Assessing the possible association between MTHFR (rs1801133) and GPx-1 (rs1050450) polymorphisms with the risk of type 2 diabetes, diabetic neuropathy, and diabetic retinopathy

Mol Biol Rep. 2024 Apr 29;51(1):583. doi: 10.1007/s11033-024-09519-0.

Abstract

Purpose: Oxidative stress in chronic hyperglycemia could injure the tissues and onset of diabetes-related complications like retinopathy and neuropathy. This study investigates the association between methylenetetrahydrofolate reductase (MTHFR) and glutathione peroxidase (GPx) genetic variants with these complications.

Methods: In this case-control study, 400 individuals, including 100 healthy subjects and 300 patients with type 2 diabetes mellitus (T2DM) in three subgroups: with retinopathy(n = 100), with neuropathy(n = 100), and without complication (n = 100) from West Iran, were studied. MTHFR (rs1801133) and GPx-1 (rs1050450) variants were identified by the PCR-RFLP method. The plasma levels of GPx activity, glutathione, malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidative stress (TOS) were measured by chemical methods.

Results: Higher BMI, TOS and MDA levels were observed in patients with neuropathy compared to other patients and controls. Diabetic patients with neuropathy had lower levels of glutathione (7.8 ± 4.5; P < 0.001), GPx activity (39.5 ± 8.5; P < 0.001), and TAC (703.1 ± 129.1; P = 0.0001) in comparison with other groups. The patients without complication and retinopathic patients had higher plasma levels of glutathione (12.2 ± 2.4; p = 0.02) and TAC (793.4 ± 124.6; P < 0.001), respectively. MTHFR TT genotype significantly correlated with lower levels of TOS (3.5 ± 1.1; P < 0.001) and OSI (0.0050 ± 0.001; P < 0.001). Subjects with the GPx-1 TT genotype had higher levels of MDA (6.8 ± 2.5; P = 0.02) and lower levels of TOS (3.7 ± 1.6; P < 0.001), which is statistically significant. TT genotype of MTHFR was associated with 3.9 fold (95% CI 1.04-4.76; P = 0.0436) increased risk of neuropathy. Also, GPx-1 CT genotype increased the risk of retinopathy [OR = 2.7 (95% CI = 1.38-5.44; P = 0.0039)].

Conclusion: The MTHFR TT genotype increased the risk of neuropathy in diabetic patients significantly. The GPx-1 CT genotype is related to increased retinopathy risk among diabetic patients. Both MTHFR and Gpx-1 TT genotypes were associated with higher BMI levels.

Keywords: GPx-1; MTHFR; Oxidative stress; Type 2 diabetes mellitus.

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetic Neuropathies* / genetics
  • Diabetic Retinopathy* / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Glutathione Peroxidase GPX1*
  • Glutathione Peroxidase* / genetics
  • Humans
  • Iran
  • Male
  • Malondialdehyde / blood
  • Malondialdehyde / metabolism
  • Methylenetetrahydrofolate Reductase (NADPH2)* / genetics
  • Middle Aged
  • Oxidative Stress / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors

Substances

  • Glutathione Peroxidase
  • Glutathione Peroxidase GPX1
  • GPX1 protein, human
  • Malondialdehyde
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • MTHFR protein, human