Hereditary hemochromatosis (HH) is a common autosomal recessive disorder causing inappropriate dietary iron absorption that affects North Europeans. HH is associated with the C282Y mutation of the HFE gene, and the H63D mutation to a lesser degree. Both mutations are abundant in Europe, with H63D also appearing in North Africa, the Middle East, and Asia. Emigration from Europe over the past 500 years has introduced C282Y and H63D to America, Australia, New Zealand, and South Africa in an essentially predictable fashion. The distinctive characteristics of the population genetics of HH are the confined racial distribution and high frequency in North European peoples. C282Y frequencies in North Europeans are typically between 5% and 10%, with homozygotes accounting for between 1/100 and 1/400 of these populations. The scarcity of the C282Y mutation in other populations accounts for the lack of HH in non-Europeans.

Most cases of genetic hemochromatosis (GH) are associated with the HFE C282Y/C282Y (p.Cys282Tyr/p.Cys282Tyr) genotype in white populations. The symptoms expressed by C282Y homozygotes are extremely variable. Only a few suffer from an overt disease. Several studies have suggested that, in addition to environmental factors, a genetic component could explain a substantial part of this phenotypic variation, although very few genetic factors have been identified so far. In the present study, we tested the association between common variants in candidate genes and hemochromatosis penetrance, in a large sample of C282Y homozygotes, using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. We focused on two biologically relevant gene categories: genes involved in non-HFE GH (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway (BMP2, BMP4, HJV, SMAD1, SMAD4, and SMAD5) and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common single-nucleotide polymorphism (SNP) in the BMP2 genic region (P=4.42x10-5). Mean ferritin level, adjusted for age and sex, is 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. Our results further suggest an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV, with a small additive effect of a SNP in BMP4. This first reported association between common variants in the BMP pathway and iron burden suggests that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. Our results also highlight the BMP regulation pathway as a good candidate for identification of new modifier genes.

The gene whose alteration causes hereditary hemochromatosis (HFE according to the international nomenclature) was, more than 20 years ago, shown to map to 6p21.3. It has since escaped all efforts to identify it by positional cloning strategies. Quite recently, a gene named HLA-H was reported as being responsible for the disease. Two missense mutations, Cys282Tyr (C282Y) and His63Asp (H63D), were observed, but no proof was produced that the gene described is the hemochromatosis gene. To validate this gene as the actual site of the alteration causing hemochromatosis, we decided to look for the two mutations in 132 unrelated patients from Brittany. Our results indicate that more than 92% of these patients are homozygous for the C282Y mutation, and that all 264 chromosomes but 5 carry either mutation. These findings confirm the direct implication of HLA-H in hemochromatosis.

present in 70% of homozygotes, and an extended ancestral A candidate gene (HFE) has been described for hereditary haplotype including HLA-A3 and other DNA markers on hemochromatosis on chromosome 6. The study of well-dechromosome 6 has been reported. [5][6][7] A candidate gene has fined atypical hemochromatosis families using genetic markbeen described (HFE), 4.5 Mb telomeric to HLA-A. 8 The use ers may increase our understanding of the sensitivity and the of haplotype analysis and the search for recombinations in specificity of genotyping in hemochromatosis. One hundred families are considered to be powerful tools for localizing a and thirteen Canadian families with genetic hemochromatosis gene responsible for a disease. However, in hemochromatowere surveyed to find atypical families as possible examples sis, it had been difficult to prove informative genetic recombiof people with genetic recombinations. All families underwent nations for several reasons: 1) the late presentation of the clinical investigations including iron studies and HLA typing.probands in the fifth or sixth decade often means that parenEach individual was typed at three polymorphic microsatellite tal DNA is not available; 2) ascertainment of the phenotypic loci (D6S105, D6S1260, and D6S299) on chromosome 6. Sixstatus may be difficult and may vary between studies; and teen subjects were studied for the two missense mutations 3) lack of heterogeneity with available DNA markers has described for the candidate gene for hemochromatosis reduced the number of informative family studies. In this (C282Y, H63D). There were eight HLA-identical siblings study, 113 Canadian families with genetic hemochromatosis found in four different families (five men, three women; age were reviewed, and DNA studies are presented in 5 atypical range 30-72) with normal transferrin saturation and ferritin families with potential recombinations. levels. There were two patients identified who were homozy- PATIENTS AND METHODS gous for the C282Y mutation without biochemical evidenceA database of 113 Canadian families that had been investigated of iron overload, and two patients with no evidence of the by family studies was reviewed to search for families with potential mutation with significant iron overload. Our conclusions are genetic recombinations. All families were white with European anas follows: 1) finding HLA-identical siblings without iron overcestry. This study included 4 families in which one or more HLAload does not confirm a genetic recombination, 2) difficulties identical sibling was found without phenotypic expression of the in phenotypic definition of disease and the description of new disease, and 1 family in which two putative homozygotes produced iron overload syndromes that may differ from classical genetic an unaffected son. The diagnosis of hemochromatosis was based HC cause complicated genetic studies, and 3) finding iron-on clinical history, physical examination, and elevated serum ferriloaded patients without a C282Y mutation and patients that tin...