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. 2004 May;112(6):746–750. doi: 10.1289/ehp.6581

Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study.

Robert O Wright 1, Edwin K Silverman 1, Joel Schwartz 1, Shring-Wern Tsaih 1, Jody Senter 1, David Sparrow 1, Scott T Weiss 1, Antonio Aro 1, Howard Hu 1
PMCID: PMC1241970  PMID: 15121519

Abstract

Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.

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Selected References

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  1. Akesson A., Stål P., Vahter M. Phlebotomy increases cadmium uptake in hemochromatosis. Environ Health Perspect. 2000 Apr;108(4):289–291. doi: 10.1289/ehp.108-1638026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barton J. C., Conrad M. E., Nuby S., Harrison L. Effects of iron on the absorption and retention of lead. J Lab Clin Med. 1978 Oct;92(4):536–547. [PubMed] [Google Scholar]
  3. Barton J. C., Patton M. A., Edwards C. Q., Griffen L. M., Kushner J. P., Meeks R. G., Leggett R. W. Blood lead concentrations in hereditary hemochromatosis. J Lab Clin Med. 1994 Aug;124(2):193–198. [PubMed] [Google Scholar]
  4. Beutler E. The significance of the 187G (H63D) mutation in hemochromatosis. Am J Hum Genet. 1997 Sep;61(3):762–764. [PMC free article] [PubMed] [Google Scholar]
  5. Bradley L. A., Johnson D. D., Palomaki G. E., Haddow J. E., Robertson N. H., Ferrie R. M. Hereditary haemochromatosis mutation frequencies in the general population. J Med Screen. 1998;5(1):34–36. doi: 10.1136/jms.5.1.34. [DOI] [PubMed] [Google Scholar]
  6. Bradman A., Eskenazi B., Sutton P., Athanasoulis M., Goldman L. R. Iron deficiency associated with higher blood lead in children living in contaminated environments. Environ Health Perspect. 2001 Oct;109(10):1079–1084. doi: 10.1289/ehp.011091079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burke W., Thomson E., Khoury M. J., McDonnell S. M., Press N., Adams P. C., Barton J. C., Beutler E., Brittenham G., Buchanan A. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. JAMA. 1998 Jul 8;280(2):172–178. doi: 10.1001/jama.280.2.172. [DOI] [PubMed] [Google Scholar]
  8. Cardoso E. M., Stål P., Hagen K., Cabeda J. M., Esin S., de Sousa M., Hultcrantz R. HFE mutations in patients with hereditary haemochromatosis in Sweden. J Intern Med. 1998 Mar;243(3):203–208. doi: 10.1046/j.1365-2796.1998.00270.x. [DOI] [PubMed] [Google Scholar]
  9. Chisolm J. J., Jr, Thomas D. J., Hamill T. G. Erythrocyte porphobilinogen synthase activity as an indicator of lead exposure in children. Clin Chem. 1985 Apr;31(4):601–605. [PubMed] [Google Scholar]
  10. Clayton E. W., Steinberg K. K., Khoury M. J., Thomson E., Andrews L., Kahn M. J., Kopelman L. M., Weiss J. O. Informed consent for genetic research on stored tissue samples. JAMA. 1995 Dec 13;274(22):1786–1792. [PubMed] [Google Scholar]
  11. Cox T. M., Kelly A. L. Haemochromatosis: an inherited metal and toxicity syndrome. Curr Opin Genet Dev. 1998 Jun;8(3):274–281. doi: 10.1016/s0959-437x(98)80081-6. [DOI] [PubMed] [Google Scholar]
  12. Datz C., Haas T., Rinner H., Sandhofer F., Patsch W., Paulweber B. Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency? Clin Chem. 1998 Dec;44(12):2429–2432. [PubMed] [Google Scholar]
  13. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R., Jr, Ellis M. C., Fullan A. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar]
  14. Garry P. J., Montoya G. D., Baumgartner R. N., Liang H. C., Williams T. M., Brodie S. G. Impact of HLA-H mutations on iron stores in healthy elderly men and women. Blood Cells Mol Dis. 1997 Aug;23(2):277–287. doi: 10.1006/bcmd.1997.0144. [DOI] [PubMed] [Google Scholar]
  15. Graziano J. H., Popovac D., Factor-Litvak P., Shrout P., Kline J., Murphy M. J., Zhao Y. H., Mehmeti A., Ahmedi X., Rajovic B. Determinants of elevated blood lead during pregnancy in a population surrounding a lead smelter in Kosovo, Yugoslavia. Environ Health Perspect. 1990 Nov;89:95–100. doi: 10.1289/ehp.908995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hammad T. A., Sexton M., Langenberg P. Relationship between blood lead and dietary iron intake in preschool children. A cross-sectional study. Ann Epidemiol. 1996 Jan;6(1):30–33. doi: 10.1016/1047-2797(95)00097-6. [DOI] [PubMed] [Google Scholar]
  17. Hu H. Bone lead as a new biologic marker of lead dose: recent findings and implications for public health. Environ Health Perspect. 1998 Aug;106 (Suppl 4):961–967. doi: 10.1289/ehp.98106s4961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hu H., Milder F. L., Burger D. E. The use of K X-ray fluorescence for measuring lead burden in epidemiological studies: high and low lead burdens and measurement uncertainty. Environ Health Perspect. 1991 Aug;94:107–110. doi: 10.1289/ehp.94-1567946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hu H., Payton M., Korrick S., Aro A., Sparrow D., Weiss S. T., Rotnitzky A. Determinants of bone and blood lead levels among community-exposed middle-aged to elderly men. The normative aging study. Am J Epidemiol. 1996 Oct 15;144(8):749–759. doi: 10.1093/oxfordjournals.aje.a008999. [DOI] [PubMed] [Google Scholar]
  20. Hu H., Rabinowitz M., Smith D. Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect. 1998 Jan;106(1):1–8. doi: 10.1289/ehp.981061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hu H., Wu M. T., Cheng Y., Sparrow D., Weiss S., Kelsey K. The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study. Environ Health Perspect. 2001 Aug;109(8):827–832. doi: 10.1289/ehp.01109827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jouanolle A. M., Fergelot P., Gandon G., Yaouanq J., Le Gall J. Y., David V. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations. Hum Genet. 1997 Oct;100(5-6):544–547. doi: 10.1007/s004390050549. [DOI] [PubMed] [Google Scholar]
  23. Mahaffey K. R., Gartside P. S., Glueck C. J. Blood lead levels and dietary calcium intake in 1- to 11-year-old children: the Second National Health and Nutrition Examination Survey, 1976 to 1980. Pediatrics. 1986 Aug;78(2):257–262. [PubMed] [Google Scholar]
  24. McLaren G. D., Nathanson M. H., Jacobs A., Trevett D., Thomson W. Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. J Lab Clin Med. 1991 May;117(5):390–401. [PubMed] [Google Scholar]
  25. Merryweather-Clarke A. T., Simonsen H., Shearman J. D., Pointon J. J., Nørgaard-Pedersen B., Robson K. J. A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations. Hum Mutat. 1999;13(2):154–159. doi: 10.1002/(SICI)1098-1004(1999)13:2<154::AID-HUMU8>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  26. Onalaja A. O., Claudio L. Genetic susceptibility to lead poisoning. Environ Health Perspect. 2000 Mar;108 (Suppl 1):23–28. doi: 10.1289/ehp.00108s123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Phatak P. D., Sham R. L., Raubertas R. F., Dunnigan K., O'Leary M. T., Braggins C., Cappuccio J. D. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med. 1998 Dec 1;129(11):954–961. doi: 10.7326/0003-4819-129-11_part_2-199812011-00006. [DOI] [PubMed] [Google Scholar]
  28. Schwartz B. S., Lee B. K., Lee G. S., Stewart W. F., Simon D., Kelsey K., Todd A. C. Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes. Environ Health Perspect. 2000 Oct;108(10):949–954. doi: 10.1289/ehp.00108949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schwartz B. S., Stewart W. F., Kelsey K. T., Simon D., Park S., Links J. M., Todd A. C. Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers. Environ Health Perspect. 2000 Mar;108(3):199–203. doi: 10.1289/ehp.00108199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Six K. M., Goyer R. A. The influence of iron deficiency on tissue content and toxicity of ingested lead in the rat. J Lab Clin Med. 1972 Jan;79(1):128–136. [PubMed] [Google Scholar]
  31. Smith C. M., Wang X., Hu H., Kelsey K. T. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect. 1995 Mar;103(3):248–253. doi: 10.1289/ehp.95103248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Waheed A., Parkkila S., Zhou X. Y., Tomatsu S., Tsuchihashi Z., Feder J. N., Schatzman R. C., Britton R. S., Bacon B. R., Sly W. S. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12384–12389. doi: 10.1073/pnas.94.23.12384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wetmur J. G., Lehnert G., Desnick R. J. The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environ Res. 1991 Dec;56(2):109–119. doi: 10.1016/s0013-9351(05)80001-5. [DOI] [PubMed] [Google Scholar]
  34. Wright R. O., Shannon M. W., Wright R. J., Hu H. Association between iron deficiency and low-level lead poisoning in an urban primary care clinic. Am J Public Health. 1999 Jul;89(7):1049–1053. doi: 10.2105/ajph.89.7.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wright R. O. The role of iron therapy in childhood plumbism. Curr Opin Pediatr. 1999 Jun;11(3):255–258. doi: 10.1097/00008480-199906000-00016. [DOI] [PubMed] [Google Scholar]

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