A gene-environment interaction analysis of plasma selenium with prevalent and incident diabetes: The Hortega study.

BACKGROUND: Selenium and single-nucleotide-polymorphisms in selenoprotein genes have been associated to diabetes. However, the interaction of selenium with genetic variation in diabetes and oxidative stress-related genes has not been evaluated as a potential determinant of diabetes risk. METHODS: We evaluated the cross-sectional and prospective associations of plasma selenium concentrations with type 2 diabetes, and the interaction of selenium concentrations with genetic variation in candidate polymorphisms, in a representative sample of 1452 men and women aged 18-85 years from Spain. RESULTS: The geometric mean of plasma selenium levels in the study sample was 84.2µg/L. 120 participants had diabetes at baseline. Among diabetes-free participants who were not lost during the follow-up (N=1234), 75 developed diabetes over time. The multivariable adjusted odds ratios (95% confidence interval) for diabetes prevalence comparing the second and third to the first tertiles of plasma selenium levels were 1.80 (1.03, 3.14) and 1.97 (1.14, 3.41), respectively. The corresponding hazard ratios (95% CI) for diabetes incidence were 1.76 (0.96, 3.22) and 1.80 (0.98, 3.31), respectively. In addition, we observed significant interactions between selenium and polymorphisms in PPARGC1A, and in genes encoding mitochondrial proteins, such as BCS1L and SDHA, and suggestive interactions of selenium with other genes related to selenoproteins and redox metabolism. CONCLUSIONS: Plasma selenium was positively associated with prevalent and incident diabetes. While the statistical interactions of selenium with polymorphisms involved in regulation of redox and insulin signaling pathways provide biological plausibility to the positive associations of selenium with diabetes, further research is needed to elucidate the causal pathways underlying these associations.

Do genes modify the association of selenium and lipid levels?

The interaction of selenium, a component of antioxidant selenoproteins, with genetic variation in lipid-related pathways has not been evaluated earlier as a potential determinant of blood lipid levels. We aimed at evaluating the effects of gene-environment interactions between plasma levels of selenium and polymorphisms in lipid metabolic pathways on plasma lipid levels in a study population from Spain (N=1,315). We observed statistically significant associations between plasma selenium and lipid levels (differences in total, low-density lipoprotein [LDL]-cholesterol, and triglycerides comparing the 80th with the 20th percentiles of plasma selenium levels were, respectively, 12.0 (95% confidence interval 6.3, 17.8), 8.9 (3.7, 14.2), and 9.0 (2.9, 15.2) mg/dl). We also found statistically significant interactions at the Bonferroni-corrected significance level (p=0.0008) between selenium and rs2290201 in FABP4 for total and LDL cholesterol levels and rs1800774 in CETP for elevated LDL cholesterol. Other polymorphisms showed statistically significant differential associations of plasma selenium levels and lipids biomarkers at the nominal p-value of 0.05. Reported statistical interactions with genes involved in lipid transport and transfer provide biological support to the positive associations of selenium with lipids shown in cross-sectional studies and lead to the hypothesis that selenium and lipid levels share common biological pathways that need to be elucidated in mechanistic studies.

Plasma selenium levels and oxidative stress biomarkers: a gene-environment interaction population-based study.

The role of selenium exposure in preventing chronic disease is controversial, especially in selenium-repleted populations. At high concentrations, selenium exposure may increase oxidative stress. Studies evaluating the interaction of genetic variation in genes involved in oxidative stress pathways and selenium are scarce. We evaluated the cross-sectional association of plasma selenium concentrations with oxidative stress levels, measured as oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8-oxo-7,8-dihydroguanine (8-oxo-dG) in urine, and the interacting role of genetic variation in oxidative stress candidate genes, in a representative sample of 1445 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.76 µg/L. In fully adjusted models the geometric mean ratios for oxidative stress biomarker levels comparing the highest to the lowest quintiles of plasma selenium levels were 0.61 (0.50-0.76) for GSSG/GSH, 0.89 (0.79-1.00) for MDA, and 1.06 (0.96-1.18) for 8-oxo-dG. We observed nonlinear dose-responses of selenium exposure and oxidative stress biomarkers, with plasma selenium concentrations above ~110 µg/L being positively associated with 8-oxo-dG, but inversely associated with GSSG/GSH and MDA. In addition, we identified potential risk genotypes associated with increased levels of oxidative stress markers with high selenium levels. Our findings support that high selenium levels increase oxidative stress in some biological processes. More studies are needed to disentangle the complexity of selenium biology and the relevance of potential gene-selenium interactions in relation to health outcomes in human populations.