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.
Beutler
Ernest
E
Department of Molecular and Experimental Medicine, Division of Hematology, The Scripps Research Institute, La Jolla, California 92037, USA. beutler@scripps.edu
West
Carol
C
D024506:5' Flanking Region / Q000235:genetics*; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D019143:Evolution, Molecular; D005293:Ferritins / Q000097:blood; D005787:Gene Frequency; D005820:Genetic Testing; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D019189:Iron Metabolism Disorders / Q000453:epidemiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D014168:Transferrin / Q000378:metabolism
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins