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

Abstract

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.

Fig. 1

Candidate gene-selenium interaction -log₁₀ P-values for adjusted odds ratios of prevalent diabetes. P-values for the interactions of log-transformed plasma selenium levels with 354 SNPs on prevalent diabetes derived from logistic regression models (dominant, recessive and additive model) adjusted for age, sex, education, urine cotinine levels (<34, 34–500, and >500 ng/mL), smoking status (never, former and current smokers) and alcohol intake (g/day) are presented (Y axis) according to the position of the SNPs on the chromosome (X axis). The horizontal solid and dashed lines correspond to a nominal significance level of 0.05 and to the effective SNP number significance level of 0.0002, respectively.