title: Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models.
abstract: BACKGROUND
  Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.
  
  
  METHODS
  Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.
  
  
  RESULTS
  Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe(-/-) mice displayed a significant reduction in blood manganese compared with Hfe(+/+) mice, replicating the altered manganese metabolism found in our human research.
  
  
  CONCLUSIONS
  Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA. bclaus@hsph.harvard.edu
authors.forename: Birgit
authors.initials: B
authors.lastname: Claus Henn
authors.forename: Jonghan
authors.initials: J
authors.lastname: Kim
authors.forename: Marianne
authors.initials: M
authors.lastname: Wessling-Resnick
authors.forename: Martha María
authors.initials: MM
authors.lastname: Téllez-Rojo
authors.forename: Innocent
authors.initials: I
authors.lastname: Jayawardene
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: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Howard
authors.initials: H
authors.lastname: Hu
authors.forename: Robert O
authors.initials: RO
authors.lastname: Wright
mesh_terms: D000818:Animals; D005260:Female; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D008345:Manganese / Q000097:blood* / Q000378:metabolism; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics*; D008800:Mexico; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D060885:Multiplex Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000623:Porphobilinogen Synthase / Q000235:genetics*; D049590:Postpartum Period; D012044:Regression Analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013054:Spectrophotometry, Atomic; D014168:Transferrin / Q000235:genetics*; D055815:Young Adult
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D008345:Manganese; D007501:Iron; D000623:Porphobilinogen Synthase
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