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. 2003 Oct;111(13):1665–1669. doi: 10.1289/ehp.6167

Vitamin D receptor Fok1 polymorphism and blood lead concentration in children.

Erin N Haynes 1, Heidi J Kalkwarf 1, Richard Hornung 1, Richard Wenstrup 1, Kim Dietrich 1, Bruce P Lanphear 1
PMCID: PMC1241691  PMID: 14527848

Abstract

Variation in blood lead concentration is caused by a complex interaction of environmental, social, nutritional, and genetic factors. We evaluated the association between blood lead concentration and a vitamin D receptor (VDR) gene polymorphism. Environmental samples and blood were analyzed for lead, nutritional and behavioral factors were assessed, and VDR -Fok1 genotype was determined in 245 children. We found a significant interaction between floor dust lead and genotype on blood lead concentration. For every 1 microg/ft(2) increase in floor dust, children with VDR -FF genotype had a 1.1% increase in blood lead [95% confidence interval (CI), 0.69-1.5], VDR -Ff, 0.53% increase (95% CI, 0.1-0.92), and VDR -ff, 3.8% increase (95% CI, 1.2-6.3); however, at floor dust levels < 10 microg/ft(2), children with VDR -ff had the lowest blood lead concentrations. These data suggest that VDR -Fok1 is an effect modifier of the relationship of floor dust lead exposure and blood lead concentration.

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Selected References

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  1. Ames S. K., Ellis K. J., Gunn S. K., Copeland K. C., Abrams S. A. Vitamin D receptor gene Fok1 polymorphism predicts calcium absorption and bone mineral density in children. J Bone Miner Res. 1999 May;14(5):740–746. doi: 10.1359/jbmr.1999.14.5.740. [DOI] [PubMed] [Google Scholar]
  2. Arai H., Miyamoto K., Taketani Y., Yamamoto H., Iemori Y., Morita K., Tonai T., Nishisho T., Mori S., Takeda E. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997 Jun;12(6):915–921. doi: 10.1359/jbmr.1997.12.6.915. [DOI] [PubMed] [Google Scholar]
  3. Bouton C. M., Pevsner J. Effects of lead on gene expression. Neurotoxicology. 2000 Dec;21(6):1045–1055. [PubMed] [Google Scholar]
  4. Canfield Richard L., Henderson Charles R., Jr, Cory-Slechta Deborah A., Cox Christopher, Jusko Todd A., Lanphear Bruce P. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med. 2003 Apr 17;348(16):1517–1526. doi: 10.1056/NEJMoa022848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dawson-Hughes B., Harris S. S., Finneran S. Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J Clin Endocrinol Metab. 1995 Dec;80(12):3657–3661. doi: 10.1210/jcem.80.12.8530616. [DOI] [PubMed] [Google Scholar]
  6. DeLuca H. F. The vitamin D system in the regulation of calcium and phosphorus metabolism. Nutr Rev. 1979 Jun;37(6):161–193. doi: 10.1111/j.1753-4887.1979.tb06660.x. [DOI] [PubMed] [Google Scholar]
  7. Faraco J. H., Morrison N. A., Baker A., Shine J., Frossard P. M. ApaI dimorphism at the human vitamin D receptor gene locus. Nucleic Acids Res. 1989 Mar 11;17(5):2150–2150. doi: 10.1093/nar/17.5.2150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Flanagan P. R., Chamberlain M. J., Valberg L. S. The relationship between iron and lead absorption in humans. Am J Clin Nutr. 1982 Nov;36(5):823–829. doi: 10.1093/ajcn/36.5.823. [DOI] [PubMed] [Google Scholar]
  9. Fullmer C. S. Intestinal interactions of lead and calcium. Neurotoxicology. 1992 Winter;13(4):799–807. [PubMed] [Google Scholar]
  10. Gennari L., Becherini L., Mansani R., Masi L., Falchetti A., Morelli A., Colli E., Gonnelli S., Cepollaro C., Brandi M. L. FokI polymorphism at translation initiation site of the vitamin D receptor gene predicts bone mineral density and vertebral fractures in postmenopausal Italian women. J Bone Miner Res. 1999 Aug;14(8):1379–1386. doi: 10.1359/jbmr.1999.14.8.1379. [DOI] [PubMed] [Google Scholar]
  11. Godwin H. A. The biological chemistry of lead. Curr Opin Chem Biol. 2001 Apr;5(2):223–227. doi: 10.1016/s1367-5931(00)00194-0. [DOI] [PubMed] [Google Scholar]
  12. Gross C., Eccleshall T. R., Malloy P. J., Villa M. L., Marcus R., Feldman D. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res. 1996 Dec;11(12):1850–1855. doi: 10.1002/jbmr.5650111204. [DOI] [PubMed] [Google Scholar]
  13. Harris S. S., Eccleshall T. R., Gross C., Dawson-Hughes B., Feldman D. The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women. J Bone Miner Res. 1997 Jul;12(7):1043–1048. doi: 10.1359/jbmr.1997.12.7.1043. [DOI] [PubMed] [Google Scholar]
  14. Heinig M. J., Nommsen L. A., Peerson J. M., Lonnerdal B., Dewey K. G. Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: the DARLING Study. Am J Clin Nutr. 1993 Aug;58(2):152–161. doi: 10.1093/ajcn/58.2.152. [DOI] [PubMed] [Google Scholar]
  15. Henry H. L. The role of parathyroid hormone in the regulation of the metabolism of 25-hydroxyvitamin D3. Miner Electrolyte Metab. 1982 Sep-Oct;8(3-4):179–187. [PubMed] [Google Scholar]
  16. Ingles S. A., Haile R. W., Henderson B. E., Kolonel L. N., Nakaichi G., Shi C. Y., Yu M. C., Ross R. K., Coetzee G. A. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prev. 1997 Feb;6(2):93–98. [PubMed] [Google Scholar]
  17. Johnson N. E., Tenuta K. Diets and lead blood levels of children who practice pica. Environ Res. 1979 Apr;18(2):369–376. doi: 10.1016/0013-9351(79)90113-0. [DOI] [PubMed] [Google Scholar]
  18. Kerper L. E., Hinkle P. M. Cellular uptake of lead is activated by depletion of intracellular calcium stores. J Biol Chem. 1997 Mar 28;272(13):8346–8352. doi: 10.1074/jbc.272.13.8346. [DOI] [PubMed] [Google Scholar]
  19. Labbok M., Krasovec K. Toward consistency in breastfeeding definitions. Stud Fam Plann. 1990 Jul-Aug;21(4):226–230. [PubMed] [Google Scholar]
  20. Lanphear B. P., Burgoon D. A., Rust S. W., Eberly S., Galke W. Environmental exposures to lead and urban children's blood lead levels. Environ Res. 1998 Feb;76(2):120–130. doi: 10.1006/enrs.1997.3801. [DOI] [PubMed] [Google Scholar]
  21. Lanphear B. P., Dietrich K., Auinger P., Cox C. Cognitive deficits associated with blood lead concentrations <10 microg/dL in US children and adolescents. Public Health Rep. 2000 Nov-Dec;115(6):521–529. doi: 10.1093/phr/115.6.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lanphear B. P., Eberly S., Howard C. R. Long-term effect of dust control on blood lead concentrations. Pediatrics. 2000 Oct;106(4):E48–E48. doi: 10.1542/peds.106.4.e48. [DOI] [PubMed] [Google Scholar]
  23. Lanphear B. P., Howard C., Eberly S., Auinger P., Kolassa J., Weitzman M., Schaffer S. J., Alexander K. Primary prevention of childhood lead exposure: A randomized trial of dust control. Pediatrics. 1999 Apr;103(4 Pt 1):772–777. doi: 10.1542/peds.103.4.772. [DOI] [PubMed] [Google Scholar]
  24. Lanphear B. P., Matte T. D., Rogers J., Clickner R. P., Dietz B., Bornschein R. L., Succop P., Mahaffey K. R., Dixon S., Galke W. The contribution of lead-contaminated house dust and residential soil to children's blood lead levels. A pooled analysis of 12 epidemiologic studies. Environ Res. 1998 Oct;79(1):51–68. doi: 10.1006/enrs.1998.3859. [DOI] [PubMed] [Google Scholar]
  25. Lanphear B. P. The paradox of lead poisoning prevention. Science. 1998 Sep 11;281(5383):1617–1618. doi: 10.1126/science.281.5383.1617. [DOI] [PubMed] [Google Scholar]
  26. Lanphear B. P., Weitzman M., Eberly S. Racial differences in Urban children's environmental exposures to lead. Am J Public Health. 1996 Oct;86(10):1460–1463. doi: 10.2105/ajph.86.10.1460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lanphear Bruce P., Hornung Richard, Ho Mona, Howard Cynthia R., Eberly Shirley, Knauf Karen, Eberle Shirley. Environmental lead exposure during early childhood. J Pediatr. 2002 Jan;140(1):40–47. doi: 10.1067/mpd.2002.120513. [DOI] [PubMed] [Google Scholar]
  28. Lin-Fu J. S. Vulnerability of children to lead exposure and toxicity (second of two parts). N Engl J Med. 1973 Dec 13;289(24):1289–1293. doi: 10.1056/NEJM197312132892407. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Manton W. I., Angle C. R., Stanek K. L., Reese Y. R., Kuehnemann T. J. Acquisition and retention of lead by young children. Environ Res. 2000 Jan;82(1):60–80. doi: 10.1006/enrs.1999.4003. [DOI] [PubMed] [Google Scholar]
  31. Melnyk L. J., Berry M. R., Sheldon L. S., Freeman N. C., Pellizzari E. D., Kinman R. N. Dietary exposure of children in lead-laden environments. J Expo Anal Environ Epidemiol. 2000 Nov-Dec;10(6 Pt 2):723–731. doi: 10.1038/sj.jea.7500131. [DOI] [PubMed] [Google Scholar]
  32. Miyamoto Y., Shinki T., Yamamoto K., Ohyama Y., Iwasaki H., Hosotani R., Kasama T., Takayama H., Yamada S., Suda T. 1alpha,25-dihydroxyvitamin D3-24-hydroxylase (CYP24) hydroxylates the carbon at the end of the side chain (C-26) of the C-24-fluorinated analog of 1alpha,25-dihydroxyvitamin D3. J Biol Chem. 1997 May 30;272(22):14115–14119. doi: 10.1074/jbc.272.22.14115. [DOI] [PubMed] [Google Scholar]
  33. Morrison N. A., Yeoman R., Kelly P. J., Eisman J. A. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6665–6669. doi: 10.1073/pnas.89.15.6665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pirkle J. L., Kaufmann R. B., Brody D. J., Hickman T., Gunter E. W., Paschal D. C. Exposure of the U.S. population to lead, 1991-1994. Environ Health Perspect. 1998 Nov;106(11):745–750. doi: 10.1289/ehp.98106745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rabinowitz M. B., Kopple J. D., Wetherill G. W. Effect of food intake and fasting on gastrointestinal lead absorption in humans. Am J Clin Nutr. 1980 Aug;33(8):1784–1788. doi: 10.1093/ajcn/33.8.1784. [DOI] [PubMed] [Google Scholar]
  36. Richardt G., Federolf G., Habermann E. Affinity of heavy metal ions to intracellular Ca2+-binding proteins. Biochem Pharmacol. 1986 Apr 15;35(8):1331–1335. doi: 10.1016/0006-2952(86)90278-9. [DOI] [PubMed] [Google Scholar]
  37. Rosen J. F., Chesney R. W., Hamstra A., DeLuca H. F., Mahaffey K. R. Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption. N Engl J Med. 1980 May 15;302(20):1128–1131. doi: 10.1056/NEJM198005153022006. [DOI] [PubMed] [Google Scholar]
  38. Saijo T., Ito M., Takeda E., Huq A. H., Naito E., Yokota I., Sone T., Pike J. W., Kuroda Y. A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: utility of single-strand conformation polymorphism analysis for heterozygous carrier detection. Am J Hum Genet. 1991 Sep;49(3):668–673. [PMC free article] [PubMed] [Google Scholar]
  39. Sayre J. W., Katzel M. D. Household surface lead dust: its accumulation in vacant homes. Environ Health Perspect. 1979 Apr;29:179–182. doi: 10.1289/ehp.7929179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Schwartz J. Low-level lead exposure and children's IQ: a meta-analysis and search for a threshold. Environ Res. 1994 Apr;65(1):42–55. doi: 10.1006/enrs.1994.1020. [DOI] [PubMed] [Google Scholar]
  42. Schwartz J., Otto D. Lead and minor hearing impairment. Arch Environ Health. 1991 Sep-Oct;46(5):300–305. doi: 10.1080/00039896.1991.9934391. [DOI] [PubMed] [Google Scholar]
  43. Six K. M., Goyer R. A. Experimental enhancement of lead toxicity by low dietary calcium. J Lab Clin Med. 1970 Dec;76(6):933–942. [PubMed] [Google Scholar]
  44. Succop P., Bornschein R., Brown K., Tseng C. Y. An empirical comparison of lead exposure pathway models. Environ Health Perspect. 1998 Dec;106 (Suppl 6):1577–1583. doi: 10.1289/ehp.98106s61577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Watson W. S., Hume R., Moore M. R. Oral absorption of lead and iron. Lancet. 1980 Aug 2;2(8188):236–237. doi: 10.1016/s0140-6736(80)90124-5. [DOI] [PubMed] [Google Scholar]
  46. Whitfield G. K., Remus L. S., Jurutka P. W., Zitzer H., Oza A. K., Dang H. T., Haussler C. A., Galligan M. A., Thatcher M. L., Encinas Dominguez C. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol. 2001 May 25;177(1-2):145–159. doi: 10.1016/s0303-7207(01)00406-3. [DOI] [PubMed] [Google Scholar]
  47. 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]
  48. Ziegler E. E., Edwards B. B., Jensen R. L., Mahaffey K. R., Fomon S. J. Absorption and retention of lead by infants. Pediatr Res. 1978 Jan;12(1):29–34. doi: 10.1203/00006450-197801000-00008. [DOI] [PubMed] [Google Scholar]

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