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The HLA‐A1‐B8 haplotype hitchhiking with the hemochromatosis mutation: does it affect the phenotype?
Author(s) -
Olsson K. Sigvard,
Ritter Bernd,
Hansson Norbeth
Publication year - 2007
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2007.00953.x
Subject(s) - haplotype , genetics , biology , transferrin saturation , hemochromatosis , locus (genetics) , proband , hereditary hemochromatosis , phenotype , population , human leukocyte antigen , ferritin , allele , mutation , gene , medicine , antigen , biochemistry , environmental health , serum ferritin
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.