title: Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes?
abstract: Most hereditary haemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, the phenotypic expression and clinical aggressiveness of the disease differs considerably from patient to patient. The main objective of this work was to study the role of variants in the SLC40A1 gene in the severity of iron overload and his clinical consequences in 100 Spanish probands homozygous for the C282Y mutation of the HFE gene. We performed automated sequencing of the coding regions, including intron-exon junctions of the SLC40A1 gene. We studied the association between polymorphisms in the SLC40A1 gene and median values of iron removed, taking into account statistical corrections for multiple comparisons. No pathogenic mutations in the SLC40A1 were detected. Five known single nucleotide polymorphisms (SNPs) were identified, and two of them were associated with phenotypic characteristics. IVS1-24 C>G was associated with the amount of iron removed and presence of liver disease: Of the 83 patients finally studied for this SNP, the amount of iron removed was above the median in 36 of 56 (64.3%) for C/C, in nine of 23(39.1%) for C/G and in zero of four (0%) for G/G patients (P=0.01). Liver damage was observed in 34 of 56 patients (60.7%) for C/C, in eight of 23 (34.8%) for C/G and in zero of four (0%) for G/G (P=0.01). Both associations remained significant at multivariate analysis (P=0.011 and P=0.023, respectively). IVS1-24 C>G on the ferroportin gene seems to be a genetic modifier for clinical aggressiveness of HFE1 haemochromatosis.
authors.affiliation: Servei Hematologia, ALTHAIA, Flor de Lis 33, 08242 Manresa, Spain. aaltesh@althaia.cat
authors.forename: Albert
authors.initials: A
authors.lastname: Altès
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bach
authors.forename: Angels
authors.initials: A
authors.lastname: Ruiz
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve
authors.forename: Angel F
authors.initials: AF
authors.lastname: Remacha
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Sardà
authors.forename: Jordi
authors.initials: J
authors.lastname: Felez
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
mesh_terms: D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013030:Spain / Q000453:epidemiology; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D000098742:Ferroportin; D007501:Iron