Oxidative stress and renal complications in Diabetes Mellitus: implications of genetic variants in CYBA, SOD3, CAT and GPX4 genes

Abstract

Evidences suggest that a genetic predisposition determines susceptibility to chronic complications of diabetes mellitus (DM), along with chronic hyperglycemia, hypertension and dyslipidemia. Since oxidative stress has been recognized as the final element of common biochemical pathways induced by hyperglycemia, the genes that encode pro-and antioxidant enzymes are candidates to confer susceptibility to complications. A study conducted in our laboratory demonstrated the association between several polymorphisms (some of them functional) in the promoter region or the 3'UTR of genes encoding enzymes of pro-oxidant systems and antioxidants and risk for the presence of diabetic nephropathy in type 1 DM of long duration recruited patients in different diabetes services in the Southeast and Southern Brazil. This project aims to extend this study, validating the association between the presence of diabetic nephropathy and these candidates polymorphisms in three French cohort of patients with type 1 DM (SURGENE cohort [n = 340]; GENEDIAB cohort [n = 494] and GENESIS cohort [n = 501]). Moreover, genotyping of polymorphisms in the genes which encode GPX4, SOD3, and catalase will be performed in two French cohort of type 2 diabetic patients (DIABHYCAR cohort [n = 3.137]; DIABHYCAR_GENE cohort [n = 607]), with the aim of evaluate the importance of oxidative stress and ROS in this clinical condition. Thinking in comparison of results observed between different cohorts, the SNPs genotiped in the French cohorts of type 2 diabetic patients will be evaluated in the Brazilian cohort of type 1 diabetic patients. The etipathogenesis of DN is believed to be similar in type 1 and type 2 diabetes mellitus, with hyperglycemia and its metabolic consequences (including the overproduction of ROS) performing a major role. Replicating results of an association between a SNP and a phenotypic trait in cohorts of patients from different geographic origins, increases the participation of that SNP and can improve understanding about its biological significance. (AU)