Genetic polymorphisms in Nrf2 and FoxO1: implications for antioxidant enzyme activity in diabetes

In diabetes, persistent hyperglycemia generates excess reactive oxygen species (ROS), leading to oxidative stress (OS). In response to OS, transcription factors (TFs) Nrf2 and FoxO1 get activated, which induce the expression of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). It is well documented that the antioxidant response in diabetic individuals is very low. Since Nrf2 and FoxO1 are the major TFs activating these genes, we were interested in determining if single nucleotide polymorphisms (SNPs) in genes for these TFs have any association with lowered antioxidant enzyme activity in diabetic individuals. The activity of CAT and SOD and total antioxidant capacity (TAC) were quantified from the serum samples of diabetic (<i>n</i> = 98) and non-diabetic (<i>n</i> = 90) individuals. Genomic DNA was isolated, and <i>Nrf2</i> and <i>FoxO1</i> were amplified and sequenced by Illumina NextSeq500. Data were screened for SNPs in amplified regions. An independent samples <i>t</i>-test to find an association between CAT, SOD, and TAC and allele frequency of SNP with the diabetic condition was carried out. We found decreased CAT and SOD activity and significantly low TAC in diabetic individuals. Thirty-two and thirty-four SNPs and Single-nucleotide variants (SNVs) were observed in <i>Nrf2</i> and <i>FoxO1</i>, respectively. However, a statistically significant difference in the allele frequency distribution between study groups was observed only in two intronic SNPs, rs17524059:A &gt; C and rs60373589:Indel(A) of <i>Nrf2</i> and <i>FoxO1</i>, respectively. SNPs, rs17524059 in the <i>Nrf2</i> and rs60373589 of <i>FoxO1</i>, were not associated with reduced CAT and SOD activity and level of TAC in Indian diabetic individuals. Communicated by Ramaswamy H. Sarma