Prevalence of HFE mutations in upper Northern Italy: study of 1132 unrelated blood donors

BACKGROUND: In the Italian general population, prevalence of C282Y is lower than in Northern European countries. We hypothesised a higher prevalence of C282Y in Northern than in Central and Southern Italy. We previously identified a nonsense mutation (W169X) in haemochromatosis probands originating from a Northern Italian region (Brianza). AIM: To define the prevalence of HFE mutations in that region. Subjects and methods. A total of 1132 unrelated blood donors from the Blood Banks of Monza and Merate were investigated for C282Y, H63D, S65C and W169X mutations by PCR-restriction assays. A total of 300 were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. RESULTS: Two C282Y homozygotes, eight C282Y/H63D compound heterozygotes, 27 H63D homozygotes and one W169X heterozygote were found. The allele frequencies of C282Y, H63D, S65C, and W169X were 3.2, 13.4, 1.3, and 0.04%, respectively. CONCLUSIONS: Our results confirm the existence of a decreasing frequency of C282Y allele from upper to lower Northern Italy. This difference is probably related to the larger Celtic component of upper Northern Italian populations in which screening studies for haemochromatosis may even be cost effective. W169X, due to its severity, should be looked for in all haemochromatosis patients of Northern ancestry with an incomplete HFE genotype.     

Analysis of HFE and TFR2 mutations in selected blood donors with biochemical parameters of iron overload

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis is a recessive condition characterized by iron accumulation in several organs, followed by organ damage and failure. The disorder is prevalently due to C282Y and H63D mutations in the HFE gene, but additional HFE and TFR2 mutations have been reported. Early iron overload may be assessed by biochemical parameters such as increased transferrin saturation and serum ferritin. DESIGN AND METHODS: Taking advantage of the collection of 178 DNA samples selected for increased transferrin saturation (>50% in males and >45% in females) from a previous large scale screening of Italian blood donors, we simultaneously assessed the presence of 14 hemochromatosis-associated molecular defects (11 of HFE and 3 of TFR2) by a reverse hybridization-based strip assay. RESULTS: In the series studied the overall C282Y allele frequency was 9% and that of the H63D and S65C was 22.2% and 1.4%, respectively. One rare HFE allele (E168Q), but no TFR2 mutation was detected. When checked at a second examination, transferrin saturation was significantly higher in C282Y homozygotes, H63D/ C282Y compound heterozygotes and H63D homozygotes as compared to wild-type subjects (p<0.05). INTERPRETATION AND CONCLUSIONS: Our results confirm previous findings on C282Y and H63D mutations in Italy, show that the C282Y allele frequency is enriched in samples selected for altered iron parameters, and that a few rare genotypes are present in Northern Italy. None of the known TFR2 mutations was identified in this series confirming the preliminary indication of their rare occurrence. Subjects with hemochromatosis-associated genotypes show a persistently higher mean transferrin saturation than do those with wild type genotypes.     

Two novel nonsense mutations of HFE gene in five unrelated italian patients with hemochromatosis

BACKGROUND & AIMS: Most hemochromatosis patients of Northern European descent are homozygous for the C282Y mutation of HFE gene. In Italy, many patients with iron overload are not homozygous for C282Y, and the presence of other mutations or other genetic determinant has been suggested. METHODS: Five unrelated Italian patients heterozygous for C282Y with the classic hemochromatosis phenotype were studied. The entire coding sequence and the exon-intron boundaries of the HFE gene were analyzed. Chromosome 6p haplotypes were defined in each patient by analysis of D6S265, D6S105, and D6S1281 microsatellites. RESULTS: Two novel nonsense HFE mutations were identified in exon 3 in the C282Y negative chromosome. The first one, a G-to-T transition at codon 168, was detected in 3 probands; the second, a G-to-A transition at codon 169, was detected in the others. CONCLUSIONS: The 2 nonsense mutations in the compound heterozygous state with C282Y result in the classic hemochromatosis phenotype in several unrelated Italian patients. This confirms that hemochromatosis in Italy is not as homogeneous as in northern Europe and suggests that other mutations can exist in C282Y or H63D heterozygotes with iron overload. These findings have practical implications for diagnostic and screening strategies for hemochromatosis.     

Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy

BACKGROUND/AIMS: The actual prevalence of the main hemochromatosis (HFE) mutations in the Italian adult population and their phenotypic expression have not yet been established. This information is key to advocate a mass-screening program. METHODS: Two thousand one hundred adults were tested for the C282Y/H63D HFE gene mutations by an automated genotyping assay as well as transferrin saturation (TS) and serum ferritin levels. RESULTS: No homozygotes for the C282Y mutation were found. Heterozygosity for the C282Y mutation was 3.1%, while heterozygosity and homozygosity for the H63D mutation were 21.5% and 2.5%, respectively. TS was significantly higher in C282Y heterozygotes and H63D homozygotes as compared to wild-type individuals (P < 0.01). Interestingly, of the HFE wild-type subjects 5.9% had a TS value above the 45% threshold. CONCLUSIONS: This study shows that (i) the predicted prevalence for C282Y homozygosity in Italy is 1:3900; (ii) the C282Y/H63D wild-type population has an increased baseline of iron parameters possibly due to genetic factors not linked to the C282Y/H63D mutations; (iii) since in the latter population the actual tissue iron burden cannot be assessed, phenotypic (TS) screening in Italy is not recommended until the true prevalence of all mutations in the HFE gene and in other hemochromatosis genes will be established.     

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

Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results 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.     

Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis

More than 80% of the patients affected by hereditary hemochromatosis, a common inherited iron disorder, are homozygotes for the 845G --> A (C282Y) mutation of the HFE gene. However, depending on the population, 10-20% of hereditary hemochromatosis can be linked either to other HFE genotypes, particularly the compound heterozygous state for C282Y and the 187 C --> G (H63D) mutation, or to mutations of new other genes. Recently, Camaschella et al. (Nat. Genet. 25, 14-15, 2000) identified a stop mutation (exon 6 nt 750 C --> T, Y250X) on the transferrin receptor-2 (TFR2) gene in two unrelated Sicilian families with hereditary hemochromatosis. The TFR2 gene is a transferrin receptor gene homologue that seems to be involved in iron metabolism. Moreover, one of the patients described by Camaschella et al. was a H63D homozygote. H63D homozygosity can be associated with various phenotypes from asymptomatic subjects to patients with a typical form of hereditary hemochromatosis. Thus, the Y250X mutation could be the molecular defect responsible for hereditary hemochromatosis in subjects with atypical HFE genotypes. We have searched for the Y250X mutation in 63 unrelated French subjects. Forty-three had a diagnosis of hereditary hemochromatosis based on classical criteria. This group included 12 H63D homozygotes, 3 C282Y heterozygotes, and 3 patients with none of the two most prevalent HFE mutants. These 18 patients had no other HFE sequence change and were subsequently subjected to DNA sequencing of the 15 last exons and flanking sequences of the TFR2 gene. The 25 remaining hereditary hemochromatosis patients who were tested for the Y250X mutant were compound heterozygotes for the C282Y and H63D mutations. Finally, we also tested for this TFR2 mutation 20 H63D homozygotes with milder manifestations of iron overload and no acquired cause of iron overload. None of the 63 tested subjects had the Y250X mutation. Concurrently, none of the 18 hereditary hemochromatosis patients who had their TFR2 gene sequenced had any deleterious mutation. Thus, TFR2 mutations are not responsible for hemochromatosis in non-C282Y homozygous patients of our area.     

Frequency of the HFE gene mutations in five Italian populations

Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), appear to be associated with milder forms of hereditary hemochromatosis. There is a high prevalence of the C282Y mutation in northern European populations, whereas in those of the Mediterranean basin the prevalence seems low and almost absent in Far East countries. This mutation seems usually to occur on the ancestral haplotype 7.1. Accordingly, a Celtic origin of this mutation has been suggested. The aim of this study was to determine the frequency of HFE gene mutations in five geographic regions in Italy. Samples were tested for C282Y, H63D, and S65C mutations of the HFE gene according to methods of each laboratory and the results were standardized with the exchange of typed samples between the different laboratories. In addition, C282Y-positive DNA samples were typed for D6S105 allele 8 and HLA-A3 by ARMS-PCR. We have found that the allele frequency of the C282Y mutation decreases from northeast Italy (Friuli, 6%) to northwest Italy (Piedmont, 4.8%) and to central Italy (Emilia-Romagna, 1.7%). However, this mutation is lacking in the two regions of the Mediterranean basin's center (Sicily and Sardinia). Accordingly, a significant difference in the frequency of the mutation was observed between these Italian regions (P = 0.07 x 10(-3)). In contrast, no difference was observed in allele frequency of H63D in the five Italian regions. Finally, as regards the S65C mutation a very low frequency was observed in Friuli, Emilia-Romagna, and Sardinia, whereas in Sicily and Piedmont we have not found this mutation. In conclusion, these data are consistent with the hypothesis that the C282Y mutation occurred in Caucasian populations of Celtic origin, whereas the H63D mutation is more ancient as demonstrated by the ubiquitous distribution.     

C282Y and H63D mutations in the HFE gene have no effect on iron overload disorders in Japan

OBJECTIVE: The gene responsible for hereditary hemochromatosis close to the human leukocyte antigen A locus was previously identified and designated as HFE. This study was performed to evaluate the clinical significance of two mutations, C282Y and H63D of HFE, in Japanese patients with hepatic iron overload. PATIENTS AND METHODS: We examined C282Y and H63D in 11 patients with primary hemochromatosis, 94 patients with chronic hepatitis C, 54 patients with miscellaneous liver diseases, and 151 healthy volunteers. The HFE gene region of DNA samples extracted from peripheral leukocytes was amplified by polymerase chain reaction. Restriction enzyme analysis was performed using SnaBI for C282Y and BclI for H63D. Direct sequence analysis was then performed when products suggested the presence of a mutation. RESULTS: All the subjects studied were free from C282Y. None of the patients with hemochromatosis had H63D. One patient with chronic hepatitis C was homozygous, and 4 patients were heterozygous for H63D. Two patients with alcoholic liver disease were heterozygous for H63D. The prevalence of chromosomes with H63D was 6/188 (3.2%) in patients with chronic hepatitis C, 2/108 (1.9%) in patients with miscellaneous liver diseases, and 8/302 (2.6%) in healthy volunteers. These differences were not significant. CONCLUSION: Our results suggested that neither C282Y nor H63D in HFE affect Japanese patients with hemochromatosis or chronic hepatitis C.     

HFE genotype in patients with hemochromatosis and other liver diseases.

BACKGROUND: Hereditary hemochromatosis is a common inherited disorder of iron metabolism. The gene HFE, which contains two missense mutations (C282Y and H63D), was recently identified. OBJECTIVE: To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of HFE mutations in a group of patients with liver disease. DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENTS: 66 patients with hereditary hemochromatosis and 132 referred patients with other liver diseases. MEASUREMENTS: At initial diagnosis, fasting transferrin saturation, ferritin level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by using genomic DNA samples. RESULTS: Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygotes, 2 (3%) were compound heterozygotes, 1 (1.5%) was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations. Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) were H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were negative for both mutations. All 66 C282Y homozygotes had an elevated hepatic iron concentration, and 65 of the 66 patients (98%) had a transferrin saturation of at least 45%. Ten of the 66 patients (15% [95% CI, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year; hemochromatosis was not suspected in 6 of the 10 patients before genotyping. Cirrhosis or substantial hepatic fibrosis was not seen in any (0% [CI, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. CONCLUSIONS: All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.     

Prevalence of hemochromatosis gene (HFE) mutations in Greece

The frequencies of the hereditary hemochromatosis gene (HFE) mutations C282Y and H63D vary between different populations. There are a limited number of reports regarding the frequency of these mutations in populations of southeastern Europe. Two hundred and sixty-four adult individuals of Greek origin were examined for the C282Y and H63D mutations to determine the allele and genotype frequencies. The HFE gene region of DNA samples extracted from peripheral leukocytes was amplified by the polymerase chain reaction. Restriction enzyme analysis was performed using RSAI for C282Y and MBOI for H63D. None of the 264 individuals carried the mutation C282Y. Forty-three individuals (16.2%) were heterozygous carriers of the H63D allele and 2 were homozygous for this mutation (0.75%). The overall H63D allele prevalence is thus estimated at 8.9%. HFE mutation frequencies were low in the population studied and this may explain, in part, the relative rarity of clinical cases of hereditary hemochromatosis in Greece.     

High prevalence of a screening-detected,HFE-unrelated,mild idiopathic iron overload in Northern Italy

BACKGROUND AND OBJECTIVES: In Italy, typical HFE mutations account for only 64% of the cases with overt hereditary hemochromatosis (HH), and a common HFE-unrelated disease was hypothesized. DESIGN AND METHODS: One thousand and fifty potential blood donors were screened by iron tests, C282Y and H63D HFE mutation analysis in a region in North Italy. Subjects with repeated fasting transferrin saturation of 45% or more and no secondary iron overload were defined as probands with idiopathic iron overload. To assess the inheritance of iron overload, relatives of probands were screened. RESULTS: The overall frequency of probands with idiopathic iron overload was 3.43% (95% confidence interval, 2.32 to 4.52). Of these, 8.4% had genotypes associated with HH (compound heterozygous for H63D/C282Y or homozygous for H63D HFE mutations), and 91.6% had atypical genotypes: 47.2% were heterozygous for C282Y or H63D HFE mutations, and 44.4% had wild type/wild type genotype. A family history of iron overload was proven in 33.3% of probands with atypical genotypes (1.04% of the overall population). Pedigree analysis excluded linkage of heterozygous HFE mutations with iron overload (cumulative lod score 2.41) and documented a recessive non-HLA-linked locus accounting for iron overload in wild type/wild type genotypes. None of the probands had clinical signs of iron accumulation; in males, serum ferritin positively correlated with age (r=0.63, p<0.01), and the regression model predicted a serum ferritin of 700 ng/mL at the age of 58. INTERPRETATION AND CONCLUSIONS: In Northern Italy an HFE-unrelated, mild idiopathic iron overload is highly prevalent. A recessive locus accounts for iron overload in at least 1.04% of the overall population.     

Hemochromatosis (HFE) gene mutations and hepatitis C virus infection as risk factors for porphyria cutanea tarda in Hungarian patients.

AIM: It is not clear whether the mutations in hemochromatosis (HFE) gene and hepatitis C virus (HCV) infection act independently in the pathogenesis of porphyria cutanea tarda (PCT). The prevalence of both risk factors varies greatly in different parts of the world. PCT patients from Hungary were evaluated to assess both factors. METHODS: The prevalence of C282Y and H63D mutations in the HFE gene was determined in 50 PCT patients and compared with the reported control frequencies. Furthermore, the presence of HCV infection was determined and related to the patients' HFE gene status. RESULTS: The C282Y mutation was found in 8/50 cases (three homozygotes and five heterozygotes), with an 11% allele frequency (vs. 3.8% control) (P<0.05). Seventeen patients were heterozygous, one was homozygous for the H63D mutation, allele frequency 19%, which did not differ significantly from the reported control prevalence of 12.3%. Twenty-two patients (44%) were HCV-RNA positive; six out of them were heterozygous for H63D mutation, one only for the C282Y mutation and one was compound heterozygous for both mutations. CONCLUSION: HCV infection and HFE C282Y mutation may probably be independent predisposing factors for development of PCT in Hungarian patients.     

C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease.

OBJECTIVE: To test the hypothesis that the heterozygous state for HFE gene mutations involved in the pathogenesis of hemochromatosis, that may induce an increase of hepatic iron content, may aggravate the liver damage induced by prolonged and excessive use of ethanol. PATIENTS AND METHODS: C282Y and H63D mutations of HFE gene were identified through polymerase chain reaction (PCR) on leukocyte DNA, in 125 consecutive patients diagnosed of advanced alcoholic liver disease (109 men, mean age 54 years, SD 11) and 181 healthy controls. All subjects were white Spaniards. RESULTS (CASES/CONTROLS): 1. Genotype distribution: a) mutation C282Y: no homozygotes, 10/23 heterozygotes, 115/158 normal (p = 0.60); b) mutation H63D: 9/5 homozygotes, 46/52 heterozygotes, 70/124 normal (Chi square 6.51, p = 0.039). 2. Allele frequencies: a) mutation C282Y: 240/339 normal, 10/23 mutated (p = 0.21); b) mutation H63D: 186/300 normal, 64/62 mutated (odds ratio 1.66, 95% CI 1.10-2.52, p = 0.01). CONCLUSIONS: Our results suggest that H63D mutation of the HFE gene, but not the C282Y mutation, is associated to the risk of developing advanced liver alcoholic disease.     

A Chinese patient with non-HFE-linked iron overload.

The gene for hemochromatosis (HFE) was recently identified and contains two missense mutations: C282Y and H63D. The C282Y mutation is found homozygous in approximately 85% to 90% of patients of Northern European ancestry with hereditary hemochromatosis. There are no previous reports with results of genetic testing in Chinese patients with regard to iron overload. In this case report, we describe a Chinese woman with marked hepatic iron overload that was nonfamilial, with unusual biopsy findings, in whom neither the C282Y nor the H63D mutations in HFE were found.     

Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload

Most cases of hemochromatosis are associated with mutations of the HFE gene on Ch6p. In southern Italy and central Alabama, the percentages of patients with hemochromatosis who have "atypical" HFE genotypes (defined as lack of C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity) are relatively great. A mutation of the transferrin receptor-2 gene (TFR2; exon 6, nt 750 C --> G, replaces TAC with stop signal TAG; Y250X) on Ch7q22 was recently identified in two Sicilian families with HFE mutation-negative hemochromatosis. We wanted to estimate the frequency of this mutation in persons from central Alabama. We evaluated Caucasian hemochromatosis probands with atypical HFE genotypes and African Americans with primary iron overload. We also studied control Caucasians, including persons of southern Italian/Sicilian heritage, and control African Americans. Analysis of genomic DNA was performed using a PCR-sequence-specific priming assay and positive control specimens from Sicilian hemochromatosis subjects heterozygous and homozygous for Y250X. Among Alabama subjects, this allele was not detected in 113 Caucasians, including 21 hemochromatosis probands with atypical HFE genotypes and 92 normal control subjects (including 27 of southern Italian/Sicilian descent). In African Americans, Y250X was not detected in 20 index cases with primary iron overload or in 274 unrelated control subjects. We conclude that Y250X is uncommon in Caucasians with hemochromatosis associated with atypical HFE genotypes, in African Americans with primary iron overload, and in the general Caucasian and African American population subgroups in central Alabama.     

HFE genotype and parameters of iron metabolism in German first-time blood donors - evidence for an increased transferrin saturation in C282Y heterozygotes

BACKGROUND: Hemochromatosis is usually inherited in an autosomal recessive mode and associated with missense mutations in the hemochromatosis gene (HFE), an HLA class 1 related gene. However the degree of penetrance is presently matter of debate. METHODS: To elucidate the frequency of HFE mutations in a German population and the relationship between genotype and phenotype, we determined the HFE C282Y and H63D genotypes in 500 first-time blood donors using an allele-specific ligase chain reaction (LCR). Ferritin and transferrin saturation (TS) of all donors found to have at least one mutation were compared to gender- and age-matched controls. RESULTS: The C282Y allele frequency was 46 in 1000 chromosomes (4.6 %). The allele frequency of H63D was 108 in 1000 (10.8 %) chromosomes. We found three persons homozygous for H63D, nine compound heterozygotes and none homozygous for C282Y. TS was elevated in C282Y heterozygotes (p = 0.002) and C282Y/H63D compound heterozygotes (p = 0.04) compared to wild-type controls. Serum ferritin tended to be elevated in compound heterozygotes (p = 0.053). Mean corpuscular volume (MCV) and hemoglobin (MCH) were not different from controls. CONCLUSION: The frequency of HFE mutations in the tested population was comparable to those of other northern European populations. The elevated TS in subjects carrying a single copy of the C282Y mutation suggests that C282Y heterozygosity is associated with an increased intestinal iron absorption and might therefore offer a selection advantage in conditions of iron depletion.     

Population screening for hemochromatosis: a study in 5370 Spanish blood donors

BACKGROUND/AIMS: Hereditary hemochromatosis is associated with homozygosity for C282Y mutation in the HFE gene, elevated serum transferrin saturation and excess iron deposits throughout the body. We conducted a population-based study in Spain to asses the prevalence of the HFE mutations and their effect on iron parameters. METHODS: We screened 5370 blood donors for the C282Y and H63D HFE mutations by allele-specific polymerase chain reaction. Serum iron, serum ferritin and transferrin saturation were also measured. RESULTS: We have found eight (five men and three women) blood donors who are C282Y homozygotes (0.15%) and 74 C282Y/H63D compound heterozygotes (1.38%). Four out of the eight C282Y homozygotes, all men, had high serum ferritin and transferrin saturation values. No woman was detected with both iron parameters increased. Only one of the 74 C282Y/H63D compound heterozygotes showed elevated serum ferritin and transferrin saturation values (penetrance 1.35%). Serum ferritin and transferrin saturation were significantly higher in C282Y homozygous men as compared with the rest of the genotypes. CONCLUSIONS: The C282Y/C282Y genotype frequency in Spain is 1 in 1004. The C282Y/C282Y genotype is clearly associated with an increase in iron parameters. Biochemical expression of the disease was found in 80% of the C282Y/C282Y men.     

Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients

Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non-HFE dependent mechanism of primary iron overload dominates in Russian population.