View Full Version : Hemochromatosis: Celtic X Viking origin of the mutation

Tuesday, December 30th, 2003, 03:38 AM
A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

Lucotte G, Dieterlen F.

International Institute of Anthropology, Paris, France. Lucotte@hotmail.com

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

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Clin Genet. 2003 Jul;64(1):36-47.

Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings.

Milman N, Pedersen P.

Department of Medicine B, Rigshospitalet, University of Copenhagen, Copenhagen and Department of Clinical Biochemistry, Naestved Hospital, Naestved, Denmark. milman@rh.dk

Hereditary hemochromatosis has been recognized as a clinical disorder for more than 100 years. The common form of the disorder is caused by the Cys282Tyr mutation (C282Y) of the HFE gene. Hereditary hemochromatosis affects predominantly people of Northern European origin. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and the founder effect. It has been estimated that the C282Y mutation appeared 60-70 generations ago. It was initially suggested that the ancestral C282Y mutation occurred within the Celtic group of peoples. However, we hypothesize that the distribution of the C282Y mutation in Europe is more consistent with an origin among the Germanic Iron Age population in Southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. The aim of the present study was to evaluate the validity of these two hypotheses. Several arguments are in favor of the 'Viking hypothesis': first, the highest frequencies (5.1-9.7%) of the C282Y mutation are observed in populations in the Northern part of Europe, i.e. Denmark, Norway, Sweden, Faeroe Islands, Iceland, Eastern part of England (Danelaw) and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from Northern to Southern Europe. Intermediate allele frequencies (3.1-4.8%) are seen in the populations in Central Europe, which is the original Celtic homeland. Low allele frequencies (0-3.1%) are recognized in populations in Southern Europe and the Mediterranean

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Immunogenetics. 1997;46(3):222-5. Related Articles, Links

Absence of the hemochromatosis gene Cys282Tyr mutation in three ethnic groups from Algeria (Mzab), Ethiopia, and Senegal.

Roth M, Giraldo P, Hariti G, Poloni ES, Sanchez-Mazas A, Stefano GF, Dugoujon JM, Coppin H.

CNRS UPR 8291, CHU Purpan, 31300 Toulouse, France.

A Celtic origin for hemochromatosis, a common genetic iron metabolism disorder, has been postulated for a long time. To check whether the two mutations recently identified in the HLA-class I candidate gene for this disease were found only in Caucasians, we examined their frequencies in individuals originating from Algeria, Ethiopia, and Senegal. The presumably disease-causing mutation, responsible for the Cys282Tyr substitution, was not found in any member of these ethnic groups, although it was shown to be highly prevalent in populations of European ancestry. This geographic distribution supports the previously suggested Celtic origin for the disease. In contrast, the mutation responsible for the His63Asp substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the Central Ethiopians and Algerians (Mzab) genotyped for this study. This second mutation, which probably represents a common variant unrelated to hemochromatosis, thus appears to have occurred earlier than that responsible for the Cys282Tyr substitution. More detailed population studies are needed to provide information on the age of these two mutations and eventually show how the hemochromatosis-causing mutation chronologically spread throughout Europe.


Int J Hematol. 2003 Jan;77(1):48-54. Related Articles, Links

Frequencies of the hereditary hemochromatosis allele in different populations. Comparison of previous phenotypic methods and novel genotypic methods.

Milman N, Pedersen P, Steig T, Melsen GV.

Department of Medicine B, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. nils.mil@dadlnet.dk

AIM: The frequencies of the hereditary hemochromatosis allele were compared for different populations assessed by previous phenotypic methods and the present genotypic methods. METHODS: From a literature survey, the calculated hemochromatosis allele frequencies from 16 studies using phenotypic biochemical markers (threshold levels for transferrin saturation [range, 46%-70%] and serum ferritin [range, 164-700 microg/L]) were compared with allele frequencies of the Cys282Tyr mutation of the hemochromatosis gene reported in 19 genotypic studies. RESULTS: Calculated phenotypic allele frequencies are high in Scandinavia: Iceland, 6.1% to 7.4%; Norway, 5.8%; central Sweden, 6.3% to 6.9%; Denmark, 6.1%. Frequencies are similarly high in Wales, Canada, Utah, South Africa, and Australia (range, 5.2%-9.8%). Frequencies are low in Finland (1.9%) and northern Italy (4.5%). Genotypic allele frequencies of the Cys282Tyr mutation are likewise high in Scandinavia. Frequencies are high in the United Kingdom and northern France and low in Finland, central Germany, northern Italy, and Greece. The phenotypic-genotypic ratios of the hemochromatosis homozygosity frequencies for the same geographic area were calculated. A ratio of 1.0 indicates that the 2 methods give similar results. In 3 studies, the ratio was above 1.0, the highest ratio of 1.67 being reported from Italy. In most studies the ratio was slightly below 1.0 (0.71-0.97). The lowest ratio was found in Finland (0.33). CONCLUSION: In most studies there was good agreement between the hemochromatosis allele frequencies determined by phenotypic and genotypic methods. A high ratio (northern Italy) may indicate that phenotypic selection criteria were too loose and/or that causes of iron overload other than the Cys282Tyr mutation are frequent in the region. A low ratio (in Finland) may indicate phenotypic selection criteria that were too stringent and/or a low penetration rate of the mutation.

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Neth J Med. 2003 Sep;61(9):291-5. Links

Two Dutch families with hereditary hyperferritinaemia-cataract syndrome and heterozygosity for an HFE-related haemochromatosis gene mutation.

Simsek S, Nanayakkara PW, Keek JM, Faber LM, Bruin KF, Pals G.

Department of Internal Medicine, University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Simsek@vumc.nl

Hereditary haemochromatosis is an autosomal recessive disorder, leading to progressive iron overload, which is very common among the Caucasian population. In the vast majority of the cases, the hereditary iron overload is caused by mutations in the HFE gene. Most prominently this is the homozygous Cys282Tyr mutation. We report two Dutch families in which both propositi were found to be heterozygous for Cys282Tyr in the work-up of hyperferritinaemia. Frequent phlebotomies had no effect on the ferritin level, but led to microcytic anaemia. Finally, the family history with bilateral cataracts was the clue for the correct diagnosis. Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disease characterised by elevated serum ferritin levels and bilateral cataracts in the absence of iron overload. Several point mutations and deletions within the iron-responsive element (IRE) in the 5' noncoding region of the L-ferritin gene have been found in HHCS families. In the first Dutch family a G to C transition at position 32 was found and a G to A mutation at the same location was found in the second Dutch family. In individuals with an isolated hyperferritinaemia (normal transferrin saturation), the presence of early onset (familial) cataract should raise the possibility of HHCS, even when Cys282Tyr heterozygosity is found.


Scand J Gastroenterol. 1999 May;34(5):529-34. Related Articles, Links

High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression.

Distante S, Berg JP, Lande K, Haug E, Bell H.

Dept. of Medicine, Aker University Hospital, Oslo, Norway.

BACKGROUND: Previous studies have shown that 5%-10% of white subjects are heterozygous for the HFE gene C282Y mutation, which is associated with hemochromatosis. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutation and its phenotypic expression in a group of healthy Norwegians. METHODS: Fasting blood samples were obtained from 505 unrelated hospital employees. Serum iron, transferrin, and serum ferritin were measured. Transferrin saturation was calculated. The presence of HFE gene mutation was determined with a polymerase chain reaction-based analysis. RESULTS: Two of the 505 subjects (0.4%) were homozygous and 75 (14.9%) were heterozygous for the C282Y mutation. Median serum ferritin among the heterozygotes was 59 microg/l, compared with 47 microg/l among individuals without the C282Y mutation (P = 0.12). Median transferrin saturation among the heterozygotes was 31%, compared with 24% among individuals without C282Y mutation (P < 0.001). Twenty-three individuals (4.6%) had a serum ferritin level > 200 microg/l. Eight of these (35%) had the C282Y mutation: two homozygotes and six heterozygotes. Transferrin saturation > 50% was observed in 25 individuals (5.0%). Twelve of these (48%) had the C282Y mutation; two were homozygotes and 10 heterozygotes. Only eight individuals (1.6%) had a transferrin saturation > 60%: one homozygote, five heterozygotes, and two individuals without mutation. CONCLUSIONS: Fifteen per cent of a healthy Norwegian population is heterozygous for the HFE gene mutation C282Y. This is among the highest reported prevalence values among healthy individuals. Half of the subjects with transferrin saturation greater than 50% were carriers of the C282Y mutation.

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Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls.

Sanchez M, Bruguera M, Bosch J, Rodes J, Ballesta F, Oliva R.

Genetics Service, Institut Clinic de Malalties Digestives, IDIBAPS, Hospital Clinic and University of Barcelona, Villarroel, Spain.

BACKGROUND/AIMS: A mutation (Cys282Tyr) of the HFE gene has recently been reported to be present in most of the patients with hereditary hemochromatosis of Northern European ancestry, but in a lower frequency in Italy. No data are so far available on the prevalence of these mutations in Spain. Therefore, we initiated the present study to determine if the reported Cys282Tyr HFE mutation is also the main cause of hereditary hemochromatosis in Spain. In addition, we investigated the presence of the His63Asp HFE mutation in patients and in controls. METHODS: Thirty-one hereditary hemochromatosis patients and 485 controls were screened for the Cys282Tyr and the His63Asp mutations, using polymerase chain reaction amplification of genomic DNA, followed by digestion with the restriction enzymes Rsa I or Dpn II, respectively, and the separation of the products by electrophoresis. RESULTS: Twenty-seven out of 31 (87.1%) hereditary hemochromatosis patients were homozygous for the Cys282Tyr mutation. None of the patients was homozygous for the His63Asp mutation, and two patients (6.5%) were compound heterozygous (Cys282Tyr/His63Asp). Only one of 512 (0.2%) controls was homozygous for the Cys282Tyr mutation, and 29 (5.7%) were heterozygous. The Cys282Tyr mutation is present with an allelic frequency of 90.3+/-7.5% in patients with hereditary hemochromatosis and 3.0+/-1.1% in controls. Twenty out of 487 (4.1%) controls were His63Asp homozygous, while 171 (35.1%) were heterozygous. The His63Asp mutation is present with an allelic frequency of 21.7+/-2.7% in controls. CONCLUSIONS: The high frequency of the Cys282Tyr mutation in hereditary hemochromatosis patients indicates that this mutation is the most common defect associated with hereditary hemochromatosis in Spain. The finding of some patients with the wild genotype at position 282 suggests the existence of other changes in the HFE gene or in other loci involved in the disease. We have found one of the highest allelic frequencies reported for the His63Asp mutation in our controls (21.7+/-2.7%).

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J Gastroenterol Hepatol. 2004 Jan;19(1):86-90. Related Articles, Links

Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India.

Thakur V, Guptan R, Hashmi A, Sakhuja P, Malhotra V, Sarin S.

Departments of Gastroenterology and Pathology, G.B. Pant Hospital, New Delhi, India.

BACKGROUND AND AIM: Hereditary hemochromatosis (HHC) is an autosomal recessive disorder causing primary iron overload syndrome and chronic liver disease (CLD). This genetic disease is commonly associated with C282Y mutation of the HFE gene, commonly seen in the Northern European population. Minor reports on HHC are available from Asia, however, so far no genetic study is available from India. We prospectively studied the prevalence of C282Y mutation in CLD patients and healthy subjects in a tertiary care referral center in India. METHODS: A total of 249 consecutive biopsy proven CLD (HBV = 112, HCV = 72, cryptogenic = 65) patients and 134 age matched healthy controls were included. Cases of secondary iron overload, pregnancy, chronic alcoholism, age < 30 years and hepatocellular carcinoma (HCC) were excluded. A transferrin saturation index (TSI) of >60% was suggestive of a phenotypic presentation of HHC. C282Y mutation was studied by restriction fragment length polymorphism (RFLP) using genomic DNA. The 387 bp fragment obtained after polymerase chain reaction was digested with 10 units of endonuclease Rsa1. The mutation was detected by creation of an additional restriction site, giving rise to fragments of 247 111 and 29 bp. RESULTS: While the mean TSI was comparable, serum ferritin was significantly higher in CLD patients compared to controls (38 +/- 16%vs 28 +/- 13%; p = not significant (NS), and 125 +/- 18 vs 42 +/- 25 ng/mL; p < 0.001). A TSI of >60% was detected in 24 (9.64%) patients. Only one restriction site was found for endonuclease Rsa1, giving rise to two fragments of 247 and 140 bp, suggesting absence of C282Y mutation in the HFE gene in all patients. CONCLUSIONS: Almost 10% of nonalcoholic CLD patients in India have iron overload, but this is independent of C282Y mutation of the HFE gene. Large population based studies are recommended to investigate the prevalence of this RARE DISORDER IN INDIA.

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Am J Hematol. 1998 Jul;58(3):213-7. Related Articles, Links

Mutation analysis of the HFE gene associated with hereditary hemochromatosis in African Americans.

Monaghan KG, Rybicki BA, Shurafa M, Feldman GL.

Department of Medical Genetics, Henry Ford Hospital, Detroit, Michigan 48202, USA.

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African-American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population.


Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis.

Lucotte G.

International Institute of Anthropology, Paris, France.

After the main hereditary hemochromatosis mutation C282Y in the HFE gene was described, we report here the C282Y frequencies for various European populations. The aim of this meta-analysis is to compile the Y allele frequencies of the C282Y mutation for 53 European populations, representing a total of 9265 unrelated people representing control samples. The most elevated values are observed in residual Celtic populations in Ireland, in the United Kingdom, and in France, in accordance with the initial hypothesis of Simon et al. (Prog. Med. Genet. 4, 135-168, 1980) concerning a Celtic origin of the hereditary hemochromatosis mutation. Copyright 2001 Academic Press.


European Footprint: Hereditary Hemochromatosis - Tracking European ancestry through a genetically inherited disease


Tuesday, December 30th, 2003, 06:12 AM
[Prevalence of C282Y and E168X HFE mutations in an Italian population of Northern European ancestry.

Salvioni A, Mariani R, Oberkanins C, Moritz A, Mauri V, Pelucchi S, Riva A, Arosio C, Cerutti P, Piperno A.

Clinica Medica, Ospedale San Gerardo, via Donizetti 106, 20052 Monza, Italy.

BACKGROUND AND OBJECTIVES: In Italy, the prevalence of C282Y is lower than in Northern European countries. We hypothesized a higher prevalence of C282Y in Northern than in Southern Italian populations. We previously identified a nonsense mutation (E168X) in hemochromatosis probands originating from a region in the north-west of Italy. We aimed to define the prevalence of C282Y and E168X in that region and the origin of the E168X mutation by haplotype analysis. DESIGN AND METHODS: Six-hundred and six blood donors were investigated for C282Y, H63D, S65C and E168X mutations by polymerase chain reaction (PCR)-restriction assays. Three hundred were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. D6S265, D6S105 and D6S1281 microsatellites were analyzed to define E168X 6p-associated haplotypes. RESULTS: One C282Y homozygote, thirteen C282Y/ H63D compound heterozygotes, four E168X heterozygotes and three E168X/H63D compound heterozygotes were found. The allele frequencies of C282Y, H63D, S65C, and E168X were 4.7%, 14.9%, 0.74% and 0.58%, respectively. INTERPRETATION AND CONCLUSIONS: The prevalence of C282Y in the region investigated was much higher than that previously reported in Italy. This finding is probably due to the heavy Celtic component of this north-western population and suggests that in populations of Northern Italian descent screening studies for hemochromatosis could be cost-effective. The prevalence of E168X in this region, although low, suggests that the mutation probably originated here many years ago and its frequency increased as a result of a local founder effect. Given its severity, we suggest that the E168X mutation should be searched for in all hemochromatosis patients of Northern ancestry with an incomplete HFE genotype.


Frequency of the HFE gene mutations in five Italian populations.

Candore G, Mantovani V, Balistreri CR, Lio D, Colonna-Romano G, Cerreta V, Carru C, Deiana L, Pes G, Menardi G, Perotti L, Miotti V, Bevilacqua E, Amoroso A, Caruso C.

Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Universita di Palermo, Palermo, Italy.

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.


Frequency of hemochromatosis C282Y and H63D mutations in Sardinia.

Melis MA, Cau M, Congiu R, Ruvoletto L, Cao A, Galanello R.

Dipartimento di Scienze Biomediche e Biotecnologie, Sezione Clinica e Biologia dell'Eta Evolutiva, Universita degli studi di Cagliari, Ospedale Regionale per le Microcitemie ASL, 8 Cagliari, Italy. amelis@mcweb.unica.it

Hereditary hemochromatosis (HH) is one of the most common autosomal recessive disorders of iron metabolism among Caucasians, and it is associated with C282Y mutation of the HFE gene in populations of Celtic origins. A second mutation, H63D, shows a very high widespread frequency, although its role in iron metabolism is still inconclusive. There are no data on the frequencies of these two mutations in Sardinia, an island in the Mediterranean sea that has not been invaded by Celtic peoples. We examined 836 chromosomes from Sardinian subjects and tested for the mutation by restriction enzyme digestion of PCR products. Among the 836 analyzed chromosomes, we found a C282Y allele frequency of 0.0036 and an H63D allele frequency of 0.173. These data could explain the observed rarity of HH in Sardinia. The high allele frequency of H63D and the rarity of HH in Sardinia is suggestive that this mutation is not a major contributor to this disease.

Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry.

Pozzato G, Zorat F, Nascimben F, Gregorutti M, Comar C, Baracetti S, Vatta S, Bevilacqua E, Belgrano A, Crovella S, Amoroso A.

Dipartimento di Medicina Clinica & Neurologia, Unita Operativa Medicina Clinica, Universita degli Studi di Trieste, Trieste, Italy.

Hereditary haemochromatosis is an inherited disorder characterised by an excessive iron absorption from the diet and is associated with several HFE gene mutations. One hypothesis is that these genetic mutations originated in the Celtic populations. The aim of this study is to determine the frequency of HFE gene mutations in a clustered Italian population of Celtic ancestry (Cimbri, Asiago plateau). One hundred and forty-nine consecutive unrelated blood donors (31 females and 118 males) were enrolled in this study. A family investigation was performed in each case to identify the ethnic origin of the individuals. The analysis of HFE gene mutations was performed by PCR amplification followed by digestion with RsaI and DpnII restriction enzymes. At least one HFE gene mutation was identified in 49 individuals (32.9%) of the studied population. The allele frequencies of the C282Y and H63D were respectively 0.037 and 0.144. When we considered only the 103 individuals with relatives born in Asiago, the prevalence of the HFE mutations rose from 32.9 to 39.8%; the allele frequencies of the C282Y and H63D were respectively 0.048 and 0.174. The mean serum iron and ferritin levels were significantly higher in individuals with the HFE mutations than in normal cases. This study indicates that the prevalence of the HFE gene mutations is surprisingly high in Italians with Celtic ancestry. This could suggest the need to perform large mass studies in selected areas of the country to detect the affected patients and prevent the disease in homozygous individuals.


Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis.

Lucotte G.

International Institute of Anthropology, Paris, France.

After the main hereditary hemochromatosis mutation C282Y in the HFE gene was described, we report here the C282Y frequencies for various European populations. The aim of this meta-analysis is to compile the Y allele frequencies of the C282Y mutation for 53 European populations, representing a total of 9265 unrelated people representing control samples. The most elevated values are observed in residual Celtic populations in Ireland, in the United Kingdom, and in France, in accordance with the initial hypothesis of Simon et al. (Prog. Med. Genet. 4, 135-168, 1980) concerning a Celtic origin of the hereditary hemochromatosis mutation. Copyright 2001 Academic Press.