HLA haplotypes associated with hemochromatosis mutations in the Spanish population

The present study is an analysis of the frequencies of HLA-A and -B antigens and HLA haplotypes in two groups of individuals homozygous for the two main HFE mutations (C282Y and H63D) and a group heterozygous for the S65C mutation.

The study population includes: 1123 healthy individuals, 100 homozygous for the C282Y mutation, 138 homozygous for the H63D mutation and 17 heterozygous for the S65C mutation. HFE and HLA alleles were detected using DNA-based and microlymphocytotoxicity techniques respectively.

An expected significant association between C282Y and the HLA-A3/B7 haplotype was found, but other HLA haplotypes carrying the -A3 antigen were found: HLA-A3/B62 and HLA-A3/B44. Also, a significant association between H63D mutation and HLA-A29/B44 haplotype was found, and again other HLA haplotypes carrying the HLA-A29 antigen were also found: HLA-A29/B14 and HLA-A29/B62. In addition, the S65C mutation seems to be associated with a HLA haplotype carrying the HLA-A26 antigen.

These findings clearly suggest that HLA-A3/B7 and HLA-A29/B44 are the ancestral haplotypes from which the C282Y and H63D mutations originated, respectively. The frequencies of these mutations in different populations, their geographical distribution, and the degree of the statistical association to the ancestral haplotypes, suggest that the H63D mutation must have occurred earlier than the C282Y mutation.