rather than recombination between A*03 and C282Y, could explain some regional disease associations with non-A*03 haplotypes.''[11] Conversely, other investigators suggest that ''another haplotype containing HLA-B*07 and HLA-Cw*0702 contains an element affording protection against hemochromatosis.''1-12-1 Locus heterogeneity also has been proposed as an explanation of the observations that the distribution of HFE genotypes in patients deviates from that expected under Hardy-Weinberg equilibrium.1-4-1 It is possible that multiple MHC haplospecific regions contribute to the hemochro-matosis phenotype.[8] For example, a modifying gene in the region of D6S105 on Ch6p may affect the severity of iron overload in hemochromatosis.1-13-1 Among hemochromatosis patients homozygous for C282Y, those with D6S105 allele 8 homozygosity had significantly higher hepatic iron indices than those heterozygous or nullizy-gous for D6S105 allele 8.[13] In contrast, an analysis of microsatellites between HLA-A*03 and HFE in C282Y homozygotes and their siblings revealed no evidence of modifier genes in this region.[14] Polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-a) gene, also located within the MHC region, have been implicated in the development of iron overload or expression of its complications by some[15] but not other investigators.[16]

In addition to Ch6p alleles, the expression of iron overload in individuals with hemochromatosis is associated with sex, age, intake of iron and other dietary factors, coinheritance of forms of hereditary anemia that stimulate iron absorption, and the severity of physiological and pathological iron and blood loss.[1,2,11] At present, only short-term longitudinal studies to ascertain the development of iron overload and its complications in C282Y

homozygotes have been reported.[17] Therefore debate regarding the penetrance of iron overload and associated complications in cohort analyses of C282Y homozygotes is unresolved.[18] Until long-term studies are conducted, estimates of penetrance will remain controversial.

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