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PubMed2002

HFE mutations and hemochromatosis in Danish patients admitted for HFE genotyping.

Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13.0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation and pathological data were collected from 38 randomly selected C282Y homozygotes, 36 H63D/C282Y compound heterozygotes, 19 H63D heterozygotes, 17 S65C heterozygotes and 144 wild-types. All of the C282Y homozygotes and 28% of the compound heterozygotes were diagnosed as HH patients. There was no evidence of HH in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection is generally adequate. However, the study showed substantial deviation in the selection efficiency among the various hospitals and general practitioners.

Blood Donors↗
PubMedDate not supplied

Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera.

A literature review reports increased erythrocyte indices [hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH), MCH concentration] in subjects with hereditary hemochromatosis (HH). We, therefore, screened 52 consecutive patients with polycythemia vera for 12 HH gene mutations, comparing iron status and red cell parameters between patients positive or negative for HH gene mutations. Our results support the evidence that there is no association between these two conditions.

Adult↗
PubMed2005

Hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a disorder of iron metabolism characterized by a progressive tissue iron overload which leads to an irreversible organ damage if it is not treated timely. The recent developments in the field of molecular medicine have radically changed the physiopathology and the diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for the detection of subjects with HH. Therapeutic phlebotomy is the mainstay of the treatment of HH. If phlebotomy is started before the onset of irreversible organ damages, the life expectancy of these patients is similar to that of normal population.

Ferritins↗
PubMed1999

Hemochromatosis: a "simple" genetic trait.

With the discovery of the causative gene, the disorder stands revealed as America's single most common mendelian disease. Unlike other genetic diseases, it is already curable. Indeed, genetic screening makes it potentially preventable. Yet a finding of disease-related genotype can also lead to stigmatization. Hemochromatosis therefore presents the issues surrounding genetic testing in especially stark form.

Chromosomes, Human, Pair 6↗
PubMed1999

Multicentric origin of hemochromatosis gene (HFE) mutations.

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </=6 Mb, suggesting that this mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </=700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

Alleles↗
PubMed2004

Hemochromatosis mutations in Iranians with hepatitis B virus infection.

In this study, the frequencies of the common hemochromatosis gene mutations were assessed in 75 Iranian subjects with chronic hepatitis B infection. We found that the major C282Y mutation was significantly more frequent in subjects infected with hepatitis B virus (4%) than in 194 control subjects (0%, P=.02; Fisher's exact test).

Adult↗
PubMed1997

Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes.

We applied several types of linkage-disequilibrium calculations to analyze the hereditary hemochromatosis (hh) locus. Twenty-four polymorphic markers in the major histocompatibility complex (MHC) class I region were used to haplotype hh and normal chromosomes. A total of 169 hh and 161 normal chromosomes were analyzed. Disequilibrium values were found to be high over an unusually large region beginning 150 kb centromeric of HLA-A and extending nearly 5 Mb telomeric of it. Recombination in this region was approximately 28% of the expected value. This low level of recombination contributes to the unusually broad region of linkage disequilibrium found with hh. The strongest disequilibrium was found at locus HLA-H (delta = .84) and at locus D6S2239 (delta = .85), a marker approximately 10 kb telomeric to HLA-H. All disequilibrium methods employed in this study found peak disequilibrium at HLA-H or D6S2239. The cys282tyr mutation in HLA-H, a candidate gene for hh, was found in 85% of disease chromosomes. A haplotype phylogeny for hh chromosomes was constructed and suggests that the mutation associated with the most common haplotype occurred relatively recently. The age of the hh mutation was estimated to be approximately 60-70 generations. Disequilibrium was maintained over a greater distance for hh-carrying chromosomes, consistent with a recent mutation for hh. Our data provide a reasonable explanation for previous difficulties in localizing the hh locus and provide an evolutionary history for disease chromosomes.

Evolution, Molecular↗
PubMed2000

Novel method for molecular detection of the two common hereditary hemochromatosis mutations.

We describe a novel molecular screening technique for hereditary hemochromatosis through which HFE genotypes at codon positions 282 and 63 are simultaneously detected. The technique combines multiplex PCR and denaturing high-performance liquid chromatography (DHPLC) and allows automated high-throughput analysis. We used this method to genotype 43 previously characterized anonymous DNA specimens in blinded fashion and found multiplex PCR/DHPLC 100% accurate when compared with PCR/restriction enzyme digestion, yet far more efficient.

Base Sequence↗
PubMed2000

5569G/A polymorphism of the HFE gene: no implications for C282Y genotyping in a hemochromatosis screening study of 65,238 individuals.

In a previous hemochromatosis screening study including a total of 65,238 individuals, 566 persons were genotyped for the C282Y and the H63D mutations. Of these, a total of 433 samples (298 homozygous C282Y and 135 homozygous wild type) were reanalyzed to investigate if the potential presence of the newly described 5569G/A polymorphism had confounded the genotyping results for the C282Y mutation. Genotyping with a polymorphism-insensitive primer pair yielded no samples that altered their genotype. By utilizing the polymorphism-sensitive primer pair and elevated annealing temperatures, 133 samples previously genotyped as heterozygous C282Y were reanalyzed to verify the presence of the polymorphism in the population studied. Out of a total of 266 chromosomes, we found the polymorphism present in 9 chromosomes, yielding an allele frequency of 0.034 in this particular subpopulation. In one of the samples, the polymorphism was present on the same DNA strand as the C282Y mutation. We conclude that in the population studied, the 5569 G/A polymorphism is present, but its presence had no implications for the outcome of the previous genotyping. Nevertheless, we recommend that C282Y genotyping by restriction endonuclease digestion of PCR products in the future should utilize a primer pair that is not influenced by the 5569G/A polymorphism.

Base Sequence↗
PubMed2000

Hereditary hemochromatosis in Spain.

The C282Y mutation of the HFE gene has been reported as the main cause of hereditary hemochromatosis (HH). Another missense mutation (H63D) has also been detected at an increased frequency in a compound heterozygote state with the C282Y mutation in HH patients. However, these two mutations are not present in all of the HH patients, indicating that other mutations in the HFE gene, or in other loci, should exist. The present study reports the frequencies of the C282Y and H63D mutations in 74 Spanish HH patients and the results of the sequencing analysis of the HFE exons, intron-exon boundaries, and 588 bp of the 5' region in 5 patients negative for the C282Y mutation. We have detected a high frequency of the C282Y mutation (85.1%) in Spanish HH patients, indicating that this mutation is the most common defect associated with the disease in Spain. The screening of the HFE regions in our patients without the C282Y mutation has revealed the presence of five polymorphisms. However, no other pathological mutations have been found. Therefore, further efforts to characterize the unscreened part of the HFE gene or other loci should be taken to identify the potential genetic factors causing HH in the C282Y-negative patients.

Base Sequence↗
PubMed2000

A pilot C282Y hemochromatosis screening in Italian newborns by TaqMan technology.

Hereditary hemochromatosis (HH) is a disorder of iron metabolism that leads to iron overload in middle age and can be caused by homozygosity for the C282Y mutation in the HFE gene. Preliminary studies have estimated the frequency of this mutation at 0.5-1% in Italy, but this has not been verified on a large sample. We analyzed 1,331 Italian newborns for the C282Y mutation in the HFE gene using dried blood spots (DBS) from the Neonatal Screening Center in Turin, Italy. The mutation was assessed using a semi-automatable 5'-nuclease assay (TaqMan technology). We detected 55 heterozygotes and no homozygotes in our sampling, resulting in an overall frequency of 2.1% +/- 0.6 for the C282Y allele. Differences in allele frequency were observed, and ranged from 2.7% +/- 1.3 in samples from Northern Italy, to 1.7% +/- 0.9 in samples from Central-Southern Italy. The low frequency of the at-risk genotype for iron overload suggests that genetic screening for HFE in Italy would not be cost effective. The present study, in addition to defining C282Y frequency, documents detection of the major HFE mutation on routine DBS samples from neonatal screening programs using a semi-automatable, rapid, reliable, and relatively inexpensive approach.

Base Sequence↗
PubMed2000

Transferrin saturation phenotype and HFE genotype screening for hemochromatosis and primary iron overload: predictions from a model based on national, racial, and ethnic group composition in central Alabama.

There is interest in general population screening for hemochromatosis and other primary iron overload disorders, although not all persons are at equal risk. We developed a model to estimate the numbers of persons in national, racial, or ethnic population subgroups in Jefferson County, Alabama, who would be detected using transferrin saturation (phenotype) or HFE mutation analysis (genotype) screening. Approximately 62% are Caucasians, 37% are African Americans, and the remainder are Hispanics, Asians, or Native Americans. The predicted phenotype frequencies are greatest in a Caucasian subgroup, ethnicity unspecified, which consists predominantly of persons of Scotch and Irish descent (0.0065 men, 0.0046 women), and in African Americans (0.0089 men, 0.0085 women). Frequencies of the HFE genotype C282Y/C282Y > or = 0.0001 are predicted to occur only among Caucasians; the greatest frequency (0.0080) was predicted to occur in the ethnicity-unspecified Caucasian population. C282Y/C282Y frequency estimates were lower in Italian, Greek, and Jewish subgroups. There is excellent agreement in the numbers of the ethnicity-unspecified Caucasians who would be detected using phenotype and genotype criteria. Our model also indicates that phenotyping would identify more persons with primary iron overload than would genotyping in our Italian Caucasian, Hispanic, and African American subgroups. This is consistent with previous observations that indicate that primary iron overload disorders in persons of southern Italian descent and African Americans are largely attributable to non-HFE alleles. Because the proportions of population subgroups and their genetic constitution may differ significantly in other geographic regions, we suggest that models similar to the present one be constructed to predict optimal screening strategies for primary iron overload disorders.

Alabama↗
PubMed2000

Early detection of genetic hemochromatosis: should all young adults be offered the genetic test?

Genetic hemochromatosis (GH) is a late-onset, autosomal recessive disorder. The majority of those at risk from iron overload and its clinical consequences may be detected by a simple genetic test. Furthermore, treatment by phlebotomy, if instituted early, removes excess iron and prevents the complications of iron overload which include arthralgia, diabetes, and cirrhosis of the liver. GH seems to be an obvious candidate for inclusion in national screening programs. However, important questions remain concerning the proportion of individuals with the high-risk genotype who eventually show clinical manifestations of iron overload and the significance of heterozygosity for haemochromatosis in terms of morbidity. Until these questions are resolved, the introduction of widespread genetic screening cannot be justified.

Adolescent↗
PubMed2000

Detection of an unusual combination of mutations in the HFE gene for hemochromatosis.

In the present paper, we describe an individual, found as part of a screening study, being homozygous for the C282Y mutation and at the same time heterozygous for the H63D mutation in the HFE gene. Identical results were obtained by three different methods, i.e., by PCR-RFLP, by sequencing, and by melting curve analysis. Thus, the common conception that the C282Y and the H63D mutations are mutually exclusive is not valid. Clinical symptoms and laboratory data on the individual were similar to hemochromatosis patients homozygous for the C282Y mutation. The implications of our finding for diagnostic analytical laboratory procedures are briefly discussed.

Adult↗
PubMed2002

A very rare association of three mutations of the HFE gene for hemochromatosis.

In the present paper, we describe a patient who is a compound heterozygote for three mutations in the HFE gene: C282Y, H63D, and E168Q. The patient's mother carries two copies of H63D and one copy of E168Q; the patient's father is heterozygous for C282Y. The family study indicates that the patient, as well as his sister, a maternal uncle, and a first cousin, all have inherited a single HFE allele that contains two mutations H63D and E168Q. The clinical symptoms and laboratory findings of the patient and his relatives are consistent with the conclusion that the E168Q mutation by itself is unlikely to result in hemochromatosis.

Adult↗
PubMed2002

Hereditary hemochromatosis: the clinical significance of the S65C mutation.

Hereditary hemochromatosis (HH) is a common genetic disease with iron overload in certain organs, especially the liver. Most cases are homozygous for the C282Y mutation in the HFE gene; a few are C282Y heterozygous, compound C282Y/H63D heterozygous, or have no known mutation. A third mutation, S65C, has been associated with HH, but this finding is disputed. We have studied the clinical significance of various genotypes with the S65C mutation. In a population-based screening for HH in 65,238 persons, 613 had high serum transferrin saturation in two blood samples and were invited for HFE genotyping. In 556 persons with complete data sets, we studied the serum ferritin concentration and the risk of being diagnosed with phenotypic HH in the various genotypic groups. The phenotypic diagnosis was given without knowing the genotypic result. Except for the C282Y homozygotes, no differences in median serum ferritin concentrations were found between the various genotypic groups. However, the C282Y/S65C compound heterozygous group had a higher risk of being diagnosed with phenotypic HH than the wild-type group, as did the C282Y homozygous and the C282Y/H63D compound heterozygous groups. When combined with the C282Y mutation, the S65C mutation is associated with an increased risk of being diagnosed with phenotypic HH.

Amino Acid Substitution↗
PubMed2004

Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis.

BACKGROUND: Research conducted before genotyping was possible suggested that subjects heterozygous for the genetic mutation associated with hemochromatosis absorbed nonheme iron more efficiently than did control subjects when tested with a fortified meal. Heme-iron absorption in these subjects has not been reported. OBJECTIVE: We compared the absorption of heme and nonheme iron from minimally or highly fortified test meals between HFE C282Y-heterozygous and wild-type control subjects. DESIGN: After prospective genotyping of 256 healthy volunteers, 11 C282Y-heterozygous and 12 wild-type control subjects were recruited, and their iron absorption was compared by using a hamburger test meal with or without added iron and ascorbic acid. After retrospective genotyping of 103 participants in previous iron-absorption studies, 5 C282Y-heterozygous subjects were compared with 72 wild-type control subjects. RESULTS: HFE C282Y-heterozygous subjects did not differ significantly from wild-type control subjects in their absorption of either heme or nonheme iron from minimally or highly fortified test meals. No differences were detected in blood indexes of iron status (including serum ferritin, transferrin saturation, and non-transferrin-bound iron) or in blood lipids or transaminases, but heterozygotes had significantly greater, although normal, fasting glucose concentrations than did wild-type control subjects. Compound heterozygotes (those who had both HFE C282Y and H63D mutations) absorbed more nonheme (but not heme) iron from meals with high (but not low) iron bioavailability. CONCLUSIONS: HFE C282Y-heterozygous subjects did not absorb dietary iron more efficiently, even when foods were highly fortified with iron from ferrous sulfate and ascorbic acid, than did control subjects. Iron fortification of foods should not pose an additional health risk to HFE C282Y heterozygotes.

Adult↗
PubMed2001

HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology.

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of HFE described to date (C282Y and H63D) are significantly correlated with HHC. Homozygosity for the C282Y mutation was found in 52-100% of previous studies on clinically diagnosed probands. In this review, 5% of HHC probands were found to be compound heterozygotes (C282Y/H63D), and 1.5% were homozygous for the H63D mutation; 3.6% were C282Y heterozygotes, and 5.2% were H63D heterozygotes. In 7% of cases, C282Y and H63D mutations were not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%. C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40--70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination.

Alleles↗