Background: Hemochromatosis is a recessively inherited disorder caused by a point mutation, C282Y of the HFE gene on chromosome 6p21.3 near the human leukocyte antigen (HLA) locus. It is unknown why some homozygotes develop a severe iron loading, while others do not. A recent study suggested that the A1-B8 haplotype may be associated with higher iron storage.
Methods: We studied HLA haplotypes of 85 probands, 31 females and 54 males, and their family members from a rural population where A1-B8 was common. We tested the hypothesis of a modifying effect of the A1-B8 haplotype.
Results: Most homozygotes had a mild phenotypic expression, and were often detected accidentally because of a laboratory routine including transferrin saturation. A disease-related morbidity [serum alanine aminotransferase (S-ALT) > 43 U] was present in 40%. Three had porphyria cutanea tarda. Two brothers with A1-B8 died of bronze diabetes, probably caused by co-inheritance of congenital spherocytosis. In females there were no significant differences in phenotypic expression between groups with regard to the presence or absence of A1-B8. Two females, <50 yr of age, with this haplotype had iron deficiency. Males with two copies of A1-B8 had significantly lower serum ferritin (P = 0.02) values than those without. Those with one A1-B8 haplotype were not different from those without. In men without A1-B8, those carrying HLA-A3 were not phenotypically different from those without this ancestral haplotype.
Conclusion: The A1-B8 haplotype hitchhiking with the C282Y mutation was not associated with a more efficient iron absorption. On the contrary, males with double copies of this haplotype expressed a milder phenotype, possibly an effect of local (environmental and/or genetic) factors.