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Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

Birgit Claus Henn1*, Jonghan Kim2, Marianne Wessling-Resnick2, Martha María Téllez-Rojo3, Innocent Jayawardene4, Adrienne S Ettinger15, Mauricio Hernández-Avila6, Joel Schwartz1, David C Christiani1, Howard Hu7 and Robert O Wright18

Author Affiliations

1 Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA

2 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA

3 Division of Statistics, Center for Evaluation Research and Surveys, National Institute of Public Health, Cuernavaca, Morelos, Mexico

4 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA

5 Center for Perinatal, Pediatric and Environmental Epidemiology, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510, USA

6 Ministry of Health, Mexico City, Mexico

7 Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA

8 Department of Emergency Medicine, Children's Hospital Boston, Boston, MA, USA

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Environmental Health 2011, 10:97  doi:10.1186/1476-069X-10-97

Published: 10 November 2011



Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.


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.


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.


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.

Iron; Manganese; Genes; Iron metabolism genes