Concordance of iron indices in homozygote and heterozygote sibling pairs in hemochromatosis families: implications for family screening

Abstract

Background/aims: Concordance of iron indices between same-sex siblings homozygous for the cysteine-to-tyrosine substitution at amino acid 282 (C282Y) mutation suggests that the variable phenotype in hereditary hemochromatosis is caused by genetic factors. Concordance of iron indices between same-sex heterozygous sibling pairs would provide further evidence of genetic modifiers of disease expression, and guidance for family screening strategies of subjects heterozygous for the C282Y mutation.

Methods: We compared the iron indices of 35 C282Y homozygous and 35 C282Y heterozygous same-sex sibling pairs. To clarify whether concordance between siblings was due to environmental or genetic factors we compared the iron indices of 164 C282Y homozygous-normal, same-sex dizygotic twins.

Results: Serum ferritin (r=0.50, P=0.003), hepatic iron concentration (r=0.61, P=0.025) and hepatic iron index (r=0.67, P=0.01) were highly concordant in C282Y homozygotes. Heterozygote siblings were concordant for serum ferritin (r=0.76, P=0.0001) and transferrin saturation (r=0.79, P=0.0001). Homozygote-normal same-sex dizygotic twins were concordant for serum ferritin (r=0.62, P=0.0001) but not for transferrin saturation.

Conclusions: Concordance of iron indices exists in C282Y homozygote and heterozygote sibling pairs. Siblings of expressing C282Y heterozygotes require phenotypic assessment. These data provide evidence for modifying genes influencing disease expression in hemochromatosis.