ArticlesPenetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA
Introduction
The revolution in molecular biology has made possible the ready determination of a person's genotype at any given locus. This opportunity has engendered some enthusiasm for the screening of populations for mutations associated with disease or disease susceptibility, particularly diseases that are readily treated or prevented. Three factors must be taken into account in deciding how appropriate and cost-effective such screening is: prevalence, effectiveness of intervention, and penetrance. For example, Tay-Sachs disease is frequent in the Ashkenazi Jewish population and the penetrance (proportion of affected individuals who show the mutation phenotype) is high; screening is readily justified in populations where termination of the pregnancy is an option.1 However, the case for screening for mutations of genes such as BRCA1 is much less clear because of the low or uncertain penetrance of mutations and the drastic nature of some of the preventative measures that have been suggested.2
Hereditary haemochromatosis is an iron-storage disease whose phenotype is characterised by biochemical changes reflecting abnormal iron homoeostasis (eg, changes in transferrin saturation and serum ferritin concentrations) and total-body iron burden; signs and symptoms (eg, darkening of the skin, arrhythmias, loss of body hair, or impotence in men); pathological changes in organs (eg, hepatic fibrosis, abnormal liver function tests, or raised blood-sugar levels); and death. The HFE gene was cloned in 1996,3 and homozygosity for the 845G→A (C282Y) mutation has been found in more than 80% of patients diagnosed with iron overload due to hereditary haemochromatosis.3, 4, 5, 6 Compound heterozygotes for the C282Y and 187C→G (H63D) mutations are also over-represented in the haemochromatosis population.7, 8 This disease has been regarded as one of the most common genetic disorders of northern Europeans9, 10—about five per 1000 population are homozygous for the C282Y mutation.
Because the homozygous genotype for haemo-chromatosis is common, and because iron overload is readily treated by phlebotomy, the mutation has been regarded as ideally suited for population screening. Even before detection of homozygotes and compound heterozygotes by DNA analysis was possible, screening was thought to be cost-effective.11 With the availability of DNA-based detection of the haemochromatosis genotypes, the case for screening has seemed even more compelling.12 However, although most patients with European ancestry who have been diagnosed clinically with haemochromatosis have either the C282Y/C282Y or the C282Y/H63D genotypes, there is scant and conflicting information about the number of people in the general population with this genotype who have clinical manifestations caused by the mutation and not merely associated with it.13 In reality, practising physicians rarely encounter patients with the “bronzed diabetes” that is the classical hallmark of the severe, advanced form of the disease.14 None of the previous studies of the penetrance of clinical manifestations of haemochromatosis compared patients with an adequate control group to make it possible to assess which symptoms were due to haemochromatosis. To address this question, we assessed more than 41 000 individuals attending a health appraisal clinic in the USA for haemochromatosis mutation status, signs and symptoms of haemochromatosis, and biochemical abnormalities suggestive of the disorder.
Section snippets
Methods
Kaiser-Permanente is a large system of integrated medical care with about 8 000 000 members in several states of the USA. The current studies were carried out in San Diego, CA, where 500 000 individuals, representing about a third of the population of the metropolitan area, are members of the Kaiser Permanente medical care programme. There is no barrier to entry into the programme for patients who join as a part of an employee group or who have MediCare. In any 4-year period, 81% of adult
Results
The present analysis was undertaken after 41 038 individuals had been screened and 152 homozygotes for the C282Y mutation and 616 compound heterozygotes for the C282Y and H63D mutations had been identified. The demographic composition of the population is summarised in table 1. Of the 152 homozygotes, 45 had previously been diagnosed with haemochromatosis. In most of these individuals, the disorder was detected during an earlier visit to the Health Appraisal Clinic at a time when attendees were
Discussion
We found that the symptoms commonly associated with haemochromatosis were not significantly more prevalent among homozygotes or compound heterozygotes than among controls. This finding was true even among subsets of older patients or of patients with raised ferritin concentrations. There was no significant aggregation of symptoms associated with hereditary haemochromatosis in C282Y homozygotes, even when stratified by age or biochemical measurements of iron load. Only a history of hepatitis or
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Presented in part at the 42nd annual meeting of the American Society of Hematology, San Francisco, CA, USA; Dec 1–5, 2000