Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis

Marie de Tayrac (1, 2, 3) , Marie-Paule Roth (4) , Anne-Marie Jouanolle (3) , Hélène Coppin (4) , Gérald Le Gac (5) , Alberto Piperno (6) , Claude Férec (5) , Sara Pelucchi (6) , Virginie Scotet (5) , Edouard Bardou-Jacquet (7) , Martine Ropert (8) , Régis Bouvet (3, 1) , Emmanuelle Génin (5) , Jean Mosser (3, 1, 2) , Yves Deugnier (9, 7)

1 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
2 IGDR - Institut de Génétique et Développement de Rennes
3 Service de Génétique moléculaire et Génomique [CHU Rennes]
4 CPTP - Centre de Physiopathologie Toulouse Purpan
5 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
6 Department of Health Sciences, Centre for Iron Disorders
7 Foie, métabolismes et cancer
8 Laboratoire de biochimie générale
9 CIC - Centre d'Investigation Clinique [Rennes]

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.

Mots clés: GWAS; HFE-hemochromatosis; Transferrin

Domaines: Hépatologie et Gastroentérologie

Marie de Tayrac, Marie-Paule Roth, Anne-Marie Jouanolle, Hélène Coppin, Gérald Le Gac, et al.. Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. Journal of Hepatology, 2015, 62 (3), pp.664-672. ⟨10.1016/j.jhep.2014.10.017⟩. ⟨hal-01091987⟩