Marie de Tayrac1, Marie-Paule Roth2, Anne-Marie Jouanolle3, Hélène Coppin2, Gérald le Gac4, Alberto Piperno5, Claude Férec4, Sara Pelucchi5, Virginie Scotet4, Edouard Bardou-Jacquet6, Martine Ropert7, Régis Bouvet8, Emmanuelle Génin9, Jean Mosser10, Yves Deugnier11. 1. 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. 2. Inserm, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France. 3. CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France. 4. Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France; Etablissement Français du Sang - Bretagne, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France. 5. University of Milano-Bicocca, Department of Health Sciences, Centre for Iron Disorders, S. Gerardo Hospital, Monza, Italy. 6. 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. 7. CHU Rennes, Service de Biochimie, Rennes, France. 8. CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France; Plate-forme Génomique Santé Biogenouest, Biosit, Rennes, France. 9. Inserm, UMR1078, Université de Brest, SFR ScInBioS, CHRU, Brest, France. 10. 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. 11. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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: Christine E McLaren; Mary J Emond; V Nathan Subramaniam; Pradyumna D Phatak; James C Barton; Paul C Adams; Justin B Goh; Cameron J McDonald; Lawrie W Powell; Lyle C Gurrin; Katrina J Allen; Deborah A Nickerson; Tin Louie; Grant A Ramm; Gregory J Anderson; Gordon D McLaren Journal: Hepatology Date: 2015-03-18 Impact factor: 17.425
Authors: Karolina Skonieczna-Żydecka; Dominika Jamioł-Milc; Krzysztof Borecki; Ewa Stachowska; Paulina Zabielska; Magdalena Kamińska; Beata Karakiewicz Journal: Int J Environ Res Public Health Date: 2020-01-08 Impact factor: 3.390