Reduced hepcidin levels leads to increased release of iron from intestinal cells and macrophages, elevating plasma ICG-001 in vivo transferrin saturation and causing deposition of iron in the liver and other tissues.4 Individuals homozygous for the mutation that leads to the C282Y substitution of tyrosine for cysteine at amino acid 282 in the HFE protein are at increased risk of iron overload5 and account

for 82%–90% of clinical diagnoses of hereditary hemochromatosis for those individuals of northern European descent.6 We have recently shown that the majority of C282Y homozygotes (82% of men and 65% of women) have elevated serum ferritin and, based on objective criteria, 28% of male and 1% of female C282Y homozygotes develop iron overload-related disease by, on average, 65 years of age. People having a single copy of both the C282Y and H63D (substitution of aspartic acid for histidine at amino acid 63) mutations in HFE (described as compound heterozygotes) have, on average, higher serum ferritin and transferrin saturation levels than people with neither HFE mutation, although they are not at increased risk of iron overload–related disease.7 Previous studies of the association

between HFE genotype and risk of colorectal cancer and breast cancer have provided inconsistent results,8–17 possibly related to the small numbers of C282Y homozygous participants (see Supporting Doxorubicin purchase Materials). We assessed the relationships between the risk of cancer including breast, colorectal, and prostate cancers and the C282Y variant acetylcholine of the HFE gene using a prospective cohort study. C282Y, substitution of tyrosine for cysteine at amino acid 282; CI, confidence interval; H63D, substitution of aspartic acid for histidine at amino acid 63; HFE, hemochromatosis protein; HR, hazards ratio. From 1990–1994, the Melbourne Collaborative Cohort Study

enrolled 41,514 people (24,469 women) aged between 27 and 75 years (99.3% were 40–69 years) in Melbourne, Australia. Participants were recruited using Electoral Rolls (voting is compulsory for Australian citizens) and by advertisements and community announcements. Approximately one-quarter of the participants were born in Greece, Italy, or Malta, but because the prevalence of the C282Y variants in the HFE gene was low in this group,18 genotyping was restricted to the 31,181 participants born in Australia, New Zealand, the United Kingdom, or Ireland. Because cancer diagnosis was ascertained prospectively, 1245 participants who had been diagnosed with any cancer before enrollment in the study were excluded from the analysis. A further 41 were excluded because their baseline blood samples were missing or they had insufficient DNA for genotyping, leaving 29,895 eligible participants. The study protocol was approved by the Cancer Council Victoria’s Human Research Ethics Committee (Project No. HREC0105).