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The influence of 4G/5G polymorphism in the plasminogen-activator-inhibitor-1 promoter on COVID-19 severity and

Tetiana Yatsenko1,2, Ricardo Rios3, Tatiane Nogueira3

  • 1Department of Research Support Utilizing Bioresource Bank, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Frontiers in Immunology
|September 16, 2024
PubMed

Insights

The 4G4G genotype of the 4G/5G plasminogen activator inhibitor-1 (PAI-1) polymorphism is linked to suppressed fibrinolysis in severe COVID-19. The 5G5G genotype is associated with inflammation-induced endothelial dysfunction and fibrinolytic overactivation.

Area of Science:

  • Genetics
  • Immunology
  • Cardiovascular Biology

Background:

  • Plasminogen activator inhibitor-1 (PAI-1) is implicated in thrombosis and endothelial dysfunction in severe COVID-19.
  • PAI-1 expression is influenced by the +43 G>A and 4G/5G promoter gene polymorphisms.

Purpose of the Study:

  • To investigate the impact of PAI-1 gene polymorphisms on COVID-19 severity and endothelial dysfunction.
  • To elucidate the mechanistic links between PAI-1 genotypes, fibrinolysis, and inflammation in COVID-19 patients.

Main Methods:

  • Analysis of clinical data, sera, and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients.
  • Genotyping for +43 G>A and 4G/5G PAI-1 promoter polymorphisms.
  • Measurement of fibrinolytic factors, interleukin-1β (IL-1β), and NFκB activation.

Main Results:

  • The 4G4G genotype of the 4G/5G polymorphism was associated with high circulating PAI-1, low IL-1β and plasmin levels, and suppressed fibrinolysis.
  • NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype.
  • The 5G5G genotype was linked to inflammation-induced endothelial dysfunction and fibrinolytic system overactivation.

Conclusions:

  • PAI-1 polymorphisms significantly influence fibrinolytic activity and inflammatory responses in severe COVID-19.
  • The 4G4G genotype correlates with impaired fibrinolysis, while the 5G5G genotype is associated with endothelial dysfunction and hyperfibrinolysis.
  • Understanding these genetic predispositions may aid in risk stratification and therapeutic strategies for COVID-19.
Abstract

Keywords:
COVID-19PAI-1 4G/5G promoter polymorphism (rs1799889)PAI-1 polymorphism +43G>A (rs6092)endothelial cellsinflammationplasmin; interleukin-1-βplasminogen activator inhibitor-1

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