HEMOCHROMATOSIS - GENETICS HELPS TO DEFINE A MULTIFACTORIAL DISEASE

Hereditary hemochromatosis (HH) is a common autosomal recessive disord er that can result in iron overload and a wide range of clinical compl ications, including hepatic cirrhosis, diabetes mellitus, hypopituitar ism, hypogonadism, arthritis, and cardiomyopathy. People with HH can b e detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic p hlebotomy provides effective treatment for iron overload and may preve nt complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screenin g who will develop serious complications of HH is unknown. The genetic s of HH may help to resolve these questions. The gene, HFE, and two mu tations, C282Y and H63D, have been identified; the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function, Most people with HH are C282Y h omozygotes, a small proportion are compound heterozygotes or H63D homo zygotes, and some have no identifiable HFE mutation ol are HFE heteroz ygotes, suggesting that additional mutations associated with HH are ye t to be found. Gender and environmental agents, such as alcohol and di etary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying fa ctors. HFE mutations also appear to increase the likelihood of iron ov erload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HPI is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene-gene and gene-environment interactions. (C) Munksgaard, 1998.