American Journal of Medical Genetics 111:356–361 (2002) HFE Based Re-evaluation of Heterozygous Hemochromatosis Romain Moirand, 1 * Dominique Guyader, 1 Michel Henry Mendler, 1 Anne Marie Jouanolle, 2 Jean Yves Le Gall, 2 Ve ´ ronique David, 2 Pierre Brissot, 1 and Yves Deugnier 2 1 Clinique des Maladies du Foie and INSERM U522, Rennes, France 2 Laboratoire de Ge´ne´tiqueMole´culaire andUPR-CNRS 6061,Ho ˆ pital Pontchaillou, Rennes, France Homozygosity for the C282Y mutation in the HFE gene is strongly associated with here- ditary hemochromatosis. More than one subject out of 10 in the general population is a heterozygote for the C282Y mutation. In this study, we address whether or not conclusions drawn from HLA-based family studies regarding the expression of hete- rozygous hemochromatosis are applicable to C282Y heterozygotes. The correlation between HLA-inferred and HFE genotypes and the variation of serum iron tests accord- ing to HFE genotype and other factors were studied in persons from well-characterized hemochromatosis pedigrees. Subjects were tested for both C282Y and H63D mutations. The following factors were studied: age, sex, alcohol consumption, body mass index, liver function tests, serum lipids and glu- cose, serum iron, transferrin saturation, and ferritin. HLA-inferred heterozygotes were C282Y heterozygotes in only 70% and com- pound heterozygotes (i.e., heterozygotes for both C282Y and H63D) in 20%. C282Y heterozygotes did not differ from wild type homozygotes in terms of serum iron tests. Only compound heterozygotes presented with slightly increased transferrin satura- tion. On the other hand, increased serum ferritin was strongly associated with over- weight or lipidic or glucose abnormalities. C282Y heterozygotes selected from family studies do not have greater serum iron tests than wild type homozygotes, except for com- pound heterozygotes, and therefore should not require special followup. The discovery of abnormal iron tests in a C282Y hetero- zygote should lead to workup for other causes of iron overload. ß 2002 Wiley-Liss, Inc. KEY WORDS: hemochromatosis; HFE gene; overweight; ferritin; trans- ferrin saturation INTRODUCTION Hemochromatosis is an autosomal recessive disorder characterized by abnormal intestinal iron absorption, which leads to progressive increase of total body iron and ultimately to clinical complications [Brissot and Deugnier, 1991]. The gene was identified in 1996 on chromosome 6 [Feder et al., 1996], and designated as the ‘‘HFE gene’’. Two main mutations have been described. The C282Y mutation is clearly associated with hemo- chromatosis, and most patients with hemochromatosis are C282Y homozygotes [Brissot et al., 1998]. The role of the H63D mutation is controversial [Beutler, 1997] except when it is associated with the C282Y mutation. Indeed, compound heterozygotes may present with hemochromatosis [Beutler, 1997; Brissot et al., 1998], but with low penetrance and mild expression [Moirand et al., 1999a], and compound heterozygosity may lead to overexpression of acquired iron overload conditions, such as the insulin resistance-associated iron overload syndrome [Mendler et al., 1999]. Before the description of the HFE gene, linkage of hemochromatosis to HLA permitted indirect assign- ment of the heterozygous genotype to family members of putative homozygous probands [Simon et al., 1977]. HLA-based studies concluded that heterozygotes pre- sented with mean serum iron tests greater than homo- zygote normals, and that the proportion of relatives with abnormal serum iron tests was greater in heterozygotes than in homozygote normals [Cartwright et al., 1979; This work was presented in part at the 49th Annual Meeting of the American Association for the Study of Liver Diseases, 1998, Chicago. Grant sponsor: Association pour la Recherche contre le Cancer; Grant sponsor: Association Fer et Foie; Grant sponsor: Comite ´ de la Recherche Clinique de Rennes; Grant sponsor: Programme Hospitalier de Recherche Clinique 1997. *Correspondence to: Romain Moirand, Clinique des Maladies du Foie, Ho ˆpital Pontchaillou, 35033 Rennes Cedex, France. E-mail: moirand@sunaimed.univ-rennes1.fr Received 28 June 2000; Accepted 20 March 2002 DOI 10.1002/ajmg.10547 ß 2002 Wiley-Liss, Inc.