Skip to main content

Advertisement

SpringerLink
Log in

Association of plasminogen activator inhibitor-1 4G5G Polymorphism with risk of diabetic nephropathy and retinopathy: a systematic review and meta-analysis

  • Review article
  • Published:
Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Background

The 4G5G polymorphism of Plasminogen activator inhibitor-1 (PAI-1) gene is reported to be associated with diabetes nephropathy and retinopathy (DNR) risk. However, the findings are conflicting. Herein, we conducted a case-control and meta-analysis study to explore the association of PAI-1 4G5G polymorphism with risk of DNR.

Methods

We retrieved PubMed, EMBASE, Web of Knowledge, and CNKI databases and screened eligible studies up to August 15, 2020. The strength of associations was assessed by odd ratio (OR) and the corresponding 95% confidence interval (95% CI).

Results

A total of 27 case-control studies including 16 studies with 1,825 cases case and 1,731 controls on DN and eleven studies with 1,397 cases and 1,545 controls on DR were selected. Pooled data showed that the PAI-1 4G5G polymorphism was significantly associated with DN (allele model: OR = 0.674, 95% CI 0.524–0.865, p = 0.002; homozygote model: OR = 0.536, 95% CI 0.351–0.817, p = 0.004; heterozygote model: OR = 0.621, 95% CI 0.427–0.903, p = 0.013; dominant model: OR = 0.575, 95% CI 0.399–0.831, p = 0.003; and recessive model: OR = 0.711, 95% CI 0.515–0.981, p = 0.038) and DR (homozygote model: OR = 0.770, 95% CI 0.621–0.955, p = 0.0.017) risk. Stratified analyses by ethnicity indicated that PAI-1 4G5G polymorphism was associated with DN and DR risk in Asians and Caucasians, respectively.

Conclusions

The present meta-analysis revealed that the PAI-1 4G5G polymorphism was associated with increased risk of DN and DR risk. However, well-designed large-scale clinical studies are required to further validate our results.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Forbes JM, Fotheringham AK. Vascular complications in diabetes: old messages, new thoughts [Internet]. Diabetologia. Springer Verlag; 2017. pp. 2129–38.

  2. Tang Z-H, Zeng F, Zhang X-Z. Human genetics of diabetic nephropathy. Ren Fail Informa Healthc. 2015;37:363–71.

    Article  CAS  Google Scholar 

  3. Mohammadi M, Raiegani AAV, Jalali R, Ghobadi A, Salari N. The prevalence of retinopathy among type 2 diabetic patients in Iran: A systematic review and meta-analysis [Internet]. Reviews in endocrine and metabolic disorders. New York: Springer New York LLC; 2019.

  4. Papatheodorou K, Papanas N, Banach M, Papazoglou D, Edmonds M. Complications of diabetes 2016. J Diabetes Res . 2016;2016:6989453 (Hindawi Limited).

    Article  Google Scholar 

  5. Lee WJ, Sobrin L, Lee MJ, Kang MH, Seong M, Cho H. The relationship between diabetic retinopathy and diabetic nephropathy in a population-based study in Korea (KNHANES V-2, 3). Investigative Ophthalmology and Visual Science. Association for Research in Vision and Ophthalmology Inc. 2014;55:6547–53.

  6. Vieira-Potter VJ, Karamichos D, Lee DJ. Ocular complications of diabetes and therapeutic approaches. BioMed Res Int. 2016;2016:3801570. Hindawi Limited. Available from.

  7. Ha M, Choi SY, Kim M, Na JK, Park Y-H. Diabetic nephropathy in type 2 diabetic retinopathy requiring panretinal photocoagulation. Korean J Ophthalmol Soc (KAMJE). 2019;33:46.

    Article  Google Scholar 

  8. Kallinikou D, Soldatou A, Tsentidis C, Louraki M, Kanaka-Gantenbein C, Kanavakis E, et al. Diabetic neuropathy in children and adolescents with type 1 diabetes mellitus: Diagnosis, pathogenesis, and associated genetic markers. Diabetes/Metabolism Research and Reviews. Hoboken: Wiley; 2019;35.

  9. Marcovecchio ML, Chiarelli F. Microvascular disease in children and adolescents with type 1 diabetes and obesity [Internet]. Pediatric nephrology. Berlin: Springer; 2011. p. 365–75.

  10. Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol Soc Diabet Nephropathy Prev. 2016;5:49–56.

    Google Scholar 

  11. Aldukhayel A. Prevalence of diabetic nephropathy among type 2 diabetic patients in some of the arab countries. Int J Health Sci Renaiss Med Publ. 2017;11:60–3.

    Google Scholar 

  12. Barot M, Gokulgandhi MR, Patel S, Mitra AK. Microvascular complications and diabetic retinopathy: Recent advances and future implications [Internet]. Futur Med Chem NIH Public Access.. 2013. p. 301–14

  13. Beltramo E, Porta M. Pericyte loss in diabetic retinopathy: Mechanisms and consequences. current medicinal chemistry [Internet]. Sharjah: Bentham Science Publishers Ltd.; 2013;20:3218–25. Available from.

  14. Maroufizadeh S, Almasi-Hashiani A, Hosseini M, Sepidarkish M, Omani Samani R. Prevalence of diabetic retinopathy in Iran: A systematic review and Meta-analysis [Internet]. Int J Ophthalmol (International Journal of Ophthalmology c/o Editorial Office). 2017:782–9.

  15. Beaser RS, Turell WA, Howson A. Strategies to improve prevention and management in diabetic retinopathy: Qualitative insights from a mixed-methods study. Diabetes Spectr American Diabetes Association Inc. 2018;31:65–74.

  16. Amoaku WM, Ghanchi F, Bailey C, Banerjee S, Banerjee S, Downey L, et al. Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group [Internet]. Eye (Basingstoke). Berlin: Springer Nature; 2020. p. 1–51.

  17. Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2007;2007:1–14.

    Article  Google Scholar 

  18. Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol. 2008;30:65–84.

    Article  CAS  Google Scholar 

  19. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? [Internet]. Indian J Endocrinol Metab. Medknow Publications; 2016. p. 546–53.

  20. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy [Internet]. Medical Clinics of North America. Med Clin North Am; 2004. p. 1001–36.

  21. Murea M, Ma L, Freedman BI. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications [Internet]. Rev Diabetic Stud. Society for Biomedical Diabetes Research; 2012. p. 6–22.

  22. Rizvi S. Association of genetic variants with diabetic nephropathy. World J Diabetes Baishideng Publishing Group Inc. 2014;5:809.

    Article  Google Scholar 

  23. Ploplis A V. Effects of Altered Plasminogen Activator Inhibitor-1 Expression on Cardiovascular Disease. Curr Drug Targets. Bentham Science Publishers Ltd.; 2011;12:1782–9.

  24. Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, et al. Plasminogen activator inhibitor-1 and diagnosis of the metabolic syndrome in a West African population. J Am Heart Assoc. John Wiley and Sons Inc.; 2016;5.

  25. Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): A key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther. 2010;28(5):e72–e91. Available from.

  26. Yarmolinsky J, Bordin Barbieri N, Weinmann T, Ziegelmann PK, Duncan BB, Schmidt MI. Plasminogen activator inhibitor-1 and type 2 diabetes: a systematic review and meta-analysis of observational studies. Sci Rep Nature Publishing Group. 2016;6:17714.

    CAS  Google Scholar 

  27. Nicholas SB, Aguiniga E, Ren Y, Kim J, Wong J, Govindarajan N, et al. Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Kidney Int [Internet]. Blackwell Publishing Inc.; 2005;67:1297–307. Available from.

  28. Jeong BY, Uddin MJ, Park JH, Lee JH, Lee HB, Miyata T, et al. Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model. Maeda S, editor. PLoS One. Public Library of Science; 2016;11:e0157012.

  29. Schaller J, Gerber SS. The plasmin-antiplasmin system: Structural and functional aspects. Cell Mol Life Sci. Springer; 2011;68:785–801.

  30. Huang X, Li Y, Huang Z, Wang C, Xu Z. Pai-1 gene variants and COC use are associated with stroke risk: a case-control study in the Han Chinese women. J Mol Neurosci. 2014;54:803–10.

    Article  CAS  Google Scholar 

  31. Jafari M, Jarahzadeh MH, Dastgheib SA, Seifi-Shalamzari N, Raee-Ezzabadi A, Sadeghizadeh-Yazdi J, et al. Association of PAI-1 rs1799889 Polymorphism with Susceptibility to ischemic stroke: a huge meta-analysis based on 44 studies. Acta Med (Hradec Kralove). NLM (Medline); 2020;63:31–42.

  32. Schneider DJ, Sobel BE. PAI-1 and diabetes: A journey from the bench to the bedside [Internet]. Diabetes Care. American Diabetes Association; 2012. p. 1961–7.

  33. Kimura H, Gejyo F, Suzuki Y, Suzuki S, Miyazaki R, Arakawa M. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy. Kidney Int Elsevier. 1998;54:1659–69.

    Article  CAS  Google Scholar 

  34. De Cosmo S, Margaglione M, Tassi V, Garrubba M, Thomas S, Olivetti C, et al. ACE, PAI-1, decorin and Werner helicase genes are not associated with the development of renal disease in European patients with type 1 diabetes. Diabetes/Metab Res Rev. 1999;15:247–53.

  35. Yan X, Pan S, Yang L, Huang L, Zhao S. Correlation analysis of polymorphisms of angiotensin converting enzyme gene, plasminogen activator inhibitor-1 gene and nephropathy in type 2 diabetes. China Med [Internet]. 2008;3:81–83 (article in Chinese). Available from.

  36. Prasad P, Tiwari AK, Kumar KMP, Ammini AC, Gupta A, Gupta R, et al. Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes. BMC Med Genet BioMed Cent. 2010;11:52.

    Article  Google Scholar 

  37. Xue J, Tian G, Shi F, Ge B. Polymorphisms of plasminogen activator inhibitor-I genes in type 2 diabetes with nephropathy in Han in Baotou. Chin Med J Metall Ind [Internet]. 2010;27::373– 375 (article in Chinese). Available from.

  38. Liu M, Yang Z, Shen L, Sun S, Li H. Association of plasminogen activator inhibitor-1 4G/5G polymorphism and type 2 diabetes with early nephropathy. Acta Acad Med Qingdao Univ [Internet]. 2011;47:35 (article in Chinese). Available from.

  39. Xu F, Liu H, Sun Y. Association of plasminogen activator inhibitor-1 gene polymorphism and type 2 diabetic nephropathy. Ren Fail Taylor Francis. 2016;38:157–62.

    Article  Google Scholar 

  40. Wong TYH, Poon P, Szeto CC, Chan JCN, Li PKT. Association of plasminogen activator inhibitor-1 4G/4G genotype and type 2 diabetic nephropathy in Chinese patients. Kidney Int. 2000;57:632–8.

    Article  CAS  Google Scholar 

  41. Tarnow L, Stehouwer CDA, Emeis JJ, Poirier O, Cambien F, Hansen BV, et al. Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy. Nephrol Dial Transplant. Oxford University Press; 2000;15:625–30.

  42. Liu S, Xue Y, Yang G, He F, Zhao X. Association o f plasminogen activator inhibitor-1 4G/4G polymorphism and type 2 diabetic nephropathy. Chin J Diabetes [Internet]. 2016;9:340 (article in Chinese). Available from.

  43. Liu S, Xue Y, Yang G, He F, Zhao X. Relationship between plasminogen activator inhibitor-1 gene 4G/5G polymorphism and type 2 diabetic nephropathy in Chinese Han patients in Guangdong Province. Di Yi Jun Yi Da Xue Xue Bao [Internet]. 2004;24:24(8):904–907 (article in Chinese). Available from.

  44. Tang K. The association between gene expression of PAl-1 in adipose tissue of type 2 diabetes and vascular disease. J Shangdong Univ (Med Sci) [Internet]. 2004;15:1126–1128 (article in Chinese). Available from.

  45. Martin RJL, Savage DA, Patterson CC, Brady HR, Maxwell AP. Common polymorphisms of the PAI1 gene do not play a major role in the development of diabetic nephropathy in Type 1 diabetes. Diab Med Wiley/Blackwell. 2007;10(1111):259–65.

    Article  Google Scholar 

  46. Wang L, Liu Y, Guo H. Correlation analysis of plasminogen activator inhibitor-1 gene polymorphism, antigen content and nephropathy in type 2 diabetes. Chin J Gerontol [Internet]. 2007;27:1485– 1487 (article in Chinese). Available from.

  47. Zheng T, Liu L, Zhou W. Correlation of plasminogen activator inhibitor-1 gene polymorphism with type 2 diabetic nephropathy in Chinese. J Shanghai Jiaotong Univ (Med Sci) [Internet]. 2007;27:774–776 (article in Chinese). Available from.

  48. Nagi DK, McCormack LJ, Mohamed-Ali V, Yudkin JS, Knowler WC, Grant PJ. Diabetic retinopathy, promoter (4G/5G) polymorphism of PAI-1 gene, and PAI-1 activity in Pima Indians with type 2 diabetes. Diabetes Care. 1997;20:1304–9.

    Article  CAS  Google Scholar 

  49. Broch M, Gutierrez C, Aguilar C, Simon I, Richart C, Vendrell J. Genetic variation in promoter (4G/5G) of plasminogen activator inhibitor 1 gene in type 2 diabetes. Absence of relationship with microangiopathy. Diabetes Care. 1998;21:463.

    Article  CAS  Google Scholar 

  50. Santos KG, Tschiedel B, Schneider J, Souto K, Roisenberg I. Diabetic retinopathy in Euro-Brazilian type 2 diabetic patients: relationship with polymorphisms in the aldose reductase, the plasminogen activator inhibitor-1 and the methylenetetrahydrofolate reductase genes. Diabetes Res Clin Pract. 2003;61:133–6.

    Article  CAS  Google Scholar 

  51. Globočnik-Petrovič M, Hawlina M, Peterlin B, Petrovič D. Insertion/deletion plasminogen activator inhibitor 1 and Insertion/deletion angiotensin-converting enzyme gene polymorphisms in diabetic retinopathy in type 2 diabetes. Ophthalmologica. 2003;217:219–24.

    Article  Google Scholar 

  52. Zietz B, Buechler C, Drobnik W, Herfarth H, Schölmerich J, Schäffler A. Allelic frequency of the PAI-1 4G/5G promoter polymorphism in patients with type 2 diabetes mellitus and lack of association with PAI-1 plasma levels. Endocr Res. 2004;30:443–53.

    Article  CAS  Google Scholar 

  53. Murata M, Maruyama T, Suzuki Y, Saruta T, Ikeda Y. Paraoxonase 1 192Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus. Diabet Med. 2004;21:837–44.

    Article  CAS  Google Scholar 

  54. Ezzidi I, Mtiraoui N, Chaieb M, Kacem M, Mahjoub T, Almawi WY. Diabetic retinopathy, PAI-1 4G/5G and – 844G/A polymorphisms, and changes in circulating PAI-1 levels in Tunisian type 2 diabetes patients. Diabetes Metab. 2009;35:214–9.

    Article  CAS  Google Scholar 

  55. Abdel, Attia FM, Ismail S, Azeem AAA, Nowier SR, Aziz MA, et al. Association between 4G/4G plasminogen activator inhibitor-1 polymorphism, PAI-1 activity, and diabetic retinopathy. Egypt J Haematol. Medknow Publications and Media Pvt. Ltd.; 2012;37:81.

  56. Lima LM, Carvalho M, das G, Fonseca Neto CP, Garcia JCF, Sousa MO. Associação de níveis plasmáticos de PAI-1 e polimorfismo 4G/5G em pacientes com doença arterial coronariana. Arq Bras Cardiol. Arquivos Brasileiros de Cardiologia; 2011;97:462–389.

  57. Saleem S, Azam A, Maqsood SI, Muslim I, Bashir S, Fazal N, et al. Role of ACE and PAI-1 Polymorphisms in the development and progression of diabetic retinopathy. Ljubimov A V., editor. PLoS One. 2015;10:e0144557.

  58. Siokas V, Dardiotis E, Sokolakis T, Kotoula M, Tachmitzi SV, Chatzoulis DZ, et al. Plasminogen activator inhibitor type-1 tag single-nucleotide polymorphisms in patients with diabetes mellitus type 2 and diabetic retinopathy. Curr Eye Res. 2017;42:1048–53.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I would like to express my sincere gratitude to Professor Seyed Mehdi Kalantar for his motivation, knowledge and support during the course of this research.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Seyed Alireza Dastgheib

  2. Department of Internal Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Farzaneh Najafi

  3. Department of Pediatrics, Yazd Branch, Islamic Azad University, Yazd, Iran

    Ahmad Shajari

  4. Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Reza Bahrami

  5. Department of Medical Laboratory Sciences, School of Paramedical Science, Shiraz University of Medical Sciences, Shiraz, Iran

    Fatemeh Asadian

  6. Department of Food Science and Technology, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Jalal Sadeghizadeh-Yazdi

  7. Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Elahe Akbarian & Seyed Alireza Emarati

  8. Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Hossein Neamatzadeh

  9. Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Hossein Neamatzadeh

Authors
  1. Seyed Alireza Dastgheib
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farzaneh Najafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmad Shajari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reza Bahrami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fatemeh Asadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jalal Sadeghizadeh-Yazdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elahe Akbarian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seyed Alireza Emarati
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hossein Neamatzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.M. and F.N. are responsible as the guarantor of integrity of the entire study, study design and concepts, definition of intellectual content, literature research. H.N. and A.S. are responsible for the clinical studies, experimental studies, data acquisition, and manuscript preparation. R.B, E.A. and S.A.E. are responsible for the data analysis, statistical analysis, and manuscript review. S.A.D and E.F. are responsible for the manuscript editing. F.A is revised the manuscript. All authors have read and agreed with the final version of this manuscript.

Corresponding author

Correspondence to Farzaneh Najafi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

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

Dastgheib, S.A., Najafi, F., Shajari, A. et al. Association of plasminogen activator inhibitor-1 4G5G Polymorphism with risk of diabetic nephropathy and retinopathy: a systematic review and meta-analysis. J Diabetes Metab Disord 19, 2005–2016 (2020). https://doi.org/10.1007/s40200-020-00675-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40200-020-00675-1

Keywords

Search

Navigation