Purpose: To determine the contribution of the C282Y and H63D mutations in the 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 HFEgenotypes with iron overload. In addition, we used data from the pooled analysis and published data to estimate the penetrance of the C282Y/C282Y genotype. Results: Hornozygosity for the C282Y mutation carried the largest risk for

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... n overload (OR = 4383, 95% C I 1374 to >10,000) and accounted forthe majority of hernochromatosis cases {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/N63D (95% CI 3.2 to 10.1, AF = 0.01); OR = 4.1 for C282Y heterozygcsity ((95% CI 2.9 to 5.8, with heterogeneity in study results, making this association uncertain); and OR = 1.6 for HGJD heterozygosity (95% CI 1 to 2.6, AF = 0.03). Estimates of penetrance for the C282Y/C282Y genotype were hrghly sens~tive to estimates of the prevalence of iron overload disease. At a prevalence of 2.5 per 1000 or less, penetrance of the C282Y/C282Y genotype is unlikely to exceed 50%. Penetrance of other HFE genotypes is 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 genotypes and thus suggest the presence of other modifiers, either genetic or environmental, that contribute to the clinical expression of hemochromatosis. Genetics In Medicine, 2000:2(5):2?1-277. Hereditary hernochromatosis is a common genetic disorder for which there is a simple and effective intervention.L2 The complications of hemochromatosis are caused by iron overloadthat is, the accumulation of excess iron in body tissues. These complications include cirrhosis, primary liver cancer, diabetes, and cardiomyopathy. they can be prevented by treatment with periodic phlebotomy.lJ The gene for hemochromatosis, designated HFE, has been sequenced, and two HFE mutations, C282Y and H63D, have been identified?" With the discovery of these mutations, genetic testing has been proposed as a means to identify people with hemochromatosis before symptoms occur, so that preventive treatment can be initiated.5-6 To use genetic testing for either screening or diagnosis, however, the association berween different HFE geno-From rhr 'Dcp~nmcr~rr u [ h W~d~~i r r n r~r~r r r l ~t h r r r u n~l h l t~~i t n t : U~lrrrnrt~~~r~'N'rrrlrinp Ion Srrtnk, lWa,bingrurr: 'Nai~iurtul Ccn~rr)br alrorrrr Diw4lrcPmmrior1 unll Hv?rlrlr P n l . mnhor~. CrrrtmJm Uirwr Conrmtand l'w~rr~rian; 'Epillr.nritltv R o h w m OIPkc Cmrrrr IhrDrwsr Cni~rmlnr~d hwnEinrt: r~nd'rlfir.:o]'Ue~~nit.~ r~r i d l l i~m w Prdkmrinn. Urrlr~~ra for Disrnw Cuntml and Prr~urrrinn, Atlarrr, U~wrgi.l. Bt&, hfll, PhD, Ihplrfmmr of klr~lml Ifishlv nrld Eflru~. Rn* 357 l2R ['rli\usliII' $ Washington, I959 NE Pnrrfi. Rwrrr hW. h~r f k WA 98195. E -w~i l : ~. J I u I~% ?~ i&mhnrffoa.d~d. R f i u i d : Mddr MW. Amprd: May 26. , mm.