Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

BACKGROUND: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters. OBJECTIVES: We evaluated the impact of iron homeo-stasis genes [divalent metal transporter 1 (SLC11A2), transferrin (TF), transferrin receptors (TFR2 and TFRC), and ferroportin (SLC40A1)] on Cd accumulation. METHODS: Subjects were nonsmoking women living in the Argentinean Andes [n = 172; median urinary Cd (U-Cd) = 0.24 mu g/L] and Bangladesh (n = 359; U-Cd = 0.54 mu g/L) with Cd exposure mainly from food. Concentrations of U-Cd and Cd in whole blood or in erythrocytes (Ery-Cd) were measured by inductively coupled plasma mass spectrometry. Fifty polymorphisms were genotyped by Sequenom. Gene expression was measured in whole blood (n = 72) with Illumina DirectHyb HumanHT-12 v4.0. RESULTS: TFRC rs3804141 was consistently associated with U-Cd. In the Andean women, mean U-Cd concentrations were 22% (95% CI: -2, 51%), and they were 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In the Bangladeshi women, mean U-Cd concentrations were 22% (95% CI: 1, 48%), and they were 58% (95% CI: -3, 157%) higher in women with GA and AA versus GG genotype, respectively [adjusted for age and plasma ferritin in both groups; p(trend) = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin (r(S) = -0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 mu g/L only, r(S) = 0.40, p = 0.046). Rs3804141 did not modify these associations or predict TFRC expression. Cd was not consistently associated with any of the other polymorphisms evaluated. CONCLUSIONS: One TFRC polymorphism was associated with urine Cd concentration, a marker of Cd accumulation in the kidney, in two very different populations. The consistency of the findings supports the possibility of a causal association.