Resumen de The Role of Selenium in Type 2 Diabetes: an Integrative Genomic Study to Inform Precision Medicine: an Integrative Genomic Study to Inform Precision Medicine
Zulema Rodríguez Hernández
Introduction. Selenium is a marketed essential trace element with important antioxidant functions in humans. However, its potential role in diabetes-related diseases remains a subject of debate.
Objectives. First, to study the potential effects of selenium on prediabetes by age. Second, to develop a toolbox for conducting Genome-wide association studies (GWAS) within large-scale meta-analysis consortia. Third, to evaluate determinants (environmental and genetics) of different selenium biomarkers. Fourth, to evaluate if selenium biomarker levels causally relate to diabetes and its complications.
Material and methods. We mainly work with the Aragon Workers Health Study (AWHS), a Spanish cohort made of middle-aged adults. Serum selenium and selenium species (glutathione peroxidase [GPx], selenoprotein P [SeP], selenoalbumin [SeAlb] and total selenometabolites [Se-metabolites]) were measured by ICP-QQQ-MS, and selenium in blood and urine by ICP-MS. Genetics analyses were performed based on TOPMed imputable SNPs. To address the first goal, the Seniors ENRICA-2 study was used to represent the elderly population, and 2011-2018 NHANES to validate findings. For the second objective, we employed R, Bash, and Python to tailor the plug-in concept. For the third objective, we studied the relative contribution of genetic and non-genetic factors in AWHS. To assess non-genetic determinants, we considered sociodemographic, dietary and a comprehensive healthy lifestyle score was constructed. To evaluate genetic determinants, candidate-gene and GWAS approaches were performed. We summarized the joint effect of genetics using polygenic scores. Finally, for the fourth objective, we studied the potential causal effect of selenium biomarkers on diabetes-related diseases through the study of genetic dose-responses, colocalization and mendelian randomization.
Results. Elevated blood selenium concentrations were positively associated to insulin resistance and ß-cell function only in middle-age adults (AWHS), suggesting that selenium-linked insulin resistance potentially triggers enhanced ß-cell function in younger individuals, diminishing with age. The metaGWASmanager toolbox was developed and successfully applied in the CKDGen (>2 million individuals and >1,800 GWAS). Positive and inverse associations were observed between healthy lifestyle (e.g. physical activity) and unhealthy habits (e.g., smoking,), respectively, with serum selenium, SeAlb and Se-metabolites. We also identified several independent genetic variants associated with all selenium markers annotated to genes participating in circadian rhythm regulation, immune system processes, signaling and receptor- and transporter-related pathways. Genetics contributed a greater proportion of variability in selenium biomarkers levels (~20%) compared to non-genetic factors (~2%). The exploitation of genetic information, overall, supports that increased serum GPx and Se-metabolites might have detrimental effects on prediabetes and diabetes complications by increasing renal disease and the presence of atherosclerosis plaque. Serum SeP, was positively related to renal disease. Conversely, increased serum selenium and SeP was potentially beneficial for atherosclerotic disease.
Conclusions. We have developed novel bioinformatics tools for the exploitation of genomic variation in epidemiologic studies and consortia. Our findings support, overall, the role of selenium on cardiometabolic risk, and provide a basis for developing new strategies and interventions for the prevention and control of diabetes complications.
