title: Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.
abstract: Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels.
authors.affiliation: *Division of Occupational and Environmental Medicine, Lund University, 221 85 Lund, Sweden; karin.broberg@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Wahlberg
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Sweden;
authors.forename: Maria
authors.initials: M
authors.lastname: Kippler
authors.affiliation: *Division of Occupational and Environmental Medicine, Lund University, 221 85 Lund, Sweden;
authors.forename: Ayman
authors.initials: A
authors.lastname: Alhamdow
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Sweden; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Mohakhali, Dhaka 1000, Bangladesh;
authors.forename: Syed Moshfiqur
authors.initials: SM
authors.lastname: Rahman
authors.affiliation: Microbiology and Environmental Toxicology, University of California, 1156 High Street, Santa Cruz, California 95064;
authors.forename: Donald R
authors.initials: DR
authors.lastname: Smith
authors.affiliation: *Division of Occupational and Environmental Medicine, Lund University, 221 85 Lund, Sweden;
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.affiliation: Microbiology and Environmental Toxicology, University of California, 1156 High Street, Santa Cruz, California 95064; Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029-5674; and Occupational Health Institute, University of Brescia, Viale Europa, 11, 25123 Brescia BS, Italy.
authors.forename: Roberto G
authors.initials: RG
authors.lastname: Lucchini
authors.affiliation: *Division of Occupational and Environmental Medicine, Lund University, 221 85 Lund, Sweden; Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Sweden; karin.broberg@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000368:Aged; D000483:Alleles; D027682:Cation Transport Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D008345:Manganese / Q000097:blood*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide; D015032:Zinc / Q000097:blood; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D008345:Manganese; D015032:Zinc
keywords: SLC30A10; blood Mn concentrations; manganese exposure; manganese neurotoxicity; manganese regulation; parkinsonism