CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

Background. Most patients with Hereditary Hemochromatosis are homozygous for the p.C282Y mutation in the HFE gene in Caucasian population. Penetrance and expression of Hemochromatosis largely differ in p.C282Y homozygous cases. Besides environmental factors, genetic factors might be implicated. Design and Methods. In the present study, we analysed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 Italian p.C282Y homozygous cases. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results. We found a series of 17 genetic variants located in different genes with possible additive effect on the studied outcomes. In order to evaluate if the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction can be achieved adding genetic information to clinical data. Among the selected polymorphisms, a significant association between rs3806562, located in the 5\u2019UTR of CYBRD1, and transferrin saturation was observed. This variant belongs to the same haplotype block which contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. Luciferase assay indicates that rs3806562 has not a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-HH, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of HH phenotype

Hepcidin Expression in Iron Overload Diseases Is Variably Modulated by Circulating Factors

Hepcidin is a regulatory hormone that plays a major role in controlling body iron homeostasis. Circulating factors (holotransferrin, cytokines, erythroid regulators) might variably contribute to hepcidin modulation in different pathological conditions. There are few studies analysing the relationship between hepcidin transcript and related protein expression profiles in humans. Our aims were: a. to measure hepcidin expression at either hepatic, serum and urinary level in three paradigmatic iron overload conditions (hemochromatosis, thalassemia and dysmetabolic iron overload syndrome) and in controls; b. to measure mRNA hepcidin expression in two different hepatic cell lines (HepG2 and Huh-7) exposed to patients and controls sera to assess whether circulating factors could influence hepcidin transcription in different pathological conditions. Our findings suggest that hepcidin assays reflect hepatic hepcidin production, but also indicate that correlation is not ideal, likely due to methodological limits and to several post-trascriptional events. In vitro study showed that THAL sera down-regulated, HFE-HH and C-NAFLD sera up-regulated hepcidin synthesis. HAMP mRNA expression in Huh-7 cells exposed to sera form C-Donors, HFE-HH and THAL reproduced, at lower level, the results observed in HepG2, suggesting the important but not critical role of HFE in hepcidin regulation

Editorial Introduction to the Third Issue

Linguistics had a strong presence at the TEI\u2019s beginnings, being represented by names as significant as those of Nancy Ide, Donald E. Walker, and Antonio Zampolli. Linguistics was mentioned explicitly in the names of two of its three founding organizations: Association for Computers and the Humanities, Association for Computational Linguistics, and Association for Literary and Linguistic Computing. It was the main focus of one of the four initial committees (http://www.tei-c.org/\u200bVault/\u200bAB/\u200babj01.txt) and, within several years of the inception of the work on the TEI Guidelines, the British National Corpus clearly demonstrated the TEI\u2019s usefulness for encoding language resources

Complex Entity Management Through EATS:The Case of the Gascon Rolls Project

Managing entities like people, places and subjects across a large corpus of textual documents can be complicated. While the TEI guidelines offer a sound basis for the encoding of a great variety of textual material, there does not seem to be a general agreement on how to manage information that goes beyond the text, like entity information and relationships between entities

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.c282y homozygous patients.

Background. Most patients with Hereditary Hemochromatosis are homozygous for the p.C282Y mutation in the HFE gene in Caucasian population. Penetrance and expression of Hemochromatosis largely differ in p.C282Y homozygous cases. Besides environmental factors, genetic factors might be implicated. Design and Methods. In the present study, we analysed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 Italian p.C282Y homozygous cases. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results. We found a series of 17 genetic variants located in different genes with possible additive effect on the studied outcomes. In order to evaluate if the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction can be achieved adding genetic information to clinical data. Among the selected polymorphisms, a significant association between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation was observed. This variant belongs to the same haplotype block which contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. Luciferase assay indicates that rs3806562 has not a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-HH, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of HH phenotype