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Genetic polymorphisms in Nrf2 and FoxO1: implications for antioxidant enzyme activity in diabetes
Dipak A Kadam1,2, Saurabh Kalamkar1, Vijay Gajjar3
1Department of Zoology, Center of Advanced Studies, Savitribai Phule Pune University, Pune, India.
Abstract:
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 (n = 98) and non-diabetic (n = 90) individuals. Genomic DNA was isolated, and Nrf2 and FoxO1 were amplified and sequenced by Illumina NextSeq500. Data were screened for SNPs in amplified regions. An independent samples t-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 Nrf2 and FoxO1, respectively. However, a statistically significant difference in the allele frequency distribution between study groups was observed only in two intronic SNPs, rs17524059:A > C and rs60373589:Indel(A) of Nrf2 and FoxO1, respectively. SNPs, rs17524059 in the Nrf2 and rs60373589 of FoxO1, were not associated with reduced CAT and SOD activity and level of TAC in Indian diabetic individuals.Communicated by Ramaswamy H. Sarma.
Insights
Single nucleotide polymorphisms (SNPs) in Nrf2 and FoxO1 genes were investigated for their association with reduced antioxidant enzyme activity in Indian individuals with diabetes. The study found no significant link between specific SNPs and lower levels of catalase and superoxide dismutase activity or total antioxidant capacity.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
- Endocrinology
Background:
- Persistent hyperglycemia in diabetes mellitus leads to increased reactive oxygen species (ROS) and oxidative stress (OS).
- Transcription factors Nrf2 and FoxO1 activate antioxidant enzymes like catalase (CAT) and superoxide dismutase (SOD) in response to OS.
- Diabetic individuals often exhibit a diminished antioxidant response, suggesting potential underlying genetic factors.
Purpose of the Study:
- To investigate the association between single nucleotide polymorphisms (SNPs) in the Nrf2 and FoxO1 genes and the activity of antioxidant enzymes in diabetic individuals.
- To determine if genetic variations in these key transcription factors correlate with reduced antioxidant capacity in diabetes.
Main Methods:
- Serum samples from diabetic (n=98) and non-diabetic (n=90) individuals were analyzed for CAT, SOD activity, and total antioxidant capacity (TAC).
- Genomic DNA was isolated, and Nrf2 and FoxO1 genes were amplified and sequenced using Illumina NextSeq500 to identify SNPs.
- Statistical analysis, including independent samples t-tests, was performed to assess the association between SNP allele frequencies and antioxidant levels in relation to diabetic status.
Main Results:
- Diabetic individuals exhibited significantly lower CAT and SOD activity and reduced TAC compared to non-diabetic controls.
- Thirty-two SNPs and 34 Single-nucleotide variants (SNVs) were identified in Nrf2 and FoxO1, respectively.
- Only two intronic SNPs, rs17524059 in Nrf2 and rs60373589 in FoxO1, showed a statistically significant difference in allele frequency distribution between the groups, but these were not associated with reduced antioxidant enzyme activity or TAC.
Conclusions:
- The investigated intronic SNPs (rs17524059 in Nrf2 and rs60373589 in FoxO1) are not associated with the observed reduced antioxidant enzyme activity (CAT, SOD) and TAC in Indian diabetic individuals.
- Further research is needed to explore other genetic or environmental factors contributing to the impaired antioxidant response in diabetes.
