Skip to main content
SpringerLink
Log in

Association of endothelial nitric oxide synthase (eNOS) and norepinephrine transporter (NET) genes polymorphism with type 2 diabetes mellitus

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

Abstract

Genetic factors in combination with environmental factors play a critical role in the development type 2 diabetes mellitus (T2DM) which is growing as an epidemic globally. In present study we aim to assess the association of eNOS (G894T, rs1799983) and NET (G1287A, rs5569) genes polymorphism with T2DM. A case–control study including a total of 400 North Indian subjects (200 T2DM cases and 200 controls) was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) approach to analyze genetic polymorphism. Alleles/genotype frequencies between cases and controls were compared using χ2 and Student’s t-tests. Odds ratios and 95% confidence intervals were calculated by logistic regression to assess the relative association between disease and genotypes. In case of NET gene, GG (P = 0.002 in T2DM males, 0.053 in overall T2DM cases) genotype and G allele (P = 0.003 in T2DM males, 0.027 in overall T2DM cases) were found to be a positive risk factors and AG genotype (P = 0.012 in T2DM males) and A allele (P = 0.003 in T2DM males, P = 0.027 in overall T2DM cases) as negative risk factor for T2DM. No association of eNOS gene polymorphism was found with T2DM (P values of all genotypes and alleles were greater than 0.05). NET gene polymorphism might be associated with the risk of T2DM whereas; eNOS gene polymorphism do not confer any risk of T2DM in North Indian Ethnic group. It is hoped that understanding genetic causes of T2DM will lead to earlier diagnosis, preventive measures and more effective and specific treatment.

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

References

  1. Agema WRP, De Maat MPM, Zwinderman AH, Kastelein JJP, Rabelink TJ, Boven JV et al (2004) An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men. Clin Sci 107:255–261

    Article  CAS  Google Scholar 

  2. American Diabetes A (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(1):S62–S69

    Article  Google Scholar 

  3. Angeline T, Krithiga HR, Isabel W, Asirvatham AJ, Poornima A (2011) Endothelial nitric oxide synthase gene polymorphism (G894T) and diabetes mellitus (type II) among South Indians. Oxid Med Cell Longevity 462607:1–4

    Article  Google Scholar 

  4. Bae J, Kim IJ, Hong SH, Sung JH, Lim SW, Cha DH et al (2010) Association of endothelial nitric oxide synthase polymorphisms with coronary artery disease in Korean individuals with or without diabetes mellitus. Exp Ther Med 1:719–724

    Article  CAS  Google Scholar 

  5. Buttenschøn HN, Kristensen AS, Buch HN, Andersen JH, Bonde JP et al (2011) The norepinephrine transporter gene is a candidate gene for panic disorder. J Neural Transm (Vienna) 118:969–976

    Article  Google Scholar 

  6. Chandrasekaran S, Sivani S, Sudarsanam D (2012) Evaluation of single nucleotide polymorphism C825T in the GNB3 gene with the development of type 2 diabetes of the South Indian population. Int J Pharma Sci Res 13(1):249–257

    Google Scholar 

  7. Colombo MG, Andreassi MG, Paradossi U, Botto N, Manfredi S, Masetti S et al (2002) Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298àAsp polymorphism; to the presence, extent, and severity of coronary artery disease. Heart 87:525–528

    Article  CAS  Google Scholar 

  8. Conen D, Glynn RJ, Buring JE, Ridker PM, Zee RY (2008) Renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms are not associated with the risk of incident type 2 diabetes mellitus: a prospective cohort study. J Intern Med 263(4):376–385

    Article  CAS  Google Scholar 

  9. Dellamea BS, Pinto LCF, Leitão CB, Santos KG, Canani LHS (2014) Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis. BMC Med Genet 15:9

    Article  Google Scholar 

  10. Demova H, Daniela JB, Hannes R, Bohumir K, Ludmila P, Ivan B et al (2012) Gene polymorphisms in patients with type 2 diabetes and diabetic nephropathy. Cent Eur J Biol 7(2):210–218

    CAS  Google Scholar 

  11. Dlugos AM, Hamidovic A, Palmer AA, de Wit H (2009) Further evidence of association between amphetamine response and SLC6A2 gene variants. Psychopharmacology 206:501–511

    Article  CAS  Google Scholar 

  12. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 18:499–502

    CAS  Google Scholar 

  13. Guo X, Cheng S, Taylor KD, Cui J, Hughes R, Quiñones MJ et al (2005) Hypertension genes are genetic markers for insulin sensitivity and resistance. Hypertension 45(4):799–803

    Article  CAS  Google Scholar 

  14. Hahn MK, Blakely RD (2002) Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenom J 2:217–235

    Article  CAS  Google Scholar 

  15. Hahn MK, Mazei-Robison MS, Blakely RD (2005) Single nucleotide polymorphisms in the human norepinephrine transporter gene affect expression, trafficking, antidepressant interaction, and protein kinase C regulation. Mol Pharmacol 68:457–466

    Article  CAS  Google Scholar 

  16. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A et al (1999) A common variant of the endothelial nitric oxide synthase (Glu298 → Asp) is major risk factor for coronary artery disease in the UK. Circulation 100:1515–1520

    Article  CAS  Google Scholar 

  17. Hingorani AD (2003) Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep 5(1):19–25

    Article  Google Scholar 

  18. International Diabetes Federation (2014) IDF diabetes atlas update poster, 6th ed. Brussel: International Diabetes Federation. http://www.idf.org

  19. Jia Z, Zhang X, Kang S, Wu Y (2013) Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus: a meta-analysis. Endocr J 60(7):893–901

    Article  CAS  Google Scholar 

  20. Kim JU, Chang HK, Lee SS, Kim JW, Kim KT, Lee SW et al (2003) Endothelial nitric oxide synthase gene polymorphisms in Beuhcet’s disease and rheumatic diseases with vasculitis. Ann Rheum Dis 62:1083–1087

    Article  CAS  Google Scholar 

  21. Kim YK, Hwang JA, Lee HJ, Yoon HK, Ko YH et al (2014) Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder. J Affect Disord 158:127–132

    Article  CAS  Google Scholar 

  22. Ksiazek P, Buraczynska K, Buraczynska M (2006) Norepinephrine transporter gene (NET) polymorphism in patients with type 2 diabetes. Kidney Blood Press Res 29:338–343

    Article  CAS  Google Scholar 

  23. Li JY, Tao F, Wu XX, Tan YZ, He L, Lu H (2015) Polymorphic variations in manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) genes contribute to the development of type 2 diabetes mellitus in the Chinese Han population. Genet Mol Res 14(4):12993–13002

    Article  CAS  Google Scholar 

  24. Marques FZ, Eikelis N, Bayles RG, Lambert EA, Straznicky NE, Hering D et al (2016) A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. Mol Psychiatry. https://doi.org/10.1038/mp.2016.40

    Article  PubMed  Google Scholar 

  25. Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E et al (2003) Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 52(5):1270–1275

    Article  CAS  Google Scholar 

  26. Nishevitha NS, Angeline T, Jeyaraj N (2009) Endothelial nitric oxide synthase (eNOS) Glu298àAsp polymorphism (G894T) among south Indians. Indian J Med Res 129:68–71

    CAS  PubMed  Google Scholar 

  27. Organization WH (2006) Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WH/IDF consultation, vol 24, p 50. Geneva

  28. Rizvi S, Raza ST, Mahdi F (2014) Association of genetic variants with diabetic nephropathy. World J Diabetes 5(6):809–816

    Article  Google Scholar 

  29. Rizvi S, Raza ST, Rahman Q, Mahdi F (2016) Role of GNB3, NET, KCNJ11, TCF7L2 and GRL genes single nucleotide polymorphism in the risk prediction of type 2 diabetes mellitus. 3 Biotech 6:255

    Article  Google Scholar 

  30. Sambrook J, Frisch EF, Maniatis T. Molecular cloning; a labortory manual. 2nd ed. New York: Cold Sping Harbor Labortory Press. 1989; 9.14-9.19

  31. Santos KG, Crispim D, Canani LH, Ferrugem PT, Gross JL, Roisenberg I (2011) Association of eNOS gene polymorphisms with renal disease in Caucasians with type 2 diabetes. Diabetes Res Clin Pract 91:353–362

    Article  CAS  Google Scholar 

  32. Santos KG, Crispim D, Canani LH, Ferrugem PT, Gross JL, Roisenberg I (2012) Relationship of endothelial nitric oxide synthase (eNOS) gene polymorphisms with diabetic retinopathy in Caucasians with type 2 diabetes. Ophthalmic Genet 33(1):23–27

    Article  CAS  Google Scholar 

  33. Shah VN, Cheema BS, Kohli HS, Sharma R, Khullar M et al (2013) Endothelial nitric oxide synthase gene polymorphism and the risk of diabetic neuropathy in Asian Indian patients with type 2 diabetes. J Diabetes Metab 4:243

    Article  Google Scholar 

  34. Shimasaki Y, Yasue H, Yoshimura M (1998) Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 31:1506–1510

    Article  CAS  Google Scholar 

  35. Srivastava K, Biswas UK, Narang R, Varghese JJ, Das N (2005) Prevalence of eNOS Glu298Asp polymorphism in healthy volunteers from a region of northern India. Community Genet 8:180–183

    PubMed  Google Scholar 

  36. Thakur GA, Sengupta SM, Grizenko N, Choudhry Z, Joober R (2012) Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy. PLoS ONE 7:e49616

    Article  CAS  Google Scholar 

  37. Wang XL, Wang J (2000) Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 70(4):241–251

    Article  CAS  Google Scholar 

  38. Wei D, Shan J, Chen Z, Shi Y (2002) The G894T mutation of the endothelial nitric oxide synthase gene is associated with coronary atherosclerotic heart disease in Chinese. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:471–474

    CAS  PubMed  Google Scholar 

  39. Whiting DR, Guariguata L, Weil C, Shawj IDF (2011) Diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321

    Article  Google Scholar 

  40. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH et al (2006) Epidemic obesity and type 2 diabetes in Asia. The Lancet 368(9548):1681–1688

    Article  Google Scholar 

  41. Zhao X, Huang Y, Ma H, Jin Q, Wang Y et al (2013) Association between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: a meta-analysis. J Affect Disord 150:23–28

    Article  CAS  Google Scholar 

  42. Zintzaras E, Papathanasiou AA, Stefanidis I (2009) Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: a HuGE review and meta-analysis. Genet Med 11:695–706

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the entire Medical and Research staff and our colleagues at Era’s Lucknow Medical College and Amity University for their support and contributions in this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Molecular Biology Lab, Department of Biochemistry, Era’s Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, 226003, India

    Saliha Rizvi, Syed Tasleem Raza, Ale Eba & Farzana Mahdi

  2. Department of Statistics, Era’s Lucknow Medical College and Hospital, Lucknow, India

    Zeashan H. Zaidi

  3. Amity University, Lucknow Campus, Lucknow, India

    Qamar Rahman

Authors
  1. Saliha Rizvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syed Tasleem Raza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qamar Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ale Eba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zeashan H. Zaidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Farzana Mahdi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Syed Tasleem Raza.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rizvi, S., Raza, S.T., Rahman, Q. et al. Association of endothelial nitric oxide synthase (eNOS) and norepinephrine transporter (NET) genes polymorphism with type 2 diabetes mellitus. Mol Biol Rep 46, 5433–5441 (2019). https://doi.org/10.1007/s11033-019-04998-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-019-04998-y

Keywords

Search

Navigation