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

The aim of this study was to assess and to compare the role of HFE polymorp hisms 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 pa irs (562 monozygotic and 571 dizygotic twins). Serum iron, transferrin, tra nsferrin saturation with iron, and ferritin were measured, and the HFE C282 Y and H63D genotypes were determined. The frequency of the C282Y allele was .072, and that of the H63D allele was .141. Significant sources of variati on in the indices of iron status included age, sex, age-sex interaction, bo dy-mass index, and both the C282Y and H63D genotypes. The iron, transferrin , and saturation values of CC and CY subjects differed significantly, but t he ferritin values did not. After correction for age and body-mass index, 2 3% and 31% of the variance in iron, 66% and 49% of the variance in transfer rin, 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 f or <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 i n iron status from the CC and HH homozygotes and that serum transferrin sat uration is more affected than is serum ferritin. There are highly significa nt effects of other as-yet-unidentified genes on iron stores, in addition t o HFE genotype.