title: CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients.
abstract: BACKGROUND
  Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors.
  
  
  METHODS
  In the present study, we analyzed 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 p.C282Y homozygous Italians. 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 effects on the studied outcomes. In order to evaluate whether 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 could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that 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. A luciferase assay indicated that rs3806562 does not have 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-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.
authors: Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy.
authors: Sara
authors: S
authors: Pelucchi
authors: Raffaella
authors: R
authors: Mariani
authors: Stefano
authors: S
authors: Calza
authors: Anna Ludovica
authors: AL
authors: Fracanzani
authors: Giulia Litta
authors: GL
authors: Modignani
authors: Francesca
authors: F
authors: Bertola
authors: Fabiana
authors: F
authors: Busti
authors: Paola
authors: P
authors: Trombini
authors: Mirella
authors: M
authors: Fraquelli
authors: Gian Luca
authors: GL
authors: Forni
authors: Domenico
authors: D
authors: Girelli
authors: Silvia
authors: S
authors: Fargion
authors: Claudia
authors: C
authors: Specchia
authors: Alberto
authors: A
authors: Piperno
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D003573:Cytochrome b Group / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000097:blood / Q000209:etiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D014168:Transferrin / Q000378:metabolism; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D003573:Cytochrome b Group; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D010088:Oxidoreductases; C422926:CYBRD1 protein, human