title: Does bilirubin protect against hemochromatosis gene (HFE) related mortality?
abstract: Serum bilirubin is an important antioxidant that is found at increased levels in hereditary hemochromatosis patients. We hypothesized that increased levels of serum bilirubin may play a protective role against oxidative stress induced by iron overload in carriers of mutations in the hereditary hemochromatosis gene (HFE). We studied the relation between serum total bilirubin, serum iron levels, the HFE C282Y and H63D mutations, and mortality. The study was conducted in 2,332 randomly selected subjects from the Rotterdam Study, a population-based follow-up study of people aged 55 years or over. Serum bilirubin levels were significantly correlated with serum iron (Pearson's correlation coefficient (r) = 0.4, P < 0.001), transferrin saturation (r = 0.4, P < 0.001), and serum ferritin (r = 0.2, P < 0.05). Carriers of the HFE mutations had higher levels of bilirubin compared to wild-type homozygotes. The relation was the strongest in H63D heterozygotes or homozygotes and C282Y heterozygotes. High levels of serum bilirubin were associated with a 2.8 (95% CI 0.9-8.8) fold reduction in mortality in H63D homozygotes and a 2.2 (1.0-4.7) fold reduction in mortality in C282Y heterozygotes. Taken together, our data suggest that the high levels of the antioxidant bilirubin may counteract the adverse effect of oxidative stress induced by iron overload. This may explain in part the reduced penetrance of the HFE mutations.
authors.affiliation: Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Omer T
authors.initials: OT
authors.lastname: Njajou
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Gerard
authors.initials: G
authors.lastname: de Jong
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Vergeer
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001663:Bilirubin / Q000097:blood*; D016009:Chi-Square Distribution; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics / Q000401:mortality; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood*; D019190:Iron Overload / Q000097:blood / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron; D001663:Bilirubin