Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

The data of present work are available from the corresponding author on reasonable request.

References

  1. Zhao Y, Zhu R, Wang D, Liu X (2019) Genetics of diabetic neuropathy: systematic review, meta-analysis and trial sequential analysis. Ann Clin Transl Neurol 6(10):1996–2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Xu W, Qian Y, Zhao L (2015) Angiotensin-converting enzyme I/D polymorphism is a genetic biomarker of diabetic peripheral neuropathy: evidence from a meta-analysis. Int J Clin Exp Med 8(1):944–948

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Papatheodorou K, Banach M, Bekiari E, Rizzo M, Edmonds M (2018) Complications of diabetes 2017. J Diabetes Res 2018:3086167

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tuttolomondo A, Maida C, Pinto A (2015) Diabetic foot syndrome as a possible cardiovascular marker in diabetic patients. J Diabetes Res 2015:268390

    Article  PubMed  PubMed Central  Google Scholar 

  5. Baum P, Toyka KV, Blüher M, Kosacka J, Nowicki M (2021) Inflammatory mechanisms in the pathophysiology of Diabetic Peripheral Neuropathy (DN)-New aspects. Int J Mol Sci. ;22(19)

  6. Pathak D, Shrivastav D, Verma AK, Alsayegh AA, Yadav P, Khan NH et al (2022) Role of metabolizing MTHFR gene polymorphism (rs1801133) and its mRNA expression among type 2 diabetes. J Diabetes Metab Disord 21(1):511–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen H, Wei F, Wang L, Wang Z, Meng J, Jia L et al (2015) MTHFR gene C677T polymorphism and type 2 diabetic nephropathy in Asian populations: a meta-analysis. Int J Clin Exp Med 8(3):3662–3670

    PubMed  PubMed Central  Google Scholar 

  8. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820

    Article  CAS  PubMed  Google Scholar 

  9. Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52(1):1–8

    Article  CAS  PubMed  Google Scholar 

  10. Kuzuya M, Ando F, Iguchi A, Shimokata H (2008) Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolic syndrome in men in a large Japanese cohort. Am J Clin Nutr 87(6):1939–1944

    Article  CAS  PubMed  Google Scholar 

  11. Beckett GJ, Arthur JR (2005) Selenium and endocrine systems. J Endocrinol 184(3):455–465

    Article  CAS  PubMed  Google Scholar 

  12. Heiran A, Azarchehry SP, Dehghankhalili S, Afarid M, Shaabani S, Mirahmadizadeh A (2022) Prevalence of diabetic retinopathy in the Eastern Mediterranean Region: a systematic review and meta-analysis. J Int Med Res 50(10):03000605221117134

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jin P, Peng J, Zou H, Wang W, Fu J, Shen B et al (2014) The 5-year onset and regression of diabetic retinopathy in Chinese type 2 diabetes patients. PLoS ONE 9(11):e113359

    Article  PubMed  PubMed Central  Google Scholar 

  14. Manaviat MR, Rashidi M, Afkhami-Ardekani M (2008) Four years incidence of diabetic retinopathy and effective factors on its progression in type II diabetes. Eur J Ophthalmol 18(4):572–577

    Article  CAS  PubMed  Google Scholar 

  15. Sadeghi A, Bayazidi Y, Davari M, Kebriaeezadeh A, Assarian A, Esteghamati A et al (2023) Individualized glycemic control in type 2 Diabetic patients in Iran: a Multi-center Data Analysis. Iran J Med Sci 48(3):286

    PubMed  PubMed Central  Google Scholar 

  16. Sadat Mahmoudi Nezhad G, Razeghinejad R, Janghorbani M, Mohamadian A, Hassan Jalalpour M, Bazdar S et al (2019) Prevalence, incidence and Ecological Determinants of Diabetic Retinopathy in Iran: systematic review and Meta-analysis. J Ophthalmic Vis Res 14(3):321–335

    PubMed  Google Scholar 

  17. Baum P, Toyka KV, Blüher M, Kosacka J, Nowicki M (2021) Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN)—new aspects. Int J Mol Sci 22(19):10835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Association AD (2023) Retinopathy, Neuropathy, and Foot Care: standards of Care in Diabetes—2023. Diabetes Care 46:S203–S15

    Article  Google Scholar 

  19. Pang L, Lian X, Liu H, Zhang Y, Li Q, Cai Y et al (2020) Understanding diabetic neuropathy: focus on oxidative stress. Oxid Med Cell Longev 2020:1–13

    Google Scholar 

  20. Méndez-Morales S, Pérez-De Marcos J, Rodríguez-Cortés O, Flores-Mejía R, Martínez-Venegas M, Sánchez-Vera Y et al (2022) Diabetic neuropathy: molecular approach a treatment opportunity. Vascul Pharmacol 143:106954

    Article  PubMed  Google Scholar 

  21. Pang L, Lian X, Liu H, Zhang Y, Li Q, Cai Y et al (2020) Understanding Diabetic Neuropathy: focus on oxidative stress. Oxid Med Cell Longev 2020:9524635

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chen H, Wei F, Wang L, Wang Z, Meng J, Jia L et al (2015) MTHFR gene C677T polymorphism and type 2 diabetic nephropathy in Asian populations: a meta-analysis. Int J Clin Exp Med 8(3):3662

    PubMed  PubMed Central  Google Scholar 

  23. Zhou T-B, Drummen GP, Jiang Z-P, Li H-Y (2015) Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus. Ren Fail 37(8):1247–1259

    Article  CAS  PubMed  Google Scholar 

  24. Zidan AR, El Mougy HM, Moustafa HS, Mohamed EF (2019) Methylenetetrahydrofolate reductase C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus. Sci J Al-Azhar Med Fac Girls 3(1):14–22

    Article  Google Scholar 

  25. Kakavand Hamidi A, Radfar M, Amoli MM (2018) Association between MTHFR variant and diabetic neuropathy. Pharmacol Rep 70:1–5

    Article  CAS  PubMed  Google Scholar 

  26. El-Fatah A (2022) Assessment of Methylenetetrahydrofolate Reductase Gene Polymorphism in Diabetic Peripheral Neuropathy. Zagazig Univ Med J 28(61):272–279

    Google Scholar 

  27. Russo G, Giandalia A, Romeo EL, Scarcella C, Gambadoro N, Zingale R et al (2016) Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin. J Endocrinol Invest 39:305–314

    Article  CAS  PubMed  Google Scholar 

  28. Bourgonje AR, Abdulle AE, Al-Rawas AM, Al-Maqbali M, Al-Saleh M, Enriquez MB et al (2020) Systemic oxidative stress is increased in postmenopausal women and independently associates with homocysteine levels. Int J Mol Sci 21(1):314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sengupta S, Wehbe C, Majors AK, Ketterer ME, DiBello PM, Jacobsen DW (2001) Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine-mixed disulfide, and cystine in circulation. J Biol Chem 276(50):46896–46904

    Article  CAS  PubMed  Google Scholar 

  30. Ismail LK, Abdel Rahman MF, Hashad IM, Abdel-Maksoud SM (2022) Contribution of glutathione peroxidase 1 (Pro200Leu) single nucleotide polymorphism and serum homocysteine levels in the risk of acute myocardial infarction in egyptians. J Genet Eng Biotechnol 20(1):1–7

    Article  Google Scholar 

  31. Hamanishi T, Furuta H, Kato H, Doi A, Tamai M, Shimomura H et al (2004) Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in Japanese type 2 diabetic patients. Diabetes 53(9):2455–2460

    Article  CAS  PubMed  Google Scholar 

  32. Huang JQ, Zhou JC, Wu YY, Ren FZ, Lei XG (2018) Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases. Free Radic Biol Med 127:108–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahmad AA, Rahimi Z, Asadi S, Vaisi-Raygani A, Kohsari M (2023) The GPx-1 gene variants (rs1050450) in obesity: Association with the risk of obesity and the GPx activity in females. Rep Biochem Mol Biol 12(1):185–194

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang X, Liu G, Guo J, Su Z (2018) The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci 14(11):1483–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Buraczynska M, Buraczynska K, Dragan M, Ksiazek A (2017) Pro198Leu polymorphism in the glutathione peroxidase 1 gene contributes to diabetic peripheral neuropathy in type 2 diabetes patients. Neuromolecular Med 19:147–153

    Article  CAS  PubMed  Google Scholar 

  36. Albadawi N, Tarazawi E, Ismail A, Altoum S, Bakheet K (2017) Association 0f Gpx-198 C/T gene polymorphism (rs1050450-198 C/T) in Sudanese with Diabetic Retinopathy. J Blood Lymph 7(162):2

    Google Scholar 

Download references

Acknowledgements

None.

Funding

Financially supported by Kermanshah University of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Soheila Asadi, Zohreh Rahimi, Maryam Kohsari, Fatemeh Babajani, Mohammad Amiri, Nazanin Jalilian & Lida Haghnazari

  2. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Zohreh Rahimi

  3. Department of Internal Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Rozita Naseri

Authors
  1. Soheila Asadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zohreh Rahimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maryam Kohsari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatemeh Babajani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Amiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nazanin Jalilian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rozita Naseri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lida Haghnazari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to designing the work; data acquisition; data analysis and interpretation of data; drafting and critically revision. All authors read and approved the final version of the manuscript and agree with all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Soheila Asadi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

The present study was approved by the ethics committee of Kermanshah University of Medical Science, Kermanshah, Iran (IR.KUMS.REC.1397.528.).

Informed consent

All participants had informed consent for the present work and after agreed to participate in the present study, their primary information were collected and recorded.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Asadi, S., Rahimi, Z., Kohsari, M. et al. 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 51, 583 (2024). https://doi.org/10.1007/s11033-024-09519-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09519-0

Keywords

Search

Navigation