Multicentric origin of hemochromatosis gene (HFE) mutations

Genetic hemochromatosis (GH) is believed to be a disease restricted to thos e of European ancestry. In northwestern Europe, >80% of GH patients are hom ozygous for one mutation, the substitution of tyrosine for cysteine at posi tion 282 (C282Y) in the unprocessed protein. In a proportion of GH patients , two mutations are present, C282Y and H63D. The clinical significance of t his second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mu tations differ, C282Y being limited to those of northwestern European ances try and H63D being found at allele frequencies >5%, in Europe, in countries bordering the Mediterranean, in; the Middle East, and in the Indian subcon tinent. The C282Y mutation occurs on a haplotype that extends less than or equal to 6 Mb, suggesting that this mutation has arisen during the past 2,0 00 years. The H63D mutation is older and does not occur on such a large ext ended haplotype, the haplotype in this case extending less than or equal to 700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and hav e found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE ge ne has been the subject of selection pressure. These selection pressures co uld be due to infectious diseases, environmental conditions, or other genet ic disorders such as anemia.