H63D is an haemochromatosis associated allele

Editor,—The UK Haemochromatosis Consortium’s report ( Gut 1997; 41 :841–4) questions the importance of the H63D allele in hereditary haemochromatosis (HHC). In their commentary, Goldwurm and Powell ( Gut 1997; 41 :855–6) also doubt the relevance of H63D. However, there is compelling evidence that the H63D allele is associated with HHC.1-12 To evaluate the association of H63D with haemochromatosis, one must first recognise that H63D and C282Y are independent mutations of the HFE gene. Because the C282Y mutation is so common and is highly penetrant, homozygous C282Y predominates among cases of haemochromatosis, and H63D is not observed in C282Y homozygotes. If one excludes from analysis the C282Y homozygotes, then the strong association of H63D with HHC becomes apparent. For five large series from North America1-5 that have been analysed in this manner, we found a highly significant (p=0.000001) twofold “enrichment” of HHC cases with H63D, compared with random control cases. For studies reported from Europe,6-10 we also found a highly significant “enrichment”, in which groups with HHC have roughly twice the frequency of H63D compared with control groups: Borot et al , p=0.003; Jouanolle et al , p=0.00004; Carella et al , p= 0.073; Martinez et al , p=0.000002; and Gottschalk et al , p=0.02. When all the data reported from Europe and from North America are combined, including those of the Consortium, the association of H63D with HHC is quite significant (p < 0.000001). The strong association of H63D with haemochromatosis might depend on the fact that patients who are compound heterozygotes—that is, C282Y/H63D, are at risk of developing clinically significant iron overload. Therefore, one may question whether H63D itself is associated with haemochromatosis. We have tested this possibility by re-analysing all the published data (combining data from 10 studies, including those of the UK Haemochromatosis … Dr Robson (email:krobson{at}hammer.imm.ox.ac.uk).