Autor(es):
Silva, Bruno 
; Pita, Lina ; Faustino, Paula
Data: 2011
Identificador Persistente: http://hdl.handle.net/10400.18/225
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): Doenças Genéticas; Iron metabolism; Hepcidin; Genetic variants
Descrição
Background: HFE is a major histocompatibility complex class I-like protein that is mutated in Hereditary Hemochromatosis (HH). Despite C282Y being the most common HH-associated HFE mutation, there are other reported mutations, such as H63D, with an uncertain role in the pathogenesis of the disease. Hepcidin is a crucial regulator of systemic iron homeostasis, controlling the absorption of iron by enterocytes and its release by macrophages. Mutations in this gene (HAMP) result in the development of a juvenile type of HH. Also, it has been shown that a polymorphism in HAMP promoter (c.-582A>G) is associated with an increase of serum ferritin levels in beta-thalassemia major patients but not in normal individuals.
Objectives/Methods: We screened for the presence of polymorphisms in the HAMP promoter in 266 individuals with ferritin levels higher than 400ng/mL, being: i) 191 individuals homozygous or heterozygous for the H63D mutation (group 1) and ii) 75 individuals carrying one or more C282Y alleles (HH/CY, HH/YY or HD/CY), (group 2). To assess whether HAMP promoter polymorphisms are changing the hepcidin expression in response to an external stimulus we performed luminescence assays in Huh-7 cell line.
Results: Our data show that, in our sample, the c.-582A>G polymorphism is in linkage with another one, the c.-1010C>T. These polymorphisms were found in a significant higher frequency in group 1 (31.2% of allele G and T, respectively) than in the general population (16.4%; p<0.001). On the contrary, they were found at a slight higher, but not significant, frequency at group 2 (21.3%), comparing with general population (p=0.186).
Functional in vitro studies, using stimulus as holo-transferrin, ferric citrate, IL-6 or GDF15, revealed no differences in the activity of the HAMP promoter in the presence or absence of the polymorphisms. However, further analysis with some other stimuli, such as hypoxia or BMPs must be performed.
Conclusions: c.-582A>G/c.-1010C>T polymorphisms seem to be modulators of iron overload development in individuals carrying the H63D mutation. However, the mechanism subjacent to this observation remains elusive.
