

confidence: 99%

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

Tomatsu

Orii

Fleming

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80 -90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y͞H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y͞H63D and H63D͞H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D͞ C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y͞C294Y > C294Y͞H67D > H67D͞ H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.knock-in mice ͉ C282Y mutation ͉ H63D mutation ͉ Cre-loxP H ereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by elevated transferrin saturations, hepatic iron overload, and variable clinical manifestations including liver cirrhosis, hypogonadism, heart failure, and arthropathy. Prevalence of mutations in the gene responsible for HH is estimated to be 2-5 per 1,000 in Caucasians. The gene mutated in HH, the hemochromatosis gene (HFE), encodes an MHC class I-like protein (1) that heterodimerizes with ␤ 2 -microglobulin (␤ 2 M). Most cases of HH arise from a founder mutation in HFE (845G to -A) that results in the amino acid substitution C282Y and prevents the association of HFE with ␤ 2 M (1-3). Functional significance of HFE-␤ 2 M complex in iron homeostasis was supported from the observations that HFE-␤ 2 M is physically associated with transferrin receptor 1 (TfR1) in human placenta (4), in crypt enterocytes of duodenum (5), and in cultured human cell lines (6, 7). The effect of HFE on transferrin-mediated iron uptake seems to depend on the particular cell type studied as well as the magnitude of expression of ␤ 2 M (8).Although the most common HFE mutation associated with HH is C282Y, the most common HFE mutation overall is H63D. Among Caucasian populations, the allele frequency of C282Y is 2-5% and that of H63D is 15-20% (9, 10). The H63D allele frequency has been reported to be as high as 30% in the Basque population of Spain (11). The H63D mutation seems to have evolutionarily predated C282Y and to have ar...

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“…The two most common mutations are the C282Y mutation, which has an estimated allelefrequency of 6%, and the H63D mutation, which has an allele-frequency of about 14% [2,3]. Most patients with clinically diagnosed hemochromatosis are homozygous for the C282Y mutation.…”

Section: Introductionmentioning

confidence: 99%

HFE genotypes and dietary heme iron: No evidence of strong gene–nutrient interaction on serum ferritin concentrations in middle-aged women

Peeters

Grobbee

et al. 2006

Nutrition, Metabolism and Cardiovascular Diseases

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Background and aim: Hereditary hemochromatosis (HH) is a disorder characterized by inappropriately high intestinal iron absorption. In populations of Northern European descent, HH is most commonly caused by mutations (C282Y/ H63D) in the HFE gene. Methods and results:We investigated the effects of dietary heme iron intake and HFE mutations on serum ferritin concentrations in a population-based random sample of 1611 women aged O50 years using analysis of covariance (ANCOVA). Higher heme iron intake was associated with significantly higher serum ferritin concentrations (P trend ! 0.001). Also, women with the compound or C282Y homozygous genotype had significantly higher serum ferritin concentrations (geometric mean 115.2 mg/L (95% CI 81.4e162.9 mg/L) than women carrying normal alleles (geometric mean 76.6 mg/L (95% CI 72.5e80.9 mg/L). We observed the highest serum ferritin concentrations among postmenopausal women who are compound heterozygous or C282Y homozygous, and who consume relatively high amounts of heme iron (geometric mean 183.9 mg/L (95% CI 97.2e347.8 mg/L).

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A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

Cited by 49 publications

References 28 publications

Evaluation of HFE Gene (C282Y) Mutation and Its Association Relation with Coronary Artery Diseases in Indian Population

Evaluation of HFE Gene (C282Y) Mutation and Its Association Relation with Coronary Artery Diseases in Indian Population

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

HFE genotypes and dietary heme iron: No evidence of strong gene–nutrient interaction on serum ferritin concentrations in middle-aged women

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