title: Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis.
abstract: The present study is an analysis of the frequencies of HFE mutations in patients with different forms of iron overload compared with the frequencies found in healthy subjects from the same region. The frequencies of HLA-A and -B antigens and HLA haplotypes were also analyzed in the same subjects. The study population included: 71 healthy individuals; 39 genetically and clinically well-characterized patients with genetic hemochromatosis (HH); and 25 patients with non-classical forms of iron overload (NCH), excluding secondary hemochromatosis. All subjects were HLA-typed and HFE-genotyped by the oligonucleotide ligation assay (OLA). The gene frequencies found for the C282Y and H63D mutations of HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 and 0.04 in HH patients, and 0.08 and 0.48 in NCH patients. An expected significant association between HH and HLA-A3 was observed, which was found to be in linkage disequilibrium with the C282Y mutation. A new association was seen, however, between HLA-A29 and NCH, in linkage disequilibrium with the H63D mutation. Again as expected, the HLA-B antigen B7 was associated with HH in linkage disequilibrium with HLA-A3. In addition, the HLA-B antigen B44 was found to be associated with NCH but not in linkage disequilibrium with either A29 or the H63D mutation. In conclusion, a new association of the HFE H63D mutation with forms of hemochromatosis other than HH and a new association between the HLA phenotype A29 and the HFE H63D mutation were found in the same patients. These findings reinforce evidence for the involvement of the major histocompatibility class I in iron metabolism, supporting the notion of a physiological role for the immunological system in the regulation of iron load.
authors.affiliation: Santo António General Hospital, Largo do Prof. Abel Salazar, no.1, P-4050 Porto, Portugal.
authors.forename: G
authors.initials: G
authors.lastname: Porto
authors.forename: H
authors.initials: H
authors.lastname: Alves
authors.forename: P
authors.initials: P
authors.lastname: Rodrigues
authors.forename: J M
authors.initials: JM
authors.lastname: Cabeda
authors.forename: C
authors.initials: C
authors.lastname: Portal
authors.forename: A
authors.initials: A
authors.lastname: Ruivo
authors.forename: B
authors.initials: B
authors.lastname: Justiça
authors.forename: R
authors.initials: R
authors.lastname: Wolff
authors.forename: M
authors.initials: M
authors.lastname: De Sousa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005293:Ferritins / Q000097:blood; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D019190:Iron Overload / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D014168:Transferrin / Q000235:genetics / Q000378:metabolism
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron