Oxidative stress pathway genes and chronic renal insufficiency in Asian Indians with type 2 diabetes

Abstract

Background: There are significant regional variations in prevalence of diabetes and diabetic chronic renal insufficiency (CRI) in India. Oxidative stress plays an important role in the development of diabetic complications. To determine the importance of the polymorphisms in the genes involved in maintenance of cellular redox balance, we performed a case control study in subjects from south and north India. Methods: Successive cases presenting to the study centers with Type 2 diabetes of >2 years duration and moderate CRI (n=194, south India 104, north India 90) diagnosed by serum creatinine ≥ 2 mg/dl after exclusion of nondiabetic causes of CRI were compared with diabetes subjects with no evidence of renal disease (n=224, south India 149, north India 75). Twenty-six polymorphisms from 13 genes from the oxidative stress pathway were analyzed using polymerase chain reaction-restriction fragment length polymorphism. Genes included were superoxide dismutases (SOD1, 2, 3), uncoupling proteins (UCP1, 2), endothelial nitric oxide synthase (NOS3), glutathione-S-transferases (GST) (M1, T1, P1), vascular endothelial growth factor (VEGF), paraoxonase (PON) 1 and 2, and nicotinamide adenine dinucleotide phosphate reduced, oxidase p22^phox. Genes were tested for their association with CRI using χ ² test. Results: In south Indian (SI) subjects there was significant allelic and genotypic association of the wild-type allele in SOD2 (Ala9Val; P=.002 and P=.013, respectively), UCP1 (-112 T>G, P=.012 and P=.009; Ala64Thr, P=.015 and P=.004), NOS3 (Glu298Asp, P=.002 and P=.009) and GSTP1 (Ile105Val, P=.003 and P=.004) genes with development of CRI. None of these observations were replicated in the north Indian (NI) subjects. A genotypic but not allelic association was observed for two markers, VEGF (−460 T>C) and PON1 (Arg192Gly) among NI diabetic CRI subjects. Conclusion: The nonreplication of association suggests differential genetic susceptibility of the two populations to diabetic chronic renal insufficiency. In the SI diabetic subjects, oxidative stress pathway genes might be an important predictor for the development of diabetic complications. Further, the association of wild-type alleles may suggest that they confer greater survival ability to comorbid complications and may be nephroprotective.