title: Variants in iron metabolism genes predict higher blood lead levels in young children.
abstract: BACKGROUND
  Given the association between iron deficiency and lead absorption, we hypothesized that variants in iron metabolism genes would predict higher blood lead levels in young children.
  
  
  OBJECTIVE
  We examined the association between common missense variants in the hemochromatosis (HFE) and transferrin (TF) genes and blood lead levels in 422 Mexican children.
  
  
  METHODS
  Archived umbilical cord blood samples were genotyped for HFE (H63D and C282Y) and TF (P570S) variants. Blood lead was measured at 24, 30, 36, 42, and 48 months of age. A total of 341 subjects had at least one follow-up blood lead level available and data available on covariates of interest for inclusion in the longitudinal analyses. We used random-effects models to examine the associations between genotype (HFE, TF, and combined HFE + TF) and repeated measures of blood lead, adjusting for maternal blood lead at delivery and child's concurrent anemia status.
  
  
  RESULTS
  Of 422 children genotyped, 17.7, 3.3, and 18.9% carried the HFE H63D, HFE C282Y, and TF P570S variants, respectively. One percent of children carried both the HFE C282Y and TF P570S variants, and 3% of children carried both the HFE H63D and TF P570S variants. On average, carriers of either the HFE (beta = 0.11, p = 0.04) or TF (beta = 0.10, p = 0.08) variant had blood lead levels that were 11% and 10% higher, respectively, than wild-type subjects. In models examining the dose effect, subjects carrying both variants (beta = 0.41, p = 0.006) had blood lead 50% higher than wild-type subjects and a significantly higher odds of having a blood lead level > 10 microg/dL (odds ratio = 18.3; 95% confidence interval, 1.9-177.1).
  
  
  CONCLUSIONS
  Iron metabolism gene variants modify lead metabolism such that HFE variants are associated with increased blood lead levels in young children. The joint presence of variant alleles in the HFE and TF genes showed the greatest effect, suggesting a gene-by-gene-by-environment interaction.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Marianne R
authors.initials: MR
authors.lastname: Hopkins
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: Ettinger
authors.forename: Mauricio
authors.initials: M
authors.lastname: Hernández-Avila
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
authors.forename: Martha María
authors.initials: MM
authors.lastname: Téllez-Rojo
authors.forename: Héctor
authors.initials: H
authors.lastname: Lamadrid-Figueroa
authors.forename: David
authors.initials: D
authors.lastname: Bellinger
authors.forename: Howard
authors.initials: H
authors.lastname: Hu
authors.forename: Robert O
authors.initials: RO
authors.lastname: Wright
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D007501:Iron / Q000378:metabolism*; D007854:Lead / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008800:Mexico; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014168:Transferrin / Q000235:genetics*
chemical_list: D017931:DNA Primers; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D007854:Lead; D007501:Iron
references.citation: Blood Cells Mol Dis. 2002 Nov-Dec;29(3):384-99
references.pmid: 12547229
references.citation: J Biol Chem. 1999 Mar 26;274(13):9022-8
references.pmid: 10085150
references.citation: Analyst. 1987 Dec;112(12):1701-4
references.pmid: 3445938
references.citation: Pediatrics. 2002 Jul;110(1 Pt 1):110-8
references.pmid: 12093955
references.citation: Environ Health Perspect. 2004 May;112(6):746-50
references.pmid: 15121519
references.citation: Neurotoxicology. 1993 Summer-Fall;14(2-3):273-82
references.pmid: 8247401
references.citation: Carcinogenesis. 1999 Jul;20(7):1231-3
references.pmid: 10383894
references.citation: Sci Total Environ. 2004 Sep 1;330(1-3):21-37
references.pmid: 15325155
references.citation: Ann Neurol. 2003 Jan;53(1):50-6
references.pmid: 12509847
references.citation: J Med Genet. 2004 Apr;41(4):261-5
references.pmid: 15060098
references.citation: Environ Health Perspect. 2001 Oct;109(10):1079-84
references.pmid: 11675273
references.citation: J Pediatr. 2003 Jan;142(1):9-14
references.pmid: 12520247
references.citation: Blood Cells Mol Dis. 1999 Oct-Dec;25(5-6):374-9
references.pmid: 10660486
references.citation: Am J Epidemiol. 2001 Aug 1;154(3):193-206
references.pmid: 11479183
references.citation: Am J Public Health. 1999 Jul;89(7):1049-53
references.pmid: 10394314
references.citation: Environ Health Perspect. 2005 Jul;113(7):894-9
references.pmid: 16002379
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1472-7
references.pmid: 9465039
references.citation: Int J Hyg Environ Health. 2003 Aug;206(4-5):363-9
references.pmid: 12971691
references.citation: Environ Health Perspect. 2008 Feb;116(2):243-8
references.pmid: 18288325
references.citation: J Lab Clin Med. 1994 Aug;124(2):193-8
references.pmid: 8051482
references.citation: Epidemiology. 2003 Mar;14(2):206-12
references.pmid: 12606887
references.citation: J Med Screen. 1998;5(1):34-6
references.pmid: 9575458
references.citation: J Lab Clin Med. 1991 May;117(5):390-401
references.pmid: 2019794
references.citation: Environ Health Perspect. 2003 Oct;111(13):1665-9
references.pmid: 14527848
references.citation: MMWR Recomm Rep. 1998 Apr 3;47(RR-3):1-29
references.pmid: 9563847
references.citation: Am J Clin Nutr. 1991 Dec;54(6):1047-58
references.pmid: 1957820
references.citation: Environ Health Perspect. 2000 Mar;108 Suppl 1:23-8
references.pmid: 10698721
references.citation: J Nutr. 2006 Sep;136(9):2378-83
references.pmid: 16920858
references.citation: Environ Health Perspect. 2000 Apr;108(4):289-91
references.pmid: 10753085
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5434-9
references.pmid: 10318901
references.citation: Nat Rev Neurosci. 2000 Dec;1(3):191-8
references.pmid: 11257907
references.citation: J Lab Clin Med. 1978 Oct;92(4):536-47
references.pmid: 712193
references.citation: MMWR Morb Mortal Wkly Rep. 2005 May 27;54(20):513-6
references.pmid: 15917736
references.citation: Curr Opin Pediatr. 1999 Jun;11(3):255-8
references.pmid: 10349106
references.citation: N Engl J Med. 2003 Apr 17;348(16):1517-26
references.pmid: 12700371
references.citation: Pediatrics. 1997 Nov;100(5):856-62
references.pmid: 9346987
references.citation: Ann Epidemiol. 1996 Jan;6(1):30-3
references.pmid: 8680621