Alleles at D6S265 and D6S105 define a haemochromatosis-specific genotype.

Hereditary haemochromatosis is an HLA-linked, recessive disorder with HLA-A3 a strong marker for the gene. We have identified molecular markers for two serologically indistinguishable subtypes of HLA-A3 and examined these in 42 patients with haemochromatosis. The common HLA-A3 subtype HLA-A*0301 (highly correlated with allele 1 of D6S265) was a slightly better marker for haemochromatosis (RR = 10.1, Chi2 = 30) than the serologically recognized A3 antigen (RR = 9.1; Chi2 = 27.3). Allele 8 of the more telomeric locus D6S105 was also strongly associated with haemochromatosis (RR = 13.0; Chi2 = 21.1) but alleles at this locus were not in strong linkage disequilibrium with HLA-A alleles in the control subjects. The co-occurrence of D6S265-1 and D6S105-8 alleles yielded a higher risk (RR = 16.9; Chi2 = 44). Homozygosity for the haplotype including these markers was specific for haemochromatosis, i.e. did not occur in 376 healthy subjects but was observed in 21.4% of patients. These results refine the HLA-A3 association with haemochromatosis, suggest that the haemochromatosis gene is located on the telomeric side of HLA-A and define a possible haplotype in which the first mutation may have occurred.