Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Abstract

The hemochromatosis gene, HFE, is located on chromosome 6 in close proximity to the HLA-A locus. Most Caucasian patients with hereditary hemochromatosis (HH) are homozygous for HLA-A3 and for the C282Y mutation of the HFE gene, while a minority are compound heterozygotes for C282Y and H63D. The prevalence of these mutations in non-Caucasian patients with HH is lower than expected. The objective of the present study was to evaluate the frequencies of HLA-A antigens and the C282Y and H63D mutations of the HFE gene in Brazilian patients with HH and to compare clinical and laboratory profiles of C282Y-positive and -negative patients with HH. The frequencies of HLA-A and C282Y and H63D mutations were determined by PCR-based methods in 15 male patients (median age 44 (20-72) years) with HH. Eight patients (53%) were homozygous and one (7%) was heterozygous for the C282Y mutation. None had compound heterozygosity for C282Y and H63D mutations. All but three C282Y homozygotes were positive for HLA-A3 and three other patients without C282Y were shown to be either heterozygous (N = 2) or homozygous (N = 1) for HLA-A3. Patients homozygous for the C282Y mutation had higher ferritin levels and lower age at onset, but the difference was not significant. The presence of C282Y homozygosity in roughly half of the Brazilian patients with HH, together with the findings of HLA-A homozygosity in C282Y-negative subjects, suggest that other mutations in the HFE gene or in other genes involved in iron homeostasis might also be linked to HH in Brazil.

Estudo das mutações C282Y, H63D e S65C do gene HFE em doentes brasileiros com sobrecarga de ferro

“…A freqüência de doentes brasileiros com sobrecarga de ferro sem mutação do gene HFE em nosso estudo é menor que a encontrada em dois estudos brasileiros, 21,47 provavelmente devido ao número reduzido de casos nestes estudos. Com relação aos estudos estrangeiros, esta freqüência encontra-se mais próxima da observada em doentes do sul da Europa, sobretudo dos italianos, que a observada em doentes norte-americanos.…”

Frequency of the S65C mutation in the hemochromatosis gene in Brazil

“…This iron systemic overload can be genetically transmitted, which is then known as hereditary hemochromatosis (HH), an autosomal recessive disease, with a prevalence of 1:200 to 1:500 individuals in the Caucasian population (Bittencourt et al, 2002;Limdi and Crampton, 2004;Cimburová et al, 2005). Due to menstruation and pregnancy, HH occurs 2 to 4 times more in men than in women (Limdi and Crampton, 2004;US Preventive Services Task Force, 2006).…”

“…The development of HH is often related to the presence of C282Y, H63D and/or S65C mutations in the gene that expresses the protein HFE (Martinelli et al, 2005;Vizzi et al, 2005;Oliveira et al, 2006), whose activity is to regulate the intestinal absorption of iron (Bittencourt et al, 2002). C282Y and H63D mutations are known as the main ones responsible for HH (Guerreiro et al, 2006;Ferreira et al, 2008).…”

Comparison of oxidative stress and the frequency of polymorphisms in the HFE gene between hemoglobin S trait blood donors and sickle cell disease patients

“…Initially, two mutations were identified in the HFE gene in patients with HH: the C282Y allele (in which a tyrosine residue is substituted for a cysteine residue at position 282) and the H63D allele (which results from an exchange of histidine to aspartic acid at amino acid 63), and they correspond to 90% of HH cases (de Souza et al, 2001;Beutler, 2004;Fleming and Britton, 2006;Siah et al, 2006). The reduced number of patients despite the higher frequency of the mutation suggests incomplete penetrance of this gene (Bittencourt et al, 2002;Bonini-Domingos, 2007).…”