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Human Molecular Genetics, 2002, Vol. 11, No. 2 185-189
© 2002 Oxford University Press

Prevalence of HFE gene C282Y and H63D mutations in a French–Canadian population of neonates and in referred patients

Joël Girouard1, Yves Giguère1,2, Robert Delage3 and François Rousseau1,2,+

1Unité de Recherche en Génétique Humaine et Moléculaire, Hôpital St-François d’Assise Research Center, Department of Medical Biology, Faculty of Medicine, Laval University, Canada, 2Center for the Development, Evaluation and Rational Implementation of New Medical Diagnostic Tools (CEDERINDT), Hôpital St-François-d’Assise (CHUQ), Quebec City, Canada and 3Laboratoire d’hématologie, CHA, Hôpital du St-Sacrement, Québec, Canada

Received October 2, 2001; Revised and Accepted November 16, 2001.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Hereditary hemochromatosis is a genetic disease characterized by exaggerated absorption of intestinal iron leading to its accumulation in some organs over the years. Its prevalence is estimated to be 3–5/1000 in Caucasians. A single mutation, C282Y in the HFE gene explains 80–90% of all diagnosed cases in populations of northwestern European ancestry. The importance of another frequent mutation in this gene, H63D, as well as of C282Y/H63D compound heterozygotes, is still a matter of debate. We estimated the prevalence of these mutations in newborns from a genetically well defined French–Canadian population, in Quebec City. We compared genotype and allele frequencies between neonates and referred patients for HFE molecular analysis. We genotyped anonymous-unlinked cord blood samples for C282Y (n = 881) and H63D (n = 870) mutations from neonates. Referred patients (n = 1084) were genotyped in two different laboratories and pooled after verifying the similarity of both groups. No C282Y homozygote was found in neonates (allele frequency = 0.043). However, we identified 163 C282Y homozygotes (15%) among 1084 referred patients leading to a, not surprising, 97-fold enrichment of this genotype. We found a similar proportion of genotypes homozygous for H63D in both groups suggesting a weak association with the disease. However, we found a 5-fold enrichment of compound heterozygotes in the referred group. Fewer C282Y homozygotes were observed in the French–Canadian population than in northwest Europe populations. However, the strong enrichment of homozygotes between the neonates and the referred patients is an argument in favour of screening for this lethal disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Hereditary hemochromatosis (HH) is a heterogeneous recessive genetic disorder characterized by an unregulated absorption of intestinal iron. Excess iron accumulates in body tissues leading to complications such as cirrhosis, hepatocellular carcinoma, diabetes and heart failure over many years (1,2). Therapeutic phlebotomies can prevent iron overload if the diagnosis is made early (3). Phlebotomy is a simple, cheap and efficient therapeutic modality. In addition, diagnostic markers are available to diagnose patients before the onset of symptoms. Thus, most criteria for disease screening are fulfilled (4,5).

Two mutations associated with HH were described in the HFE gene: a G->A transition in position 845 (C282Y) and a C->G transition in position 187 (H63D) (6). The frequency of the C282Y mutation in unrelated HH patients diagnosed using clinical criteria alone varies from 64 to 95% (6–13). Caucasian patients from northern European descent are more likely to have this mutation. The role of the H63D mutation is still a matter of debate: it is frequent in control populations and few patients are H63D homozygotes. C282Y/H63D compound heterozygotes have been reported in a subset of patients (6,9,12).

Before implementing large-scale screening for a disease, it is necessary to know its prevalence in the population of interest. This has not been determined for HFE mutations in the French–Canadian population. Only one prevalence study from Canada, including mainly English–Canadian subjects, reported a prevalence of 0.3% C282Y homozygotes with an allele frequency of 0.045 among 5211 samples from blood donors (14).

The objective of this study was to compare the prevalence of the two major HFE mutations (C282Y and H63D) in neonates from a French–Canadian population (Quebec City area, Canada) to a group of patients referred to our laboratories for HFE molecular diagnosis. In addition, we discuss the relevance of screening for HH in our population.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Amongst 881 neonates, we found no homozygote and 76 heterozygotes for C282Y corresponding to an allele frequency of 0.043 [95% confidence interval (CI) 0.034–0.053]. The extrapolated frequency of homozygotes based on Hardy–Weinberg equilibrium is 1/538 (0.002) with a 95% CI of 1/361 to 1/883. We found more individuals homozygous for H63D than in the United States and Scandinavian studies but no statistical difference was found in the compound heterozygotes prevalence between populations (Table 1). In neonates, genotype frequencies of C282Y and H63D mutations followed Hardy–Weinberg equilibrium (P = 0.36 and 0.49, respectively). In referred patients, the C282Y mutation did not follow Hardy–Weinberg equilibrium (P < 0.0001). Of note, the H63D mutation was in Hardy–Weinberg equilibrium (P = 0.70), suggesting a modest contribution to the burden of disease.


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  		Table 1. Prevalence of the C282Y and H63D mutations in selected populations (number of subjects)
 
We found strong linkage disequilibrium between the two mutations whether we analysed alleles or genotypes (chi-square test, P < 0.0001 for both) and all observed mutant alleles appeared in trans on chromosomes. These results are in keeping with other reports from different population studies (Table 1).

As expected, genotype and allele frequencies for the C282Y mutation were quite different between newborns and the referred group (Table 2). The male-to-female ratio amongst C282Y homozygotes was 1.9 in the referred sample. There was a significant difference in the prevalence of compound heterozygotes between these two groups as well (P < 0.0001). We found a significant difference for the H63D mutation (allele and genotypes) between both groups, but the difference is much weaker than for C282Y.


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  		Table 2. Genotypes and allele frequencies between neonates and referred patients
 
Finally, we calculated enrichment factors for the genotypes of interest (Table 3). The C282Y-YY genotype showed a 97-fold increase in the referred group as compared to neonates. The enrichment factors for H63D-DD (2.3x) and compound heterozygotes (5x) were weaker although statistically different from one.


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  		Table 3. Proportions of the mutated homozygotes C282Y, homozygotes H63D and compound heterozygotes in neonates compared with the referred patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
In this study, we report the prevalence of HFE mutations (C282Y and H63D) in a French–Canadian population from the metropolitan area of Quebec City (Quebec, Canada). Cord blood from neonates was used because they are considered representative of the general population and exempt of selection bias. The prevalence of these HFE mutations in the sample of neonates was compared to a group of individuals referred for molecular analysis of the HFE gene.

To date, the two Quebec City reference laboratories for HFE diagnosis have identified 163 C282Y homozygotes out of the predicted 1395 based on a prevalence of homozygotes of 1/538 (Results). This suggests that either HH is underdiagnosed or that C282Y mutation has a variable penetrance according to factors such as gender. We believe that both phenomena are present and that some patients known to have HH may not have been tested for HFE mutations.

Significantly, fewer C282Y homozygotes (0%) were found in our population-based sample as compared to studies from Scandinavia (0.7%) (15) and Ireland (1.2%) (8) (Table 1). Two reports from France (16,17) found more C282Y homozygotes although the differences were not significant. Interestingly, a study from Saguenay-Lac St-Jean, a region northeast of Quebec City, reported that only 44% of 32 unrelated HH patients were homozygous for C282Y (18). The population of this region is also composed of French–Canadians although the founder effect in that region is greater than in the Quebec City area. Unfortunately, a control population was not included in the study and some of the patients seemed to have a different form of hemochromatosis.

We used a group of referred patients for the molecular diagnosis of HH to assess the frequencies of C282Y and H63D mutations in at-risk individuals. This is a conservative approach to estimate the prevalence of the mutations among HH patients in our population. One potential bias of this study is the difference between the geographical distribution of the two samples compared. However, analysis of this distribution using the ‘forward sortation areas’ information within Canadian postal codes showed that 91% of referred patients lived in the same area of residence as neonates (Quebec City metropolitan area), suggesting little influence from differences in geographical distribution between samples.

The observed 97-fold enrichment in C282Y homozygotes in the referred group as compared to neonates supports systematic screening for C282Y among people at risk (clinical symptoms, biochemical anomalies or family history of HH). The association between H63D mutation and HH is much weaker. There is a high prevalence of the mutant allele ‘D’ in the control population and the enrichment in homozygotes H63D between neonates and the referred group is marginal (2.3x). In our opinion, screening for H63D mutation is not justified in our population given the current data available.

Significant differences between wild-type and compound heterozygote genotypes for transferrin saturation and ferritin blood levels have been reported (19,20). In addition, case-control studies (9,12,21,22) have showed a higher prevalence of compound heterozygotes among HH patients as compared to controls but this is still controversial (7,23,24). A careful analysis of these studies reveals a tendency to find more HH patients bearing a compound heterozygotes genotype in populations where C282Y homozygotes are less prevalent (<85%). This could be related to the strong linkage disequilibrium between these mutations but also because of heterogeneity of patients between samples. In our study, the frequency of compound heterozygotes is higher among referred patients and there is a 5-fold enrichment of this genotype with respect to neonates. This suggests that C282Y-H63D compound heterozygote status may influence iron homeostasis but that other factors such as modifier genes or environmental exposures are likely to be involved in this process.

In conclusion, there is a trend for a lower frequency of C282Y homozygotes in the French–Canadian population as compared to populations from northwest Europe. However, in our population, there is a significant enrichment in C282Y-YY in patients referred for molecular diagnosis of HH as compared to neonates. These findings suggest that screening for C282Y mutation could be relevant although a screening algorithm has to be defined in order to incorporate (or not) biochemical parameters and possibly identify subgroups, which are at higher risk for the disease. However, in our opinion, screening for H63D mutation does not seem relevant, as it is unlikely that significantly more cases will be diagnosed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Subjects
We genotyped 881 neonates for the C282Y mutation and 870 for the H63D mutation using cord blood. These unlinked neonates were randomly selected from a sample of 2000 cord bloods, which were anonymized before genotyping. They were born in a tertiary centre in obstetrics between June 1999 and May 2000. Postal codes analysis showed that 96% of neonates were from the Quebec City metropolitan area. The rest originated from the rural areas surrounding the city. 1084 patients referred for the molecular testing of the HFE gene were genotyped for the C282Y mutation in two different centres. In addition, 548 of these patients were genotyped for the H63D mutation. These individuals were referred based on clinical symptoms, biochemical abnormalities or family history and 88% of them originated from the Quebec City metropolitan area. We pooled the results from the two centres, which are located in the same city. Using chi-square analysis, we compared the two subgroups for genotype and allele frequencies and found no significant difference between the two groups of referred patients (P > 0.05). The Quebec City metropolitan area (population ~750 000) is composed of over 93% French–Canadians.

Genetic analysis
Genotyping of referred samples was performed in two different laboratories. In one centre, DNA was extracted from whole blood samples with the Qiagen 96-well procedure and reagents (Qiagen, Mississauga, Ontario, Canada). In the second centre, the method of Saiki et al. (25) was used to extract DNA from whole blood. Neonates were genotyped by a validated multiplex polymerase chain reaction (PCR)/double digestion assay (J.Girouard, R.Delage, L.Jacques and F.Rousseau, manuscript in preparation). This method is a PCR/restriction-digest assay for the simultaneous detection of C282Y and H63D mutations. Briefly, two pairs of oligonucleotide primers, one flanking the H63D locus (forward 5'-GTCTCCAGGTTCACACTCTC'-3 and reverse 5'-TGTTCCGACCCCTAAAAAGG-3') and one flanking the C282Y locus (forward 5'-CAATGGGGATGGGACCTACC-3' and reverse 5'-CACTGATGACTCCAATGACT-3') were designed (software OLIGO® 4.0, National Biosciences, Plymouth, MN). The PCR was performed with 0.8 U Taq Hot Star (Qiagen), Qiagen PCR buffer 1x, 200 µM dNTPs, 6 pmol of each primers and ~50 ng of DNA in a final volume of 10 µl. Temperature cycles were: 95°C for 15 min, 30 cycles at 95°C for 45 s, 57°C for 30 s, 72°C for 20 s and a final elongation at 72°C for 7 min. Then, the PCR products were digested with SnaB1 (2.5 U) and BspH1 (2.5 U) (New England Biolabs, Missisauga, Ontario, Canada) at 37°C for 90 min (total volume = 30 µl). C282Y mutation creates a unique SnaB1 restriction site. Inversely, the H63D mutation retrieves a unique BspH1 restriction site. Referred patients (n = 358) from one laboratory were genotyped with a standard PCR/digestion assay (26). For the 726 other patients, an allele-specific oligonucleotide (ASO–PCR) assay was used (27). All PCR fragments were detected on agarose gel with ethidium bromide staining.

Statistical analysis
We calculated allele and genotype frequencies for both mutations in neonates and in referred patients. Fisher’s exact test was used to compare the frequencies observed in neonates with other population studies from different countries. We performed chi-square tests to verify Hardy–Weinberg equilibrium for both mutations and to compare genotype and allele frequencies of the neonates and referred patients. Enrichment factors were calculated between neonates and referred individuals for each genotypes of interest with respect to HH (C282Y-YY, H63D-DD and compound heterozygotes). We used enrichment factors instead of odd ratios because the referred group contains individuals with other diseases clinically similar to HH. We assessed linkage disequilibrium between the two mutations with chi-square analysis. Only phased chromosomes were included for allele calculations.


   ACKNOWLEDGEMENTS
 
We thank Ms Louise Jacques of the haematology laboratory of St-Sacrement’s Hospital for her helpful collaboration in collecting samples and compiling patients results. The Research Centre and Research Unit is supported by the Fonds de la Recherche en Santé du Québec. Y.G. holds a research scholarship from the FRSQ. F.R. is a CIHR Scientist.


   FOOTNOTES
 
+ To whom correspondence should be addressed at: Unité de Génétique Humaine et Moléculaire, CHUQ, Hôpital St-François d’Assise, 10 rue de l’Espinay, G1L 3L5 Québec, Canada. Tel: +1 418 525 4470; Fax: +1 418 525 4429; Email: francois.rousseau@crsfa.ulaval.ca Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
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