MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ASSOCIATIONS IN IRON OVERLOAD - EVIDENCE FOR A NEW LINK BETWEEN THE HFE H63D MUTATION, HLA-A29, AND NONCLASSICAL FORMS OF HEMOCHROMATOSIS

The present study is an analysis of the frequencies of HFE mutations i n patients with different forms of iron overload compared with the fre quencies found in healthy subjects from the same region. The frequenci es of HLA-A and -B antigens and HLA haplotypes were also analyzed in t he same subjects. The study population included: 71 healthy individual s; 39 genetically and clinically well-characterized patients with gene tic 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 assa y (OLA). The gene frequencies found for the C282Y and H63D mutations o f HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 an d 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 a ssociation was seen, however, between HLA-A29 and NCH, in linkage dise quilibrium with the H63D mutation. Again as expected, the HLA-B antige n B7 was associated with III-I 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 mutatio n. In conclusion, a new association of the HFE H63D mutation with form s of hemochromatosis other than HH and a new association between the H LA phenotype A29 and the HFE H63D mutation were found in the same pati ents. These findings reinforce evidence for the involvement of the maj or histocompatibility class I in iron metabolism, supporting the notio n of a physiological role for the immunological system in the regulati on of iron load.