Journal Article

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

Heissig, Beate, Adachi, Eisuke, Rios, Ricardo, Salama, Yousef, Osada, Taro, Takahashi, Satoshi, Takahashi, Kazuhisa, Tabe, Yoko, Nogueira, Tatiane, Hattori, Koichi, Yatsenko, Tetiana, Hattori, Nobutaka, Naito, Toshio

2024

Overview

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

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adult / Aged / Angiostatin / Bats / Body mass index / Cardiovascular disease / Comorbidity / Coronaviruses / COVID-19 / COVID-19 - blood / COVID-19 - genetics / Cytokines / Diabetes / Endothelial cells / Female / Fibrin / Fibrinolysis / Gene polymorphism / Genotype / Genotype & phenotype / Heart / Humans / Hypertension / IL-1β / Inflammation / Interleukin-1beta - genetics / Leukocytes (mononuclear) / Leukocytes, Mononuclear - metabolism / Male / Middle Aged / NF-κB protein / PAI-1 4G/5G promoter polymorphism (rs1799889) / PAI-1 polymorphism +43G>A (rs6092) / Patients / Peripheral blood mononuclear cells / Plasmin / Plasminogen Activator Inhibitor 1 - genetics / plasminogen activator inhibitor-1 / Plasminogen activator inhibitors / Polymerase chain reaction / Polymorphism / Polymorphism, Single Nucleotide / Promoter Regions, Genetic - genetics / Risk factors / SARS-CoV-2 - physiology / Severity of Illness Index / Thrombosis