Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal)

Abstract

Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that result from mutations in the HFE gene. Almost all patients with Hereditary Hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to Hereditary Hemochromatosis. One hundred and fifty four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y and S65C, by Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33% and 1% for H63D, C282Y and S65C, respectively. Accordingly to our estimates, both genotypes associated to Hereditary Hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population.Response to Reviewers: . In this revised version we included the four references recommended by reviewers: Reviewer #1: The introduction to a large extent repeats well known facts about HFE hemochromatosis and should be shortened at least by 3/4 page. Authors: we shortened the introduction.Reviewer #1: There are several spelling errors. Authors: We made a spelling revision.Reviewer #1: In recent years, Annals of Hematology has published many papers on HFE haemochromatosis, among others by the authors Remacha AF, Pedersen P, Milman N, ect. I strongly suggest the authors make a screening on PubMed to identify these AOH papers and include them in the reference list. Authors: We added a paper from Remacha published in Annals of Hematology.

Evaluation of a High Throughput Method for the Detection of Mutations Associated with Thrombosis and Hereditary Hemochromatosis in Brazilian Blood Donors

“…These data suggest that the prevalence of FV Leiden and FII G20210A, associated with thrombophilic events, is lower in Brazilian blood donors than that reported in previous studies concerning blood donors of other countries [ 38 – 40 ]. For HFE mutations (C282Y, H63D and S65C), associated with an iron overload in homozygous or compound genotypes characteristic of HH, we observed a higher frequency (20.3% heterozygous and 1.6% homozygous) of H63D, consistent with previous studies reported internationally [ 21 ] and in a Brazilian population of blood donors from São Paulo [ 41 ]. We did not observe the presence of a homozygous genotype for either C282Y or S65C among the studied population, and the heterozygous compound genotype C282Y/H63D was observed in only one sample.…”

“…Thus, patients with HH might benefit from frequent blood donation [ 18 , 19 ]. The most common genetic variants associated with HH are C282Y (rs1800562), H63D (rs1799945) and S65C (rs1800730) [ 20 , 21 ]…”

Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

“…In general, the frequency of c.845A [p.282Tyr] in Europe shows a decreasing north-south cline, with values ranging from 5 to 10% in north Europe, and from 1 to 5% in central and south Europe [ 33 ]. The frequency of the c.845A mutation in São Miguel was similar to the one reported in north/central mainland Portugal [ 28 ], but significantly higher than in the Azores Terceira Island [ 27 ], south mainland Portugal [ 28 ], and Madeira Island [ 34 ]. This data validates previous results where mainland Portuguese, especially from north/center, were the main contributors to the Azorean settlement.…”

An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population

“…Three HFE mutations have now been identified: C282Y, H63D and S65C. [9][10][11] C282Y, a G-to-A transition at nucleotide 845 (G845A) in exon 4 of the HFE gene, results in a cysteine-to-tyrosine substitution at position 282. H63D is a C-to-G transition at nucleotide 187 (C187G) in exon 2, causing a histidineto-aspartic acid substitution at amino acid 63.…”