Introduction

Many chromosomal loci occur in different forms in different individuals; these different forms are called alleles. A haplotype can be defined as the alleles at different loci that are inherited from one parent. The presence of an ancestral haplotype in hemochromatosis, concomitant with a common ancestral origin for the disorder, was first proposed by Simon et al. in 1987. The aim of this chapter is to present the evidence that such a haplotype exists, and to describe its geographical distribution and likely origin. Because the HFE gene has now been identified, the characterization of the ancestral haplotype postgene identification will be discussed, together with the implications this has on our understanding of the apparent correlation between the presence of the ancestral haplotype and severe clinical expression of hemochromatosis.

Haplotype analysis in hemochromatosis

A significant step towards understanding the pathogenesis of hemochromatosis came in 1975 with the demonstration that the gene for hemochromatosis was clearly linked to HLA-A3 in the Brittany population in France. Subsequent studies confirmed the HLA-A3 association in other countries: for example, the UK3, Canada, Australia, Germany Sweden, and the US. The HLA-A gene is a classical class I MHC gene, which lies close to the other classical class I genes of the MHC on the short arm of chromosome 6 at 6p21.3. These genes are highly polymorphic and are thus represented by many allelic forms. Alleles at HLA-A and HLA-B are usually inherited together in an HLA haplotype, their joint inheritance being a function of their close physical proximity.