Contribution of different HFE genotypes to iron overload disease: a pooledanalysis

Purpose: To determine the contribution of the C282Y and H63D mutations in t he HFE gene to clinical expression of hereditary hemochromatosis. Methods: Pooled analysis of 14 case-control studies reporting HFE genotype data, to evaluate the association of different HFE genotypes with iron overload. In addition, we used data from the pooled analysis and published data to estim ate the penetrance of the C282Y/C282Y genotype. Results: Homozygosity for t he C282Y mutation carried the largest risk for iron overload (OR = 4383, 95 % CI 1374 to >10,000) and accounted for the majority of hemochromatosis cas es (attributable fraction (AF) = 0.73). Risks for other genotypes were much smaller: OR = 32 for genotype C282Y/H63D (95% CI 18.5 to 55.4, AF = 0.06); OR = 5.7 for H63D/H63D (95% CI 3.2 to 10.1, AF = 0.01); OR = 4.1 for C282Y heterozygosity (95% CI 2.9 to 5.8, with heterogeneity in study results, ma king this association uncertain); and OR = 1.6 for H63D heterozygosity (95% CI 1 to 2.6, AF = 0.03). Estimates of penetrance for the C282Y/C282Y genot ype were highly sensitive to estimates of the prevalence of iron overload d isease. At a prevalence of 2.5 per 1000 or less, penetrance of the C282Y/C2 82Y genotype is unlikely to exceed 50%. Penetrance of other HFE genotypes i s much lower. Conclusions: C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk. Our data indicate a gradient of risk associated with different HFE genotyp es and thus suggest the presence of other modifiers, either genetic or envi ronmental, that contribute to the clinical expression of hemochromatosis.