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.
CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.c282y homozygous patients.
BUSTI, Fabiana;GIRELLI, Domenico;
2012-01-01
Abstract
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.
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