HFE mutations, iron deficiency and overload in 10 500 blood donors

Abstract

Summary. People with genetic haemochromatosis (GH) accumulate iron from excessive dietary absorption. In populations of northern European origin, over 90% of patients are homozygous for the C282Y mutation of the HFE gene. While about 1 in 200 people in the general population have this genotype the proportion who develop clinical haemochromatosis is not known. The influence of HFE genotype on iron status was investigated in 10 556 blood donors. The allele frequencies of the C282Y and H63D mutations were 8´23% and 15´3% respectively. Heterozygosity for C282Y occurred in 1 in 7´9 donors, for H63D in 1 in 4´2 donors, and 1 in 42 were compound heterozygotes. Homozygosity for H63D occurred in 1 in 42 donors and 1 in 147 (72) were homozygous for C282Y. Mean values increased for transferrin saturation (TS) and serum ferritin (sFn), and decreased for unsaturated iron binding capacity (UIBC) in the order: donors lacking the mutations, H63D heterozygotes, C282Y heterozygotes, H63D homozygotes, compound heterozygotes and C282Y homozygotes, but serum ferritin (sFn) concentrations were no higher in H63D heterozygotes and C282Y heterozygous women than in donors lacking mutations. The percentage of donors failing the screening test for anaemia or of those with sFn , 15 mg/l did not differ among the genotype groups. C282Y and H63D heterozygotes and donors homozygous for H63D were at no greater risk of iron accumulation than donors lacking mutations, of whom 1 in 1200 had both a raised TS and sFn. The risk was higher for compound heterozygotes (1 in 80, P 0´003) and for C282Y homozygotes (1 in 5, P , 0´0001). There was no correlation between sFn and either age or donation frequency in C282Y homozygotes. None of the 63 C282Y homozygous donors interviewed showed physical signs of overload or were aware of relatives with haemochromatosis. The Welsh Blood Service collects blood from about 140 000 people each year including an estimated 950 who are homozygous for HFE C282Y. They are probably healthy and unaware of any family history of iron overload.

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

“…Ironically, two probands in our series, who had not received diagnoses of HH, were heterozygous for either the HFE C282Y or H63D substitutions. Heterozygosity for these polymorphisms was not associated with an iron overload phenotype in a large population study 25 and inheritance of these alleles in our HHCS probands did not alter their HHCS phenotype.…”

The molecular genetics of haemochromatosis

“…30 The highest frequencies have thus been reported in Ireland (28.4), 31 Brittany (17.4; unpublished result obtained from a sample of 796 subjects) and Wales (16.6), 32 whereas the lowest frequencies have been observed in Italy (3.2) and Greece (2.6). 11 These observations have often been related to the existence of a founder Celtic effect, 27,33 but a link with the Viking conquests and migrations has also been suggested.…”

A 6-year survey of HFE gene test for hemochromatosis diagnosis

“…The overall frequencies of HFE C282Y and H63D alleles, 7.7% and 14%, respectively, and genotypes among the Brittany population are comparable to other data available for the European population indicating 5% to 10% and 10% to 20% of C282Y and H63D allele frequencies, respectively. 32,33 The frequencies of the genotypes based on the detection of 478 probands phenotypically diagnosed before gene discovery from Brittany population agree with those reported about European Table 3 Genotype frequencies in prospectively HFE tested subjects after gene discovery (n ϭ 14) (n ϭ 10) (n ϭ 14) (n ϭ 713) (n ϭ 707) (n ϭ 712) descent, with 82.3% to 100% C282Y/C282Y and 4% to 5.44% C282Y/H63D. 14 -18 In the population of Brittany, the carrier prevalence of C282Y and H63D alleles, 12%, and 23.6%, respectively, underlined the high rate of transmission of alleles potentially associated with iron overload.…”