Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins

Am J Hum Genet. 2000 Apr;66(4):1246-58. doi: 10.1086/302862. Epub 2000 Mar 15.


The aim of this study was to assess and to compare the role of HFE polymorphisms and other genetic factors in variation in iron stores. Blood samples were obtained from 3,375 adult male and female twins (age range 29-82 years) recruited from the Australian Twin Registry. There were 1,233 complete pairs (562 monozygotic and 571 dizygotic twins). Serum iron, transferrin, transferrin saturation with iron, and ferritin were measured, and the HFE C282Y and H63D genotypes were determined. The frequency of the C282Y allele was.072, and that of the H63D allele was.141. Significant sources of variation in the indices of iron status included age, sex, age-sex interaction, body-mass index, and both the C282Y and H63D genotypes. The iron, transferrin, and saturation values of CC and CY subjects differed significantly, but the ferritin values did not. After correction for age and body-mass index, 23% and 31% of the variance in iron, 66% and 49% of the variance in transferrin, 33% and 47% of the variance in transferrin saturation, and 47% and 47% of the variance in ferritin could be explained by additive genetic factors, for men and women, respectively. HFE C282Y and H63D variation accounted for <5% of the corrected phenotypic variance, except for saturation (12% in women and 5% in men). We conclude that HFE CY and HD heterozygotes differ in iron status from the CC and HH homozygotes and that serum transferrin saturation is more affected than is serum ferritin. There are highly significant effects of other as-yet-unidentified genes on iron stores, in addition to HFE genotype.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Twin Study

MeSH terms

  • Adult
  • Age Factors
  • Alleles
  • Amino Acid Substitution / genetics*
  • Australia
  • Biological Transport
  • Body Mass Index
  • Environment
  • Ethnicity / genetics
  • Female
  • Ferritins / blood
  • Ferritins / metabolism
  • Gene Frequency
  • Genetic Variation / genetics*
  • Genotype
  • HLA Antigens / genetics*
  • Haplotypes / genetics
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / genetics*
  • Humans
  • Iron / blood
  • Iron / metabolism*
  • Male
  • Membrane Proteins*
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Sex Factors
  • Statistics as Topic
  • Transferrin / metabolism


  • HFE protein, human
  • HLA Antigens
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Transferrin
  • Ferritins
  • Iron