title: Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.
abstract: OBJECTIVE
  Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes.
  
  
  METHODS
  We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres.
  
  
  RESULTS
  One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001).
  
  
  CONCLUSIONS
  This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely.
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université de Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France; CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France. Electronic address: Marie.detayrac@univ-rennes1.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: de Tayrac
authors.affiliation: Inserm, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.affiliation: CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Jouanolle
authors.affiliation: Inserm, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Coppin
authors.affiliation: Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France; Etablissement Français du Sang - Bretagne, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: le Gac
authors.affiliation: University of Milano-Bicocca, Department of Health Sciences, Centre for Iron Disorders, S. Gerardo Hospital, Monza, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Piperno
authors.affiliation: Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France; Etablissement Français du Sang - Bretagne, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: University of Milano-Bicocca, Department of Health Sciences, Centre for Iron Disorders, S. Gerardo Hospital, Monza, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pelucchi
authors.affiliation: Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France; Etablissement Français du Sang - Bretagne, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Scotet
authors.affiliation: CHU de Rennes, Liver Unit and French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, Rennes, France; INSERM, UMR 991, Equipe Fer et Foie, Rennes, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Bardou-Jacquet
authors.affiliation: CHU Rennes, Service de Biochimie, Rennes, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Ropert
authors.affiliation: CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France; Plate-forme Génomique Santé Biogenouest, Biosit, Rennes, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Bouvet
authors.affiliation: Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université de Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France; CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.affiliation: CHU de Rennes, Liver Unit and French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, Rennes, France; INSERM, UMR 991, Equipe Fer et Foie, Rennes, France; INSERM, Centre of Clinical Investigation 0203, CHU de Rennes, Rennes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Deugnier
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D005602:France; D060045:Genes, Modifier; D055106:Genome-Wide Association Study; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D014168:Transferrin / Q000235:genetics* / Q000378:metabolism
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D007501:Iron
keywords: GWAS; HFE-hemochromatosis; Transferrin