Diagnostic utility of HFE variants in Spanish patients: Association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia

Rodríguez‐López, Raquel; Donoso, Marisol; Fernández-Cavada, Maria Jesús; González, Luz María; Margallo, Aranza; Corral, César; Gallego, María Esther Quintana; Cáceres, María Teresa García de; Herrera, T. Villegas; González, Cristina; Vagace, José Manuel; Gervasini, Guillermo

doi:10.1016/j.gene.2012.10.090

Cited by 12 publications

(13 citation statements)

References 28 publications

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“…Researchers6,26,27 described an association between HFE mutation variants, iron storage and concomitant disease progression. There are also preliminary reports considering the impact of HFE variants and susceptibility to acute lymphoblastic leukemia in childhood 6,28,29. Taking into consideration presented data and cited authors the impact of HFE mutation in childhood still needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children

Kaczorowska-Hac¹,

Łuszczyk

Antosiewicz

et al. 2017

Journal of Pediatric Hematology/Oncology

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Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

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Section: Discussionmentioning

confidence: 99%

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children

Kaczorowska-Hac¹,

Łuszczyk

Antosiewicz

et al. 2017

Journal of Pediatric Hematology/Oncology

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“…Iron may also suppress host defence cell activity and promote cancer cell proliferation. It is increasingly reported that two mutations in HFE – C282Y (rs1800562G>A) and H63D (rs1799945 C>G) – are associated with an increased risk of cancers, including hepatocellular , breast , colorectal and prostate cancer , as well as others . However, some other studies have shown no association between haemochromatosis genotype and neoplasia .…”

Section: Introductionmentioning

confidence: 99%

The risk of new‐onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants

Chang

Hua

et al. 2016

J Cellular Molecular Medi

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To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta‐analysis of all available case–control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448–2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large‐scale studies considering gene–environment interactions and functional research should be conducted to further investigate this association.

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“…However, tissue distribution and expression level of HFE varies markedly. In addition, at least nine variants of HFE, ranging in sizes from 8.8 kDa to 40 kDa, have been identified [27]. Tissue distribution and expression level of each of these variants differ significantly.…”

Section: Resultsmentioning

confidence: 99%

“…Tissue distribution and expression level of each of these variants differ significantly. Not all of these variants are generated by exon skipping or alternate splicing [27-28]. In order to investigate transcription regulation of HFE gene, a 1675 bp fragment (H1675) comprising 1637 bp upstream and 37 bp downstream of the reported transcription start site was PCR amplified from human genomic DNA and inserted into pGL3 Basic luciferase-reporter vector.…”

Section: Resultsmentioning

confidence: 99%

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Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter

Pelham

Jiménez

Rodova

et al. 2013

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700 bp (−1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression.

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Diagnostic utility of HFE variants in Spanish patients: Association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia

Cited by 12 publications

References 28 publications

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children

The risk of new‐onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants

Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter

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