Polygenic Variants Linked to Oxidative Stress and the Antioxidant System Are Associated with Type 2 Diabetes Risk and Interact with Lifestyle Factors

Abstract

Oxidative stress is associated with insulin resistance and secretion, and antioxidant systems are essential for preventing and managing type 2 diabetes (T2DM). This study aimed to explore the polygenic variants linked to oxidative stress and the antioxidant system among those associated with T2DM and the interaction of their polygenic risk scores (PRSs) with lifestyle factors in a large hospital-based cohort (n = 58,701). Genotyping, anthropometric, biochemical, and dietary assessments were conducted for all participants with an average body mass index of 23.9 kg/m². Genetic variants associated with T2DM were searched through genome-wide association studies in participants with T2DM (n = 5383) and without T2DM (n = 53,318). The Gene Ontology database was searched for the antioxidant systems and oxidative stress-related genes among the genetic variants associated with T2DM risk, and the PRS was generated by summing the risk alleles of selected ones. Gene expression according to the genetic variant alleles was determined on the FUMA website. Food components with low binding energy to the GSTA5 protein generated from the wildtype and mutated GSTA5_rs7739421 (missense mutation) genes were selected using in silico analysis. Glutathione metabolism-related genes, including glutathione peroxidase (GPX)1 and GPX3, glutathione disulfide reductase (GSR), peroxiredoxin-6 (PRDX6), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase alpha-5 (GSTA5), and gamma-glutamyltransferase-1 (GGT1), were predominantly selected with a relevance score of >7. The PRS related to the antioxidant system was positively associated with T2DM (ORs = 1.423, 95% CI = 1.22-1.66). The active site of the GASTA proteins having valine or leucine at 55 due to the missense mutation (rs7739421) had a low binding energy (<-10 kcal/mol) similarly or differently to some flavonoids and anthocyanins. The PRS interacted with the intake of bioactive components (specifically dietary antioxidants, vitamin C, vitamin D, and coffee) and smoking status (p < 0.05). In conclusion, individuals with a higher PRS related to the antioxidant system may have an increased risk of T2DM, and there is a potential indication that exogenous antioxidant intake may alleviate this risk, providing insights for personalized strategies in T2DM prevention.

Keywords: antioxidants; bioactive compounds; coffee; oxidative stress; type 2 diabetes; vitamin D.

Figure 1

Functional enrichment analysis of the response to oxidative stress and antioxidant system-related genes. (A) The Gene Ontology (GO) term for the response to oxidative stress-related genes. (B) The Kyoto Encyclopedia of Genes and Genome terms (KEGG) for the response to oxidative stress-related genes. (C) The GO term for the antioxidant system-related genes. (D) The KEGG term for the antioxidant system-related genes.

Figure 1

Functional enrichment analysis of the response to oxidative stress and antioxidant system-related genes. (A) The Gene Ontology (GO) term for the response to oxidative stress-related genes. (B) The Kyoto Encyclopedia of Genes and Genome terms (KEGG) for the response to oxidative stress-related genes. (C) The GO term for the antioxidant system-related genes. (D) The KEGG term for the antioxidant system-related genes.

Figure 2

Association of polygenic risk scores (PRS) with type 2 diabetes risk (A) and fasting plasma glucose concentration (B,C) according to PRS in the allelic genetic model. The PRS models for the antioxidant system and the response to oxidative stress associated with type 2 diabetes risk. The PRS was calculated by summing the number of risk alleles of each SNP in the assigned model. The PRS for the antioxidant system was similarly categorized into <9, 9–11, and ≥12. The PRS for the response to oxidative stress was classified into the low, medium, and high groups, namely, <8, 8–9, and ≥10. In (A), the adjusted ORs for the PRS models were calculated by adjusting age, gender, education, income, occupation, residence area, and energy intake (percentage of estimated energy requirement) (covariate set 1), or variables in covariate set 1 plus regular exercise, alcohol intake, and smoking status (covariate set 2). Adjusted means and standard errors were calculated after adjusting for covariate set 2 in (B) and (C). Abbreviations: OR, odds ratio; PRS, polygenic risk score.

Figure 2

Association of polygenic risk scores (PRS) with type 2 diabetes risk (A) and fasting plasma glucose concentration (B,C) according to PRS in the allelic genetic model. The PRS models for the antioxidant system and the response to oxidative stress associated with type 2 diabetes risk. The PRS was calculated by summing the number of risk alleles of each SNP in the assigned model. The PRS for the antioxidant system was similarly categorized into <9, 9–11, and ≥12. The PRS for the response to oxidative stress was classified into the low, medium, and high groups, namely, <8, 8–9, and ≥10. In (A), the adjusted ORs for the PRS models were calculated by adjusting age, gender, education, income, occupation, residence area, and energy intake (percentage of estimated energy requirement) (covariate set 1), or variables in covariate set 1 plus regular exercise, alcohol intake, and smoking status (covariate set 2). Adjusted means and standard errors were calculated after adjusting for covariate set 2 in (B) and (C). Abbreviations: OR, odds ratio; PRS, polygenic risk score.

Figure 3

Genotype-Tissue Expression (GTEx) of genes according to their mutation. (A) GPX3_ rs8177426 in the cortex of the brain (β = 0.26, p = 0.0015). (B) GPX3_ rs8177426 in the left ventricle of the heart (β = 0.21, p = 9.1 × 10⁻⁷). (C) GGT1_ rs2076999 in the liver (β = 0.36, p = 2.7 × 10⁻⁷). (D) GGT1_ rs2076999 in the pancreas (β = 0.81, p = 1.4 × 10⁻³⁵). (E) GGT1_ rs2076999 in the thyroid (β = 0.55, p = 8.8 × 10⁻⁵⁷). (F) GGT1_ rs2076999 in the tibial nerve (β = −0.15, p = 0.00032). Abbreviations: GPX, glutathione peroxidase; GGT1, gamma-glutamyltransferase 1.

Figure 4

Molecular docking and molecular dynamic simulation (MDS) of CK-malonate on the wildtype (Val, C) of GSTA5_rs7739421(Val55Leu) and the mutated type (Leu, T). (A) Molecular docking of (cyanidin 3-O-beta-glucoside)(kaempferol 3-O-(2-O-beta-glucosyl-beta-glucoside)-7-O-beta-glucosiduronic acid) malonate (CK-malonate) to the GSTA5_rs7739421 wildtype. (B) The interaction force between CK-malonate and the GSTA5_rs7739421 wildtype. (C) Molecular docking of CK-malonate on the GSTA5_rs7739421 mutated type. (D) The interaction force between CK-malonate and the GSTA5_rs7739421 mutated type. (E). RMSD of CK-malonate on the GSTA5_rs7739421 wild and mutated types. (F) RMSF of CK-malonate on the GSTA5_rs7739421 wild and mutated types. Abbreviations: GSTA5, glutathione S-transferase alpha 5; RMSD, root- mean-square deviation; RMSF, root-mean-square fluctuation.

Figure 4

Molecular docking and molecular dynamic simulation (MDS) of CK-malonate on the wildtype (Val, C) of GSTA5_rs7739421(Val55Leu) and the mutated type (Leu, T). (A) Molecular docking of (cyanidin 3-O-beta-glucoside)(kaempferol 3-O-(2-O-beta-glucosyl-beta-glucoside)-7-O-beta-glucosiduronic acid) malonate (CK-malonate) to the GSTA5_rs7739421 wildtype. (B) The interaction force between CK-malonate and the GSTA5_rs7739421 wildtype. (C) Molecular docking of CK-malonate on the GSTA5_rs7739421 mutated type. (D) The interaction force between CK-malonate and the GSTA5_rs7739421 mutated type. (E). RMSD of CK-malonate on the GSTA5_rs7739421 wild and mutated types. (F) RMSF of CK-malonate on the GSTA5_rs7739421 wild and mutated types. Abbreviations: GSTA5, glutathione S-transferase alpha 5; RMSD, root- mean-square deviation; RMSF, root-mean-square fluctuation.

Figure 4

Molecular docking and molecular dynamic simulation (MDS) of CK-malonate on the wildtype (Val, C) of GSTA5_rs7739421(Val55Leu) and the mutated type (Leu, T). (A) Molecular docking of (cyanidin 3-O-beta-glucoside)(kaempferol 3-O-(2-O-beta-glucosyl-beta-glucoside)-7-O-beta-glucosiduronic acid) malonate (CK-malonate) to the GSTA5_rs7739421 wildtype. (B) The interaction force between CK-malonate and the GSTA5_rs7739421 wildtype. (C) Molecular docking of CK-malonate on the GSTA5_rs7739421 mutated type. (D) The interaction force between CK-malonate and the GSTA5_rs7739421 mutated type. (E). RMSD of CK-malonate on the GSTA5_rs7739421 wild and mutated types. (F) RMSF of CK-malonate on the GSTA5_rs7739421 wild and mutated types. Abbreviations: GSTA5, glutathione S-transferase alpha 5; RMSD, root- mean-square deviation; RMSF, root-mean-square fluctuation.