The HFE 5569A allele defines a low-risk haplotype for hereditary hemochromatosis

Hereditary hemochromatosis (HH; MIM 235200) is an autosomal recessive disorder of iron metabolism that is estimated to affect approximately 1 in 300 individuals of northern European origin. Several missense mutations have been reported in the HFE gene including: C282Y accounting for 80% to 90% of HH chromosomes, H63D which has been found on 40% to 70% of non-C282Y HH chromosomes, and S65C which has been found on 5% to 10% of non-C282Y HH chromosomes. In addition, HFE single nucleotide polymorphisms (SNPs) have been identified, including 5569G/A in intron 4. We analyzed 336 unrelated individuals that had been referred for hereditary hemochromatosis molecular testing. Each sample was tested for C282Y, H63D, S65C, and 5569G/A status, and data were compiled relative to clinical status. All sequence variants appeared to be in linkage disequilibrium, such that there were no individuals with any combination of more than two of these nucleotide changes. Allele frequencies for Y282, D63, and C65 were significantly greater in clinically affected individuals (as has been previously reported), whereas the frequency of the 5569A allele was significantly elevated in unaffected individuals in our population (P < 0.000001). These findings suggest that 5569G/A genotype screening can be used to modify the probability of HH when mutation screening results are inconclusive.