Polymorphisms in the 5′ Flanking Region of the HFE Gene: Linkage Disequilibrium and Relationship to Iron Homeostasis,

We have discovered two single-nucleotide polymorphisms in the 5′ flanking region of the HFE gene. These mutations are −970 T→G and −467 C→G, numbering from the ATG start codon. When a T was present at −970, a C was always found at −467. The C allele was the less common at nt −467 with a gene frequency of 0.31 in white subjects with wild-type HFE. Slightly lower gene frequencies were observed in a small number of Hispanic and African–American subjects and a slightly higher frequency in a few Asian subjects. The less common −467 mutation was found in almost 12 chromosomes that bore the 845G→A (C282Y) mutation and was significantly more prevalent in chromosomes containing the 187C→G (H63D) mutation. Although this mutation is near an HNF3B/HFH2 site, its presence did not seem to affect iron metabolism as judged by the serum ferritin or transferrin saturation levels. The tighter association of the −467 polymorphism with the C282Y mutation is consistent with other data that suggest that the C282Y mutation has occurred relatively recently and that the H63D mutation is considerably older.