HFE gene mutations in Brazilian thalassemic patients

Abstract

Hereditary hemochromatosis is a disorder of iron metabolism characterized by increased iron intake and progressive storage and is related to mutations in the HFE gene. Interactions between thalassemia and hemochromatosis may further increase iron overload. The ethnic background of the Brazilian population is heterogeneous and studies analyzing the simultaneous presence of HFE and thalassemia-related mutations have not been carried out. The aim of this study was to evaluate the prevalence of the H63D, S65C and C282Y mutations in the HFE gene among 102 individuals with alpha-thalassemia and 168 beta-thalassemia heterozygotes and to compare them with 173 control individuals without hemoglobinopathies. The allelic frequencies found in these three groups were 0.98, 2.38, and 0.29% for the C282Y mutation, 13.72, 13.70, and 9.54% for the H63D mutation, and 0, 0.60, and 0.87% for the S65C mutation, respectively. The chi-square test for multiple independent individuals indicated a significant difference among groups for the C282Y mutation, which was shown to be significant between the beta-thalassemia heterozygote and the control group by the Fisher exact test (P value = 0.009). The higher frequency of inheritance of the C282Y mutation in the HFE gene among betathalassemic patients may contribute to worsen the clinical picture of these individuals. In view of the characteristics of the Brazilian population, the present results emphasize the need to screen for HFE mutations in beta-thalassemia carriers.

Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis

“…The frequencies of C282Y and H63D mutations found in this study are greater than those reported for the general Brazilian population, 1,8,11,13,15,[17][18][19][20][21][22] but are smaller than the genotypic frequencies among patients with HH. 2,3,4 It is unquestionable that C282Y is the main mutation responsible for HH in all studied populations, as the majority of published reports worldwide cite its prevalence in more than 80% of individuals with clinical manifestations of HH, 1,[4][5][6]12,15,17,23 thus several other diagnostic guides are based on the result of C282Y mutation genic testing.…”

“…2,6,7,15 It is not different for the Brazilian population, as in the paper by Bittencourt et al, 1 homozygous individuals for this mutation present an earlier onset for pathological aspects compared to heterozygous individuals with an onset at an earlier age than the wild allele, 282CC. The allele frequency of 282Y in the present study was 7.9%; a rate considerably greater than other Brazilian studies (2% in general population), 11 indicating a relationship between this mutation and clinical suspicion of HH.…”

“…3 In the present study, the allele frequency of H63D was 0.196 and in accordance with the majority of the other world populations, in which the frequency ranges from 0.1 to 0.2; it is important to note that Spain and Portugal, countries that greatly influenced colonization of Brazil, present frequencies greater than 0.2 in their general populations. 4,11 The frequency of 0.03 for C282Y/H63D compound heterozygotes is in accordance with data already reported for the American population, 14 but it does not concur with Brazilian data, 1,11,15,21,22 probably because of the quantitative difference of the studied populations and because of the fact that this paper assessed individuals with clinical suspicion of HH. Thus, this frequency values the role of the C282Y/ H63D genotype in the development of HH.…”

“…The frequencies of HFE gene mutations encountered in Brazilian publications endorse the variability of the results found, as well as the inherent variables of each experiment (sample size, geographic inclusion of the population). 1,8,11,13,15,[19][20][21][22] Brazil is constituted by one of the most heterogeneous world populations, which reflects in the genetic parameters of different hereditary diseases, providing a genic diversity in the population and, also, the necessity of well conducted studies which assist in clarifying the enigmas of these diseases. With this in mind, the present paper shows the frequencies of C282Y and H63D mutations, according to gender and age aiming at helping the selection of diagnostic examinations, in respect to the populational profile of studied individuals, which could act as an important clinical benefit for health in Brazil.…”

“…3,10 Generally, this is associated to mild forms of HH. 1,4,11 A minority of C282Y/ H63D heterozygotes (1 to 2% on average) develop clinical symptoms of hemochromatosis; 2,9 Beutler et al 14 reported that, generally, Caucasians with clinical evidence of HH are either homozygous for C282Y or compound heterozygous for C282Y/H63D.…”