THE ANCESTRAL HEMOCHROMATOSIS HAPLOTYPE IS ASSOCIATED WITH A SEVERE PHENOTYPE EXPRESSION IN ITALIAN PATIENTS

We evaluate the relation between genotype and phenotype in 47 Italian male patients with homozygous genetic hemochromatosis (GH). Phenotype evaluation was based on the ratio of amount of iron removed (IR) by ph lebotomy and age (IR/age), Patients were divided in two classes of phe notype expression: class I included 26 patients with less severe iron overload (IR/age less than or equal to 0.33) and class II included 21 patients with a more marked one (IR/age >0.33). Genetic variability wa s assessed by haplotype analysis combining alleles at HLA-B, D6S265, H LA-A, and D6S105 loci, A common ancestral haplotype carrying D6S265-1, HLA-A3, and D6S105-8 alleles was present in 13 of 52 (25%) chromosome s in class I and in 24 of 42 (57%) chromosomes in class II (P = .0027) , Homozygotes and heterozygotes for the ancestral haplotype had higher iron indices than patients carrying two haplotypes other than the anc estral one, Seven of the eight patients homozygous for the ancestral h aplotype were in class II, heterozygotes were equally distributed betw een the two classes, whereas 14 of 18 carriers of other haplotype comb inations were in class I, Our results suggest that the gene defect lin ked to the ancestral haplotype is the result of a single, severe mutat ion. The high variability of phenotype expression in heterozygotes for the ancestral haplotype could be accounted for the contribution of th e mutation carried by the second haplotype. Combination of different m utations could be responsible for the variable degrees of iron overloa d found in patients with GH.