EVIDENCE THAT THE ANCESTRAL HAPLOTYPE IN AUSTRALIAN HEMOCHROMATOSIS PATIENTS MAY BE ASSOCIATED WITH A COMMON MUTATION IN THE GENE

Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been ident ified. The aim of this study was to look for clinical evidence that th e predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metab olism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two c opies, one copy, and no copies of the ancestral. haplotype). We also e xamined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. T hese analyses indicate that (i) HC patients with two copies of the anc estral haplotype show significantly more severe expression of the diso rder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the prese nce of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.