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

Front Immunol. 2024 Aug 30:15:1445294. doi: 10.3389/fimmu.2024.1445294. eCollection 2024.

Abstract

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear.

Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied.

Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1β (IL-1β) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1β and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype.

Discussion: Mechanistically, IL-1β enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.

Keywords: COVID-19; PAI-1 4G/5G promoter polymorphism (rs1799889); PAI-1 polymorphism +43G>A (rs6092); endothelial cells; inflammation; plasmin; interleukin-1-β; plasminogen activator inhibitor-1.

MeSH terms

  • Adult
  • Aged
  • COVID-19* / blood
  • COVID-19* / genetics
  • Female
  • Genotype
  • Humans
  • Interleukin-1beta / genetics
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Plasminogen Activator Inhibitor 1* / genetics
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic* / genetics
  • SARS-CoV-2* / physiology
  • Severity of Illness Index

Substances

  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • Interleukin-1beta

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported partly by JSPS KAKENHI Grant Numbers 24K10435 (BH), 24K11549 (KH), JP22F21773(BH), JP22KF0337(BH), JP17K09941(KH), JP21K08404(KH), JP21K08692(TO), JP22K07206 (ST), a grant from The Japanese Society of Hematology Research Grant (KH), Nakatani Foundation (KH), Terumo Life Science Foundation (KH), a grant from The Japanese Society of Hematology Research Grant (KH), Okinaka Memorial Institute for Medical Research (KH), Grants from the Society of iodine science (KH), Radiation effects association (KH) and International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo (KH, BH), The Uehara Memorial Foundation (BH), Taiki Life Welfare Foundation (KH), Heiwa Nakajima foundation grant (BH), and a grant from Institute for Environmental & Gender-specific Medicine, Juntendo University (BH).