Study highlights role of genetic factors in thrombosis and inflammation in COVID-19

Despite global vaccination efforts, COVID-19 continues to pose significant risks and lead to serious complications and deaths. These risks are caused by impaired coagulation, impaired fibrinolysis, the process by which blood clots dissolve, and increased inflammatory reactions. The fibrinolytic system, crucial for maintaining balance within the coagulation cascade, relies on plasmin-mediated fibrin degradation. Plasminogen activators convert plasminogen into plasmin, an enzyme that dissolves blood clots. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) in COVID-19 patients disrupt this balance, leading to a hypofibrinolytic state with reduced plasmin formation, impaired clot lysis, and increased risk of thrombosis.

The situation is further complicated by polymorphisms in the PAI-1 gene, particularly the 4G/5G polymorphism in its promoter region, which is associated with various cardiovascular diseases. A recent study from Japan, published in Frontiers in immunology on August 30, 2024 examines how the 4G/5G polymorphism influences thrombotic and inflammatory responses in Japanese patients with COVID-19 and sheds light on the genetic factors that contribute to different COVID-19 outcomes. This research was carried out by specially appointed Associate Professor Beate Heissig and Associate Professor Koichi Hattori from the Graduate School of Medicine, Juntendo University, in collaboration with Dr. Tetiana Yatsenko from Juntendo University and the Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine in Kyiv.

Researchers conducted a case-control study to examine the impact of the 4G/5G polymorphism on the severity of COVID-19. Blood samples were taken from the patients, DNA was extracted and genotyped to identify the polymorphism. Patients were categorized based on disease severity using LEOSS criteria, which included hospitalization, oxygen supplementation, and intensive care unit admission. The study examined markers of endothelial dysfunction, including PAI-1 transcript and protein levels, as well as other markers of thrombosis and inflammation. In addition, researchers analyzed the expression of NFκB and KLF2 and the effects of IL-1β on endothelial cells to understand the association between PAI-1 polymorphisms and COVID-19 severity.

The study shows that the 4G and 5G alleles of the PAI-1 promoter polymorphism have different effects on fibrinolysis, thrombosis risk and inflammatory responses.

The 4G allele is associated with inhibition of fibrinolysis and risk of thrombosis, whereas the 5G allele is associated with increased fibrinolytic activity and overactivation of inflammation and immune response-related growth factors in the body.”

Beate Heissig, associate professor, Juntendo University

In particular, the 4G allele is associated with increased levels of PAI-1, which impairs the breakdown of blood clots and increases the risk of thrombosis. This allele correlates with lower IL-1β levels and higher NFκB activity in PBMCs and accelerates clot formation by reducing clot breakdown. Conversely, the 5G allele is characterized by lower PAI-1 levels, promoting increased fibrinolysis and more active cytokine responses. It is associated with higher cytokine levels, possible inflammation-related endothelial dysfunction, and more pronounced clot breakdown.

Comorbidities such as obesity, diabetes, and hypertension may influence PAI-1 expression and severity of COVID-19 by altering fibrinolytic activity and increasing the risk of thrombosis. However, the study did not find a direct correlation between these comorbidities or clinical biomarkers and the genotypes for the +43 G>A or 4G/5G PAI-1 polymorphisms.

The results of this study have significant implications for the management and management of COVID-19, particularly in identifying individuals at higher risk of severe disease. Understanding the role of 4G/5G polymorphism in COVID-19 severity could lead to personalized treatment strategies.

Dr. Heissig adds: “Determination of genotype could help estimate the risk of inflammation-related thrombosis and cytokine storms, which would enable targeted therapies to manage endothelial dysfunction and reduce the risk of thrombosis. A key component of these therapies is endothelial dysfunction, which is an important risk factor for many cardiovascular diseases, including myocardial infarction and stroke. For patients at high risk based on their genotype, doctors might consider antithrombotic or anti-inflammatory therapies to prevent serious complications.”

This study contributes to the growing body of research on genetic factors that influence disease progression, particularly in COVID-19. The findings are consistent with broader research highlighting the influence of genetic polymorphisms on disease susceptibility and progression. Understanding genetic variations such as the 4G/5G polymorphism expands our knowledge of disease mechanisms and opens opportunities for precision medicine approaches not only in the treatment of COVID-19, but also other diseases with similar genetic underpinnings.

In summary, the study highlights the importance of the 4G/5G polymorphism in the PAI-1 gene promoter as a factor influencing COVID-19 severity and endothelial dysfunction. Integrating genetic information into clinical practice can help identify and treat high-risk patients, ultimately improving outcomes and reducing the burden of COVID-19. Future research should investigate the potential of PAI-1 inhibitors and other therapeutic interventions to mitigate the impact of the 4G/5G polymorphism on COVID-19 outcomes.